hrev_master veins and lymphatics 2015; volume 4:5246 [veins and lymphatics 2015; 4:5246] [page 53] laser-assisted strategy for reflux abolition in a modified chiva approach sergio gianesini, erica menegatti, michele zuolo, mirko tessari, paolo spath, simona ascanelli, savino occhionorelli, paolo zamboni vascular diseases center, university of ferrara, italy abstract the aim of this study was to assess feasibility and efficacy of an endovenous laser (el) assisted saphenous-sparing strategy in chronic venous disease (cvd). fourteen cvd patients (c2,3,4s ep as pr1,2,3) underwent a saphenofemoral junction (sfj) treatment by el just from below the superficial epigastric vein downward for a limited tract, together with a flush ligation of the incompetent tributaries of the great saphenous vein (gsv) along the leg. the following gsv parameters were assessed 15 cm below the sfj: reflux time, caliber, peak systolic velocity (psv), end diastolic velocity (edv), resistance index (ri). venous clinical severity score and the clinical, etiological, anatomical, and pathophysio logical (ceap) classification clinical classes were assessed. at 1 year follow up 3 cases were considered failures because of a gsv thrombosis, even if they presented a gsv recanalization with a laminar flow within at the 2 years follow-up. eleven procedures succeeded because neither minor nor major peri-procedural complications were reported, apart 2 cases of self-healing bruising. in these last 11 cases the procedure led to a gsv reflux suppression (from 3.1±0.4 s to a retrograde laminar draining flow), to a gsv caliber reduction (from 9.4±0.5 to 3.1±0.2 cm, p<0.001), to a psv reduction (from 50.2±4.6 to 18.4±3.5 cm/s, p<0.001), to a ri reduction (from 0.9±0.2 to 0.51±0.2, p<0.005) and to an oscillatory flow suppression (edv from �–8.9±1.6 to 6.2±2.3 cm/s, p<0.001). both ceap and venous clinical severity score improved from 3 to 1 (p<0.001) and from 7±2 to 2±1 (p<0.05), respectively. the gsv flow reappeared below the shrunk tract draining into the re-entry perforator. sapheno-femoral reflux suppression can be obtained by just a gsv segmental closure. an almost 80% of success rate of the present investigation paves the way for an even wider diffusion of endovenous techniques, moreover erasing the surgical requirements for those who would like to perform a saphenoussparing strategy. in this way new devices could be used inside equally innovative strategies. introduction in the last decade, endovenous techniques (et) have been offering us more powerful and precise devices for the great saphenous vein (gsv) ablation.1 however this technology advancement has not been followed by an equivalent strategy innovation. whatever brand new tool is used, whenever ablating the gsv, the strategy choice is the gsv abolition, as in the surgical stripping. the most recent reviews point out a possible better pain control and post-operative quality of life following the et, but at the same time provide overlapping outcomes in reflux suppression whenever making a comparison with the surgical gsv ablation.2 conversely, through the years, chiva saphenous sparing surgical techniques have demonstrated their efficacy as an alternative strategy option to deliver an improved outcome.3 it is possible to postulate that a not only technically but also strategically less aggressive approach could reduce the recurrence risk.4,5 in 2013 we reported the first two patients in which we successfully implied this new alternative approach to combine the laser-based mini-invasiveness together with the saphenous-sparing efficacy.6 in these patients the incompetent sapheno-femoral junction (sfj) was treated by an endovenous laser (el) aiming for the obliteration of only the proximal segment to induce the closure from below the superficial epigastric vein (sev) downward for a maximum of 10 cm of gsv. in this way the rest of the distal gsv segment remains patent/intact to allow the draining reversely toward a re-entry perforator located distally on the same gsv.6 aim of the present study is to answering those hemodynamics questions that were raised based on our preliminary experience. materials and methods this study included 14 chronic venous disease (cvd) cases (m/f: 1/1) (c2,3,4s ep as pr1,2,3). two patients were c2, 10 were c3, 2 c4. the mean pre-operative venous clinical severity score (vcss) was 7±2.7 all the patients presented incompetent tributaries of the gsv together with a sfj reflux at the femoral side of the terminal valve, both at the valsalva and calf muscle compression/relaxation maneuver.8 in all the cases the re-entry perforator was on the gsv. according to the saphenous-sparing terminology all the cases were type i+n3 shunts.9,10 all the patients underwent an echo-colordoppler assessment and pre-operative mapping on the same procedural day, eliciting the flow both by active dorsiflexion (wunstorf maneuver) and manual compression/relaxation maneuvers (figure 1). the following gsv parameters were assessed 15 cm below the sfj: reflux time, diameter, peak systolic velocity (psv), end diastolic velocity (lowest detectable velocity at the end of the muscular diastole) (edv) and resistance index (ri). psv represents the highest velocity assessed during the muscular systole. edv is the lowest velocity value at the end of the diastolic phase.11-15 ri is the ratio among the difference of psv and edv divided by the psv according to the formula (psvedv)/psv.11,13 the same parameters were assessed at 1week, 1-6-12-month follow-ups, together with a clinical, etiological, anatomical, and pathophysiological (ceap) classification and vcss. (table 1) data were calculated as mean±standard deviation. the results were compared by using student’s t-test or mann-whithney as appropriate. statistical significance was defined as p<0.05. operative procedure all the patients underwent a flush ligation of the incompetent gsv tributaries along the leg. the sfj was treated by an el segmental closure according to the following protocol: percutaneous gsv access at the distal third of the thigh with the patient in a reversetrendelenburg position, insertion of a 600 �m radial fiber (1470 nm, 6w). correspondence: sergio gianesini, university of ferrara, via aldo moro 8, 44100 cona (fe), italy. tel.: +39.0532.236524 fax: +39.0532.237144. e-mail: sergiogianesini@hotmail.com key words: saphenous-sparing strategy; endovenous laser; chronic venous disease. conflict of interest: the authors declare no potential conflict of interest. conference presentation: accepted for poster presentation at the 2014 american college of phlebology meeting, november 7-2014, phoenix, az, usa. received for publication: 22 april 2015. revision received: 17 june 2015. accepted for publication: 18 june 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s. gianesini et al., 2015 licensee pagepress, italy veins and lymphatics 2015; 4:5246 doi:10.4081/vl.2015.5246 no n c om me rci al us e o nly article [page 54] [veins and lymphatics 2015; 4:5246] a tumescent anesthesia (lidocaine 2% 5 cc + sodium bicarbonate 5 cc + saline solution 10 cc) was administered perivenously by a 25 g needle, under echo-color-doppler (ecd) guidance, just along the segmental gsv tract to be shrunk below the sev. the el was then activated, shrinking the gsv at 200 j/cm for the first cm and at 100 j/cm for the following tract. an above-knee 20 mmhg elastic stocking compression was prescribed to all the patients for three days and nights, then just during the daytime for the following three weeks. all the patients gave their informed consent. results mean follow-up was 1 year. three cases were considered the failures because of a thrombosis that developed distally to the shrunk segment of gsv. nevertheless in these three cases, at the 2 years follow up, at the ecd scanning the thrombosis disappeared resulting in a significantly reduced gsvs (from 9.8±0.3 mm to 2.8±0.2 mm), inhabited by a laminar flow draining retrogradely into the reentry perforator. at the 1 year follow up the remaining eleven procedures were considered successful with neither minor nor major peri-procedural complications except 2 cases of mild bruising that rapidly resolved spontaneously. in these last 11 cases the procedure led to a gsv reflux suppression, to a gsv caliber reduction (from 9.4±0.5 to 3.1±0.2 mm, p<0.001), to a psv reduction (from 50.2±4.6 to 18.4±3.5 cm/s, p<0.001), to a ri reduction (from 0.9±0.2 to 0.5±0.2, p<0.005) and to a oscillatory flow suppression (edv from �8.9±1.6 to 6.2±.3 cm/s, p<0.001)(inversion of the end diastolic value from negative to positive, thus from refluxing bidirectional to laminar monodirectional flow). both ceap and vcss improved from 3 to 1 (p<0.001) and from 7±2 to 2±1 (p<0.05), respectively (table 1). the shrunk gsv segment was 6.8±1.7 cm long and always distal to the sev. the gsv flow reappeared below the shrunk tract as a laminar reverse drainage directed toward the re-entry perforator focused on the same gsv. the total energy delivery recorded the following parameters: laser on-time 111±45 s, total joules delivered: 671±67 j. the average tumescence volume was 69.2±8.3 cc. at 1-year follow-up a single recurrence was reported in the flush ligated gsv tributaries, without clinical complaints and only ecd detectable. the remaining ten cases demonstrated a laminar drainage toward the same gsv tributary re-entry perforator. gsv reflux was abolished in all the eleven cases. discussion the constantly increasing demand for miniinvasiveness in saphenous refluxes treatment is surely pushing the phlebology world toward et.16,17 in the last decade, ablative surgery has assisted to its progressive replacement by the foam sclerotherapy, radiofrequency, and endovenous lasers.18 despite some analysis biases coming out from a not totally homogeneous study population, reliable reviews suggest et to be as effective as the surgery in the treatment of saphenous vein refluxes.2,19 moreover, et has been considered not only as efficacious as stripping in the reflux suppression, but also able to provide a faster and less painful post-operative course.20-22 following the randomized controlled trials and network meta-analysis pointing out the endovenous performances, up to now, in technically suitable cases, the international guidelines favor ablative et over open surgery with a grade 1 b evidence.23 the same literature confirms that technological advancement through the last decade has offered a better chance of improved treatment in terms of mini-invasiveness of the procedure and post-operative quality of life. but at the same time it states that the successful rate in reflux suppression hasn’t been changed significantly from the old surgical ablative procedure time.20-22 on the contrary, chiva saphenous-sparing varicose vein strategy have produced long-term efficacy data through the years, claiming both better long term outcomes and competitiveness with the surgical ablative option.24-41 on this basis, we thought to explore the feasibility and outcome of a brand new strategy combining the laser mini-invasiveness together with the table 1. hemodynamic parameters assessment: pre-operative (pre-op) and 1-year follow-up post-operative (post-op) great saphenous vein hemodynamic parameters assessment at 15 cm from the sapheno-femoral junction (sfj) (p<0.05). hemodynamics parameters pre-op post-op (15 cm below the sfj) rt (s) 3.1±0.4 retrograde laminar draining flow diam (mm) 9.4±0.5 3.1±0.2 psv (cm/s) 50.2±4.6 18.4±3.5 edv (cm/s) –8.9±1.6 6.2±2.3 ri 0.9±0.2 0.51±0.2 ceap 3 1 vcss 7±2 2±1 rt, reflux time; psv, peak systolic velocity; edv, end diastolic velocity; ri, resistance index; ceap, clinical, etiological, anatomical, and pathophysiological classification; vcss, venous clinical severity score. figure 1. preoperative assessment: all the patients underwent to a pre-operative echo-color-doppler assessment and mapping on the same procedural day. gsv, great saphenous vein; sfj, saphenofemoral junction; eps, external superficial epigastric vein.no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:5246] [page 55] saphenous-sparing long-term efficacy. as we published previously, two cases of sfj refluxes were treated successfully with a saphenous-sparing principle delivering a segmental gsv closure below the sev downward for a 10 cm and 7 cm long tract, respectively, to maintain physiological retrograde drainage through a well preserved gsv segment.6 the present investigation follows these two cases to answer some of the many hemodynamic questions which were raised through the previous publication. first of all, the sfj incompetence treatment was achievable by just an only segmental closure which created a not refluxing but rather reversed flow, draining the preserved gsv trunk toward a previously selected re-entry perforator (figure 2a and b). the presence of a re-entry perforator on the gsv (around 40% of reflux patterns)10 is mandatory for the procedure. alternatively, a significant stasis occurs leading to the thrombotic risk. the oscillatory flow suppression is testified by the edv post-operative inversion, thus characterizing a laminar flow that according to the recent literature leads to an anti-inflammatory endothelial phenotype.42 the post-operative gsv laminar flow significantly (figure 3a) differs from the pre-operative reflux (figure 3b). pre-operative a multidirectional flow can be detected, together with a high psv and an inverted edv (figure 3a). after the sfj ev closure the pressure gradient is suppressed, in favor of drainage of the gsv blood into the re-entry perforator, so leading to the assessment of a monodirectional and slow flow in which the edv presents the same psv direction (figure 3b). the amount of shrunk centimeters does not look like to be the parameter that really matters for the maintenance of a draining gsv, rather it is the flow coming from the gsv tributaries distal to the shrunk tract. the failure that occurred in 3 out of 14 cases (21.4%) was associated to a gsv thrombosis that developed distally to the shrunk tract. this fact led us to reason about the main factors to take into account whenever planning an el assistedhemodynamic correction of the saphenous system. for example, the giacomini vein was not detected in these 3 unsuccessful cases in contrast to the other 11 successful cases. together with the re-entry perforators hemodynamics, this vein features could represent a fundamental data to be verified before performing this new hemodynamic procedure. indeed, the role of giacomini vein in lower limbs for venous drainage have drawn increasing attention lately (figure 4a and b).42-48 moreover, the gsv recanalization at 2 years figure 2. post-operative flow: preserved great saphenous vein (gsv) (a) trunk presenting a laminar flow from below the shrunk tract downward toward its re-entry perforator (b). figure 4. giacomini vein: pre(a) and post-operative (b) flow patterns. (a) pre-operatively a closed circuit (red line) is formed starting by the sapheno-femoral junction (sfj) incompetent leaking point. a reflux is present into the great saphenous vein (gsv) until the confluence with a perforating vein (pv) which drains into the deep system (ds). at the following muscular systo-diastolic push the blood will go back into the incompetent sfj. giacomini vein (gv) presents a competent flow. (b) after laser assisted segmental sfj ablation the closed circuit is interrupted, leading to a laminar monodirectional flow into the spared gsv and draining the same gsv into the pv (green line). scxv, superficial circumflex vein; sev, superficial epigastric vein; spv, superficial pudendal vein. figure 3. pre and post-operative flow changes: (a) pre-operatively, the great saphenous vein (gsv) reflux is characterized by a high peak systolic velocity (psv), an inverted end diastolic velocity (edv) and an evident turbulence. (b) post-operatively, the edv presents the same psv direction and the flow decreases its mean velocity, being drained into the re-entry perforator. rt, reflux time. no n c om me rci al us e o nly article [page 56] [veins and lymphatics 2015; 4:5246] in these three cases of post-operative thrombosis, together with the resolution of the preoperative reflux and the vein caliber reduction, offer a preliminary data for future hemodynamics investigations. whenever compared to a traditional surgical saphenous-sparing option, the herein presented technique is surely less cost-effective for the need of the laser device and fiber acquisition. nevertheless a deeper cost-analysis is recommended to analyzing the indirect income derived by the greater numbers of procedures performed daily because of the faster procedural time coming from the endovenous rather than surgical act. certainly, this new hemodynamic approach mandates further investigations and the herein reported successful outcome (79.6%) will contribute on better understanding for this hemodynamic approach as well as new implication of the mini-invasive technology into the cvd field.49,50 another topic of further research is the percentage of candidates to the strategy. considering that in cvd almost half of the sapheno-femoral junctions are competent and that a re-entry perforator must be found on the gsv in order to apply this strategy, future investigations should be addressed to determine the effective role of the gsv tributaries along the leg in maintaining a draining flow. the availability of a saphenous sparing option also for not surgical operators could lead to an increasing interest toward advanced hemodynamics, so rising also the interest toward advanced scanning in phlebology. this could lead both to an age of not only new devices but also of innovative strategies and to a collective better understanding of the intricate venous drainage pathophysiology. references 1. guex jj. endovenous chemical (and physical) treatments for varices: what’s new? phlebology 2014;29:45-8. 2. nesbitt c, eifell rkg, coyne p, et al. endovenous ablation (radiofrequency and laser) and foam sclerotherapy versus conventional surgery for great saphenous vein varices (review). cochrane database syst rev 2011;10: cd005624. 3. bellmunt-montoya s, escribano jm, dilme j, martinez-zapata mj. chiva method for the treatment of chronic venous insufficiency. cochrane database syst rev 2013;7:cd009648. 4. disselhoff bc, der kinderen dj, kelder jc, moll f. randomized clinical trial comparing endovenous laser ablation of the great saphenous vein with and without ligation of the saphenofemoral junction: 2-year results. eur j vasc endovasc surg 2008;36:713-8. 5. van rij am, jones gt, hill gb, jiang p. neovascualrization and recurrent varicose veins: more histologic and ultrasound evidence. j vasc surg 2004;40:296-302. 6. gianesini s, menegatti e, zuolo m, et al. short endovenous laser ablation of the great saphenous vein in a modified chiva strategy. veins and lymphatics 2013;2:e21. 7. rutherford rb, padberg ft, comoerota aj, et al. venous severity scoring: an adjunct to venous outcome assessment. j vasc surg 2000;31:1307-12. 8. cappelli m, molino lova r, ermini s, zamboni p. hemodynamics of the saphenofemoral junction. patterns of reflux and their clinical implications. int ang 2004;23:25-8. 9. franceschi c. theorie et pratique de la cure conservatrice et hemodynamique de l’insuffisance veinuse en ambulatoire. paris: editions de l’armancon; 1988. 10. franceschi c. venous hemodynamics. new york: nova science publisher; 2009. 11. baumgartner rw, nirkko ac, müri rm, gönner f. transoccipital power-based colorcoded duplex sonography of cerebral sinuses and veins. stroke 1997;28:1319-23. 12. stolz de, kaps m, kern a, babacan ss. reference data from 130 volunteers transcranial color-coded duplex sonography of intracranial veins and sinuses. stroke 1999;30:1070-5. 13. zamboni p, menegatti e, bartolomei i, et al. intracranial venous haemodynamics in multiple sclerosis. curr neurovasc res 2007;4:252-8. 14. zamboni p, menegatti e, pomidori l, et al. does thoracic pump influence the cerebral venous return? j appl physiol (1985) 2012;112:904-10. 15. tisato v, zamboni p, menegatti e, et al. endothelial pdgf-bb produced ex vivo correlates with relevant hemodynamic parameters in patients affected by chronic venous disease. cytokine 2013;63:92-6. 16. almeida j, kabnick l, wakefield t, et al. management trends for chronic venous insufficiency across the united states: a report from the american venous registry. j vasc surg venous lymph disord 2013; 1:100. 17. sadek m, kabnick ls, berland t, et al. update on endovenous laser ablation. perspect vasc endovasc ther 2011;23:233-7. 18. rasmussen lh, lawaetz m, bjoern l, et al. randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam scleortherapy and surgical stripping for great saphenous varicose veins. br j surg 2011;98:1079-87. 19. van den bos r, arends l, kockaert m, et al. endovenous therapies of lower extremity varicosities: a meta-analysis. j vasc surg 2009;49:230-9. 20. rasmussen lh, lawaetz m, bjoern l, et al. randomized clinical trial comapring endovenous laser ablation, radiofrequency, foam sclerotherapy and surgical stripping for great saphenous varicose veins. br j surg 2011;98:1079-87. 21. carrol c, hummel s, leaviss j, et al. clinical effectiveness and cost-effectiveness of minimally invasive techniques to manage varicose veins: a systematic review and economic evaluation. health technol assess 2013;17:1-141. 22. carrol c, hummel s, leaviss j, et al. systematic review, network meta-analysis and exploratory cost-effectiveness model of randomized trials of minimally invasive techniques versus surgery for varicose veins. br j surg 2014;101:1040-52. 23. gloviczki p, gloviczki ml. guidelines for the management of varicose veins. phlebology 2012;27:2-9. 24. carandina s, mari c, de palma m, et al. varicose vein stripping vs haemodynamic correction (chiva): a long term randomised trial. eur j vasc endovasc surg 2008;35:230-7. 25. pares jo, juan j, tellez r, et al. varicose vein surgery: stripping versus the chiva method: a randomized controlled trial. ann surg 2010;251:624-31. 26. maeso j, juan jj, escribano jm, et al. comparison of clinical outcome of stripping and chiva for treatment of varicose veins in the lower extremities. ann vasc surg 2001;15:661-5. 27. iborra-ortega e, barajau-urrea e, vila-coll r, et al. comparative study of two surgical techniques in the treatment of varicose veins of the lower extremitities: results after five years of follow up. angiologia 2006;58:459-68. 28. mowatt-larssen e, shortell c. treatment of primary varicose veins has changed with the introduction of new techniques. semin vasc surg 2012;25:18-24. 29. mowatt-larssen e, shortell c. chiva. semin vasc surg 2010;23:118-22. 30. gianesinis, occhionorelli s, menegatti e, et al. chiva strategy in chronic venous disease treatment: instructions for users. phlebology 2014 [epub ahead of print]. 31. zamboni p, cisno c, marchetti f, et al. reflux elimination without any ablation or disconnection of the saphenous vein. a haemodynamic model for surgery. eur j vasc endovasc surg 2001;21:361-9. 32. escribano jm, juan j, bofill r, et al. durability of reflux-elimination by a minimal invasive chiva procedure on patients with varicose veins. a 3year prospective case study. eur j vasc endovasc surg 2003;25:159-63. no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:5246] [page 57] 33. zamboni p, escribano jm. regarding reflux elimination without any ablation or disconnection of the saphenous vein. a haemodynamic model for surgery and durability of reflux-elimination by a minimal invasive chiva procedure on patients with varicose veins. a 3year prospective case study. eur j vasc endovasc surg 2004; 28:567-8. 34. zamboni p, gianesini s, menegatti e, et al. great saphenous varicose vein surgery without saphenofemoral junction disconnection. br j surg 2010;97:820-5. 35. zamboni p, cisno c, marchetti f, et al. minimally invasive surgical management of primary venous ulcers vs. compression treatment: a randomized clinical trial. eur j vasc endovasc surg 2003;25:313-8. 36. mendoza e. chiva 1988-2008. review of studies on the chiva method and its development in different countries. gefasschirurgie 2008;13:249-56. 37. milone m, salvatore g, maietta p, et al. recurrent varicose veins of the lower limbs after surgery. role of surgical technique (stripping vs chiva) and surgeon’s experience. g chir 2001;32:460-3. 38. mendoza e, berger v, zollmann c, et al. diameter-reduction of the great saphenous vein and common femoral vein after chiva. phlebologie 2011;40:73-8. 39. zamboni p, marcellino mg, cappelli m, et al. saphenous vein sparing surgery: principles, techniques and results. j cardiovasc surg 1998;39:151-62. 40. pittaluga p, chastanet s, rea b, barbe r. midterm results of the surgical treatment of varices by phlebectomy with conservation of a refluxing saphenous vein. j vasc surg 2009;50:107-18. 41. pittaluga p, chastanet s, locret t, barbe r. the effect of isolated phlebectomy on reflux and diameter of the great saphenous vein: a prospective study. eur j vasc endovasc surg 2010;40:122-8. 42. tisato v, zauli g, gianesini s, et al. modulation of circulating cytokinechemokine profile in patients affected by chronic venous insufficiency undergoing surgical hemodynaic correction. j immunol res 2014;2014:473765. 43. atasoy mm, gumus b, caymaz i, oguzkurt l. targeted endovenous treatment of giacomini vein insufficiency-associated varicose disease: considering the reflux patterns. diagn interv radiol 2014 [epub ahead of print]. 44. prakash, kumari j, nishanth reddy n, kalyani rao p, et al. a review of literature along with a cadaveric study of the prevalence of the giacomini vein (the thigh extension of the small saphenous vein) in indian population. rom j morphol embryol 2008;49:537-9. 45. barberini f, cavallini a, caggiati a. the thigh extension of the small saphenous vein: a hypothesis about its significance, based on morphological, embryological and anatomocomparative reports. ital j anat embryol 2006;111:187-98. 46. georgiev m, kenneth myers a, belcaro g. the thigh extension of the lesser saphenous vein: from giacomini’s observations to ultrasound scan imaging. j vasc surg 2003;37:558-63. 47. bush rg, hammond k. treatment of incompetent vein of giacomini (thigh extension branch). ann vasc surg 2007; 21:245-8. 48. delis kt, knaggs al, khodabakhsh p. prevalence, anatomic patterns, valvular competence, and clinical significance of the giacomini vein. j vasc surg 2004; 40:1174-83. 49. passariello f. office based chiva (ob chiva). acta phlebol 2011;12:26-7. 50. ferracani e. internal laser valvuloplasty and venous remodelling using 1470 laser. initial experience. flebologia 2013;3:39-40. no n c om me rci al us e o nly hrev_master veins and lymphatics 2016; volume 5:6249 [veins and lymphatics 2016; 5:6249] [page 43] 2016: the year of phlebological olympic games paolo zamboni department of morphology, surgery, and experimental medicine; vascular diseases center and section of translational medicine and surgery, university of ferrara, italy summer 2016, the summer of the olympic games, reserves challenging news also in the field of venous and lymphatic diseases. the editorial would make the point, while updating friends and colleagues. the market increasingly pushes the endovascular handling of varicose veins. stripping is killed and even chiva shows a tendency to move forward intravascularly.1-3 thermal laser or radio frequency techniques have now been able to supplant the traditional surgical techniques and turn the preference of surgeons toward them.1,2 they are ablative techniques that do not involve the surgical incision and overcome any previous problem stripping-related by the means of standardized tumescence anesthesia. in addition, the office independent feasibility of tumescent thermal ablation makes both approaches preferable to stripping.1,2 however, even the tumescence is likely to be overcome by the surgical glue, leading to a scenario unthinkable only few years ago. summer 2016 introduces to the phlebological community the wawes study, very exciting for everybody who are fanatic of the 1000 ways to cook the saphenous vein. recent introduction of the endovascular glue will lead toward office saphenous vein ablation, non-thermal, nontumescent, non postoperative compression. certainly a big achievement in the field, something like the new olympic record in varicose veins treatment. the waves trial is a single-centre study evaluating the venaseal system in the treatment of one or more incompetent n2 veins (greater saphenous vein, small saphenous vein or anterior accessory saphenous vein) with no postoperative compression stockings. the trial enrolled 50 patients and data were presented at the evf meeting in london last july.4 medtronic and the pi gibson have not had the patience to wait for a more prolonged and significant follow-up for a chronic disease, and in london we were informed that at one month they recorded 100 % of successful procedures, equaling the world record set by all the competitors procedures. one of the funniest aspects introduced by the use of intravenous techniques are represented by the recommendation for their proper use. for example, it should not be used when the saphenous vein has a diameter between that of a python and that of an anaconda, is twisted like a sleeping rattlesnake, and it is even complicated by an ulcer. from this point of view waves trial differs from the veclose trial, which compared cyanoacrylate embolization and radiofrequency ablation for incompetent great saphenous veins. in the waves trial the human limits were abundantly passed, veins up to 20mm were allowed, compared to 12mm for veclose, and also multiple segments were treated in the same session, and no compression stockings were used postoperatively. in the waves trial even the challenging ceap clinical class 5 was allowed to be treated.4 the mirage of treating varicose vein intravascularly without any anesthesia has prompted numerous phlebologists to propose other personal techniques. then here frullini proposes holmium laser technology that delivers a so lower energy that do not require tumescent anesthesia.5,6 given that this technology respects endothelium and does not obliterate the saphenous vein, this author proposes to finally obtain the obliteration using the tessari foam. just the latter together with zini, quite the contrary, proposes to use at the beginning of the procedure the endovascularvapplication of foam sclerotherapy followed by the boiled interaction of holmium laser.7 anyway, both procedures are cheaper respect to current cyanoacrylate market cost, and lead to minimally thermal non-tumescent, successfully office saphenous vein closure. what no one openly confesses in these studies is that varicose veins, which are the main problem, continue to be complementary treated with two old office based techniques, both always non-thermal and non tumescent: the muller technique and/or foam sclerotherapy. all the technological effort is focused on how to take out the saphenous vein without anyone feel pain and pretend to remain too long in the vicinity of our operating room, as well. however, the main point still remains the fact that at least 50 % of varicose patients exhibit a competent saphenous terminal valve (figure 1).8 in these cases, an accurate preoperative ultrasound study allows to efficiently correspondence: paolo zamboni, vascular diseases center, university of ferrara, ao s. anna, via aldo moro 8, 44124 loc. cona, ferrara, italy. e-mail: paolozamboni@icloud.com received for publication: 28 augusst 2016. revision received: 13 september 2016. accepted for publication: 13 september 2016. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright p. zamboni, 2016 licensee pagepress, italy veins and lymphatics 2016; 5:6249 doi:10.4081/vl.2016.6249 figure 1. ultrasound preoperative assessment of the saphenous terminal valve, as described in reference 8. doppler sample volume herein represented by a circle, have to be placed on the femoral side of the junction. evaluation requires both valsalva and squeezing reflux elicitation manoeuver. sisty-one percent of pattients exhibited no reflux at both or at one of the two manoeuvers and were considered with competent terminal valve. the same patients when examined with squeezing at the saphenous side of the valve showed reflux in 100% of cases. reflux at both manoeuvers at both sides of the terminal valve were detected in the remaining 39% of patients with valve incompetence. no n c om me rci al us e o nly editorial [page 44] [veins and lymphatics 2016; 5:6249] select patients for office-based saphenous vein sparing techniques, like chiva2 or muller/asval. correct preoperative ultrasound selection permits to sparing surgery to be absolutely competitive at 3 years in terms of recurrences.8 there are also ethical considerations in the overtreatment of the saphenous vein, a vessel that can potentially be saved not only for limb drainage but also for its potential use as a vascular graft. it has been recently shown that surgical correction of the bidirectional flow that characterizes the phenomenon of reflux, alone is able either to efficiently reduce the cross sectional area of the vein or especially to correct the inflammatory phenotype that distinguishes chronic venous disorders.9 in addition to this there are economic considerations. the use of techniques such as muller/asval or chiva 2 in about 50% of patients is certainly less expensive than endovascular treatments, with great benefit for patients and also for the economic management of the surgical activity both in private practice and in countries with nhs. this means that saphenous ablation is unfair and expensive in approximately half the cases. is this a good science? references 1. fernando rsw, muthu c. adoption of endovenous laser treatment as the primary treatment modality for varicose veins: the auckland city hospital experience. n zeal med j 2014;127:1399. 2. lin jc, nerenz dr, migliore p, et al. cost analysis of endovenous catheter ablation versus surgical stripping for treatment of superficial venous insufficiency and varicose vein disease. j vasc surg venous lymphat disord 2014;2:98-103. 3. gianesini s, menegatti e, zuolo m, et al. feasibility of endovenous laser in type i chiva procedure: a new minimally invasive and saphenous paring therapeutic option. veins and lymphatycs 2015;4:5246. 4. vascular news. waves trial shows 100% vein closure at one month with short return to work and normal activities. available from: http://vascularnews.com /waves-trialshows-100-vein-closure-at-one-monthwith-short-return-to-work-and-normalactivities/ accessed: august 16, 2016. 5. frullini a, fortuna d. laser assisted foam sclerotherapy (lafos): a new approach to the treatment of incompetent saphenous veins. phlebologie 2013;66:51-4. 6. gianesini s, gafà r, occhionorelli s, et al. histologic and sonographic features of holmium laser in chronic venous disease treatment. int ang 2016 [epub ahead of print]. 7. zini f, tessari l, torre r. sclerofoam assisted laser therapy for saphenous refluxes: an innovative tumescence-free technique veins and lymphatics 2015;4:5141. 8. zamboni p, gianesini s, menegatti e, et al. great saphenous varicose vein surgery without saphenofemoral junction disconnection. br j surg 2010;97:820-5. 9. zamboni p, spath p, tisato v, et al. oscillatory flow suppression improves inflammation in chronic venous disease. j surg res 2016;205:238-45. no n c om me rci al us e o nly hrev_master veins and lymphatics 2015; volume 4:5182 [page 48] [veins and lymphatics 2015; 4:5182] elastic stockings effect on leg volume variability in healthy workers under prolonged gravitational gradient exposure mirko tessari, sergio gianesini, erica menegatti, michele zuolo, anna maria malagoni, maria elena vannini, paolo zamboni vascular diseases center, university of ferrara, italy abstract the aim of this study was to determine the elastic stockings effect on healthy workers (hw) who are exposed to a prolonged hydrostatic pressure overload for professional reasons. the cohort was composed by 20 hw who voluntarily underwent a water plethysmography test before and after eight hour of standing up in an operating room, wearing elastic stockings. after 8 h of gravity exposure, we demonstrated the absence of leg volume increase in case of elastic stockings use. in the morning measurement we found that the lower limb volume was 1967.5 ml±224, while in the evening it was 1962.5 ml±227 (p<0.0828). the decreased volume is significantly correlated with the time that was spent under gravity forces for working purpose wearing elastic stockings (r2=0.99, p<0.0001). our experiment demonstrates that elastic stockings may effectively counteract the increased leg volume over time in workers who are exposed to prolonged gravitational gradient. further longitudinal studies are needed to determine if the above effect could correct one of the major risk factors for the development of chronic venous insufficiency. introduction chronic venous insufficiency (cvi) of the lower limbs is very common in the developed countries and leads to a considerable morbidity. established risk factors for cvi include older age, female gender, geographic factors, pregnancy, family history of venous disease, obesity and work in orthostatic position. in particular, an association between cvi and prolonged standing has been reported.1-6 the common experience of legs that swell at the end of a working day is the result of a physiologic phenomenon. it is caused by extravasation of fluid from the venules because of a steadily increased venous pressure in the dependent regions of the body.7 some studies showed that healthy workers who stood for prolonged periods during their working day had significantly higher levels of reactive oxygen species after work than controls.8 elastic stockings compression therapy was first introduced in the fifties: it remains the most widely accepted treatment of cvi.9 particularly, by means of air plethysmography a significant improvement of venous functional parameters with elastic stockings has been demonstrated.10 looking at the literature, good evidences for the use of compression can be found for some clinical indications, even if little is known about the specific dosimetry, timing and type of compression to be applied.11 although it is generally accepted that therapeutic outcomes are directly related to the quality of compression therapy, delivering precise and sustained compression therapy is an ongoing challenge for healthcare professionals.12,13 a meta-analysis suggests that leg compression at a pressure of 10-15 mmhg is an effective treatment for venous disorders.14 another study reported that legs edema is a physiological phenomenon occurring after long periods of sitting and standing. knee-length compression stockings exerting a pressure range of 1121 mmhg can reduce evening edema.15,16 the aim of the present study is to objectively assess by means of water plethysmography (wp) the physiological lower limbs volume changes during an ordinary surgery day in healthy physician wearing elastic stockings. materials and methods study population the study took place in a period of three months. the evaluated population was constituted by 20 healthy workers (hw), who were previously screened for the absence of either cvi or evident subcutaneous edema by validated clinical and ultrasonographic criteria.17,18 particularly, duplex protocol to assess absence of reflux and/or obstruction in the great and small saphenous veins, as well as in the main deep veins, was used to exclude cvi.19-21 even if according to the most recent guidelines a lymphoscintigraphy is requested to exclude lymphedema, not considering ethical to perform an invasive test on healthy cases we used high resolution b-mode imaging of soft tissue to detect eventual subcutaneous edema, as an exclusion factor.22-24 the group was composed by practitioner surgeons, 10 females and 10 males, who voluntarily underwent the tests, before and after 8 standing still working hours in the operating room, all performing the same long surgery procedure, wearing stockings exerting 23-28 mmhg of pressure at the ankle. four consecutive measurements of the same patient leg were performed by two different observers, showing a very low intra-individual variability (1.3%). overall, 320 wp measurements were carried out for each observer. the mean age was 28.6±3.2 years old. leg volume assessment the wp permits the foot, ankle and calf volume measurement. thirteen liters of water are poured into the wp with reference points at every 50 ml. the water temperature ranged between 28-30°c and was monitored by an electrical thermometer. this temperature was higher than the 27-28°c proposed by thulesius, in order to better exclude cutaneous venomotor responses.25 the wp is tall 40 cm and the container is all filled up till the marked level. subsequently, the 3000 ml transparent container is placed under the draining spout in order to contain the water that will leak once the lower limb will be inserted into the instrument. the subject slowly inserts the foot into the water inside the wp until putting the foot sole on the base of the instrument. the subject has to maintain a correspondence: mirko tessari, university of ferrara, via aldo moro 8, 44124 cona (fe), italy. e-mail: mirko.tessari@unife.it key words: edema; posture; gravity; water plethysmography; elastic stockings; hydrostatic pressure. contributions: mmt, design, data acquisition, analysis and interpretation, drafting and final approval; sg, drafting, data acquisition, analysis and interpretation, revision and final approval; em, mz, mev, data acquisition and final approval; amm, data acquisition, analysis and interpretation and final approval; pz, design, analysis and interpretation, revision and final approval. conflict of interest: vascular diseases center of the university of ferrara, chaired by paolo zamboni md, received a research grant by new medical service, italy. received for publication: 30 march 2015. revision received: 20 may 2015. accepted for publication: 28 may 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright m. tessari et al., 2015 licensee pagepress, italy veins and lymphatics 2015; 4:5182 doi:10.4081/vl.2015.5182 no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:5182] [page 49] sitting posture of 90° between the thigh and the leg so that that the latter is perpendicular to the base of the wp. once the leg has been inserted inside the device, the exceeding water discharge is expected at the blowhole spout where the 3000 ml transparent container was previously placed. the collected water volume will give the measurement of the same inserted leg volume and will be expressed in milliliters. these values were reported in a database. the assessment were consecutively repeated for three times for the left limb and three times for the right limb for each subject for reproducibility assessment. during the examination the patient is asked not to move in order to allow water level stabilization. the measurements duration is approximately 15 min for each subject. experiment in workers who were exposed to a prolonged gravitational gradient with elastic stockings the 20 hw cohort was previously screened for comorbidities. then they underwent leg volume assessment at 7.00 a.m., immediately after their arrival at the hospital. subsequently, they had been working for 8 hours in the operating room, in a condition of prolonged standing posture with elastic stockings. right after, they underwent wp once again at 3.00 p.m. all the measurements were performed right outside the operating room with the same temperature (23°c). elastic stockings material in this study a below-knee tubular graduated elastic stocking in both legs was used. these elastic stockings are composed by 75% polyamide and 25% elastam. the compression class was 23-28 mmhg of pressure at the ankle. statistical analysis the data were analyzed with the program instat 03 for macintosh and are expressed as mean±standard deviation, median and interquartile range (iqr). for the statistical comparison of the different measurements the paired t-student test was used. the linear regression analysis between time and leg volume was performed with the pearson test. p values<0.05 have been considered significant. results the right lower limb baseline volume was 1970 ml±221.5 (median 1925; iqr 275.0) and resulted to be totally comparable with the left leg volume 1965 ml±233.5 (median 1950; iqr 362.5). the volume ranged from 1650 ml to the maximum volume of 2400 ml. in the measurement after 8 h of standing wearing elastic stockings, the two limbs volumes were respectively 1962.5 ml±220.6 (median 1925; iqr 312.5) for the right leg and 1957.5 ml±239.7 (median 1925; iqr 362.5) for the left leg. the minimum volume was 1600 ml and the maximum volume was 2400 ml. the difference between both the right and the left limbs in the morning and the same limb after the prolonged gravitational exposure was 7.5 ml in both legs. this is not statistically significant in according to the t-student test p<0.08 (figures 1 and 2). moreover, the variation of fluids decrease in the venous-lymphatic compartment results to linearly and correlate with the time that was spent under gravity forces for working purpose wearing elastic stockings, with a high significance (r2=0.99, p<0.0001). figures 3 and 4 clearly show the legs volume figure 1. right lower limbs (ll) volume slight decrease after 8 h of prolonged standing in an operating room with elastic stocking. figure 2. left lower limbs (ll) volume slight decrease after 8 h of prolonged standing in an operating room wearing elastic stocking. no n c om me rci al us e o nly article [page 50] [veins and lymphatics 2015; 4:5182] decrease overtime, together with the linear correlation respect to the time spent under gravity, with elastic stockings, from morning to evening, respectively. therefore, the time spent wearing the greater is the elastic stockings during the work in a standing position, the greater is the volume reduction, or rather edema decrease. discussion leg volume assessment by wp is an evaluation to be highly precise.26 tape measurement of the leg circumference at different leg levels followed by calculation of leg volumetry with the mathematical formula of a truncated cone shows a very good correlation with wp measurements for both legs and arms.27,28 nevertheless, this method does not include the foot in the measurement and for this reason was not used in our study. legs can swell not only in patients with venous insufficiency but also physiologically in normal volunteers working in a prolonged sitting or a standing position.7,29 this natural phenomenon is exacerbated in those pathologic conditions causing a venous leg pump deficiency. these include ankle stiffness or paresis and valve damage. in these conditions, edema formation may become a clinical problem leading to induration and trophic disturbances of the skin.26,30 in healthy individuals the evening swelling is mostly asymptomatic and will disappear overnight. nevertheless, unpleasant subjective feelings of heaviness and tiredness may be reported.31 venous hypertension of the lower limbs is the main mechanism involved in the onset and progression of cvi and leads to an inflammatory process in the microcirculation. several mediators of vessel wall damage are activated, including reactive oxygen species which induce chemotaxis as well as leukocyte and platelet activation.32,33 oxidative damage of the endothelial membrane and increased vascular permeability is followed by skin changes and edema. as these mechanisms work together, cell damage and venous stasis increases.32,33 in this condition, gravity leads to a venous pressure increase in the dependent regions of the body. according to the starling’s law, an increased venous pressure in the leg will lead to extravasation of fluid from the venules and to the edema formation. in a normal population, this so-called occupational leg edema quickly disappears whenever venous pressure is reduced because of walking or lying down and elevating the legs.7,29 the ordinary activity of people working for a prolonged period in standing has been shown to alter normal venous hemodynamic. bishara et al. showed a significant decrease in venous refilling time in healthy women after their normal daily activity, requiring them to stand up for a minimum of 5 h, with an abnormal venous refilling time in 21% of the examined limbs.34 katz et al. had similar findings in normal subjects, they showed significant increases in venous filling index and significant shortening of venous filling time, comparing early morning with late afternoon.35 by using duplex ultrasound scanning, labropoulos found a significantly higher prevalence of venous insufficiency in a group of clinically healthy vascular surgeons, predominantly involving the greater saphenous system, compared with the control group of men with occupations not requiring long periods of standing.36 compression therapy remains the best method for the treatment of cvi and elastic stockings remains the most widely used form of this therapy. in a previous paper of ours, the same healthy population herein investigated underfigure 3. the correlation shown is that between volume at 7 a.m. and the volume at 3 p.m. in right lower limb (ll) in standing conditions with elastic stockings. figure 4. the correlation shown is that between volume at 7 a.m. and the volume at 3 p.m. in left lower limb (ll) in standing conditions with elastic stockings. no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:5182] [page 51] went a prolonged standing in a homogeneous condition of hours exposure, daytime and temperature, but without elastic stockings use. not wearing hosiery led to a significantly increased lower limb volume (p<0.0001).7 in the present study we investigated and evaluated the effects of elastic stockings (23-28 mmhg at the ankle) on healthy practitioner surgeons exposed to prolonged standing in the operatory room. differently from the vast majority of the literature on compression topic that is focused on cvi patients, our study is exclusively targeted to healthy subjects without cvi (hw). our results led us to point out that there is not just a simple pressure balance between the gravitational gradient and the elastic stockings exerted pressure, but rather that the last one is greater than the gravity gradient overload itself: in fact, we found lower volumes in the afternoon than in the morning. this volume reduction, although not significant (p=0.08), suggested a statistical trend. it would be interesting to increase the population in a further investigation. more interestingly, the reduced leg volume was correlated with the time spent working with elastic stockings r2=�0.99, p<0.0001. in fact, the greater is the time spent wearing elastic stockings during the work in a standing position, the greater is the volume reduction, or rather edema decrease. this study shows that the use of elastic stockings can be helpful in the reduction of evening edema (table 1). moreover, the use of elastic stockings can reduce volumetric variations in the legs during work. certainly the legs volume did not change and there was no increase. the major limitation of our study is the height of 40 cm of the wp device. this height cannot change, therefore the measurement cannot be placed in legs that are longer than 40 cm from foot to calf. the second limitation of our study is that this is a pilot study with hw with elastics stocking. in this study we do not have a control group. for the future we would make a cross over randomized study with and without the stocking. another bias to take into consideration is the possible variability coming from the different habit of the investigated subjects from the time in which they wake up and the distance covered to get to the working place. in conclusion, our experiment demonstrates that the elastic stockings may effectively counteract the increased leg volume over time in workers who are exposed to a prolonged gravitational gradient.9,22 age, gender, pregnancy, genetics are all risk factors for the cvi development, together with exposure to gravity for working reason. however, only the latter is a modifiable risk factor. in perspective, elastic stockings at work might correct one of the major risk factor for the development of chronic venous insufficiency. references 1. beebe-dimmer jl, pfeifer jr, ewngle js, et al. the epidemiology of chronic venous insufficiency and varicose veins. ann epidemiol 2005;15:175-84. 2. krijnen rm, de boer em, ader hj, et al. venous insufficiency in male workers with a standing profession. part 1: epidemiology. dermatology 1997;194:111-20. 3. kontosic i, vukelic m, drescik i, et al. work conditions as risk factors for varicose veins of the lower extremities in certain professions of the working population of rijeka. acta med okayama 2000;54:33-8. 4. maurins u, hoffmann bh, lösch c, et al. distribution and prevalence of reflux in the superficial and deep venous system in the general population results from the bonn vein study. germany. j vasc surg 2008;48:680-7. 5. lee aj, evans cj, allan pl, et al. lifestyle factors and the risk of varicose veins: edinburgh vein study. j clin epidemiol 2003;56:171-9. 6. chiesa r, marone em, limoni c, et al. demographic factors and their relationship with the presence of cvi signs in italy: the 24-cities cohort study. eur j vasc endovasc surg 2005;30:674-80. 7. tessari m, menegatti e, gianesini s, et al. assessment of lower limbs edema in healthy workers who are exposed to longterm gravity. veins and lymphatics 2013;1:e19. 8. fiore r, gerardino l, santoliquido a, et al. reduction of oxidative stress by compression stockings in standing workers. occupat med 2007;57:337-41. 9. buhs cl, bendick pj, glover jl. the effect of graded compression elastic stockings on the lower leg venous system during daily activity. j vasc surg 1999;30:830-5. 10. christopoulos dg, nicolaides an, szendro g, et al. air-plethysmography and the effect of elastic compression on venous hemodynamics of the leg. j vasc surg 1987;5:148-59. 11. belczak ce, de godoy jm, ramos rn, et al. rate of occupational leg swelling is greater in the morning than in the afternoon. phlebology 2009;24:21-5. 12. partsch h, flour m, smith pc, et al. indications for compression therapy in venous and lymphatic disease consensus based on experimental data and scientific evidence. under the auspices of the iup. int angiol 2008;27:193-219. 13. moffatt c. variability of pressure provided by sustained compression. int wound j 2008;5:259-65. 14. amsler f, blattler w. compression therapy for occupational leg symptoms and chronic venous disorders a meta-analysis of randomized controlled trials. eur j vasc endovasc surg 2008;35:366-72. 15. jonker mj, de boer em, adèr hj, et al. the oedema-protective effect of lycra support stockings. dermatology 2001;203:294-8. 16. belczak ce, de godoy jm, ramos rn, et al. is the wearing of elastic stockings for half a day as effective as wearing them for the entire day? br j dermatol 2010;162:42-5. 17. nicolaides an, cardiovascular disease educational and research trust, european society of vascular surgery, et al. investigation of chronic venous insufficiency: a consensus statement (france, march 5-9, 1997). circulation 2000;14:126-63. 18. porter jm, moneta gl. reporting standards in venous disease: an update. international consensus committee on chronic venous disease. j vasc surg 1995;21:635-45. 19. franceschi c, zamboni p. principles of venous haemodynamics. new york: nova biomedical books; 2009. pp.12-30. 20. coleridge-smith p, labropoulos n, partsch h, et al. duplex ultrasound investigation table 1. comparison of the volume change in the lower limbs after a working day with and without elastic stockings. comparison between the previous study without elastic stockings and this study with elastic stockings. without elastic stocking with elastic stocking right leg left leg right leg left leg 7:00 a.m. 1857.5±196.9 1850±194.7 1970±221 1965±233.5 3:00 p.m. 1945±209.6 1940±216.2 1962.5±220 1957.5±239.7 no n c om me rci al us e o nly article [page 52] [veins and lymphatics 2015; 4:5182] of the veins in chronic venous disease of the lower limbs--uip consensus document. part i. basic principles. eur j vasc endovasc surg 2006;31:83-92. 21. cavezzi a, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs--uip consensus document. part ii. anatomy. eur j vasc endovasc surg 2006;31:288-99. 22. szuba a, rockson sg. lymphedema: classification, diagnosis and therapy. vasc med 1998;3:145-56. 23. weissleder h. diagnosis of lymphostatic edema of the extremities. fortschr med 1997;115:32-6. 24. international society of lymphology. the diagnosis and treatment of peripheral lymphedema: 2013 consensus document of the international society of lymphology. lymphology 2013;46:1-11. 25. thulesius o, norgren l, gjöres je. footvolumetry, a new method for objective assessment of edema and venous function. vasa 1973;2:4. 26. blazek c, amsler f, blaettler w, et al. compression hosiery for occupational leg symptoms and leg volume: a randomized crossover trial in a cohort of hairdressers. phlebology 2013;28:239-247. 27. auvert jf, vayssairat m. volumetrics: an indispensable complementary test in lymphology. med intern 2002;23:388se90s. 28. karges jr, mark be, stikeleather sj, et al. concurrent validity of upper-extremity volume estimates: comparison of calculated volume derived from girth measurements and water displacement volume. phys ther 2003;83:134e45. 29. mosti g, partsch h. occupational leg oedema is more reduced by antigraduated than by graduated stockings. eur j vasc endovasc surg 2013;45:523-7. 30. mosti g, picerni p, partsch h. compression stockings with moderate pressure are able to reduce chronic leg oedema. phlebology 2012;27:289-96. 31. partsch h, winiger j, lun b. compression stockings reduce occupational leg swelling. dermatol surg 2004;30:737-43. 32. coleridge-smith pd. deleterious effects of white cells in the course of skin damage in cvi. int angiol 2002;21:26-32. 33. khodabandehlou t, boisseau mr, le devehat c. blood rheology as a marker of venous hypertension in patients with venous disease. clin hemorheol microcirc 2004;30:307-12. 34. bishara ra, sigel b, rocco k, et al. deterioration of venous function in normal lower extremities during daily activity. j vasc surg 1986;3:700-6. 35. katz ml, comerota aj, kerr rp, et al. variability of venous hemodynamics with daily activity. j vasc surg 1994;19:361-5. 36. labropoulos n, delis kt, nicolaides an. venous reflux in symptom-free vascular surgeons. j vasc surg 1995;22:150-4. no n c om me rci al us e o nly michael d dake, md and l. hopkins, md-produced by ptm healthcare marketing, inc. youtube aboutpresscopyrightcontact uscreatorsadvertisedeveloperstermsprivacypolicy & safetyhow youtube workstest new features© 2022 google llc hrev_master veins and lymphatics 2015; volume 4:5400 [page 62] [veins and lymphatics 2015; 4:5400] may symptoms of chronic cerebrospinal venous insufficiency be improved by venous angioplasty? an independent 4-year follow up on 366 cases pietro m. bavera vascular surgeon at the university of milano; vascular imaging diagnostician for medick-up vascular lab, milano, italy abstract the aim of the study was to collect results from 366 chronic cerebrospinal venous insufficiency (ccsvi) affected patients that were regularly duplex controlled after having received vein angioplasty following diagnosis for ccsvi. the procedures were all performed in the same centre and same equipment. the patients were divided into three groups according to the attributed severity of the associated multiple sclerosis: 264 relapse-remitting (rr) (72%): 179 females (67.8%) and 85 (32.2%) males; 62 secondary progressive (17%): 37 (59.7%) females and 25 (40.3%) males; 40 primary progressive (11%): 22 (55%) females and 18 (45%) males. a data base revealed eleven most frequent disturbs and symptoms, together with working capacities, and was kept up-todate at every duplex control aiming to establish a novel rapid ccsvi symptoms questionnaire assessment in 4 years follow up. the symptoms were: diplopia, fatigue, headache, upper limb numbness/mobility, lower limb numbness/mobility, thermic sensibility, bladder control, balance coordination, quality of sleep, vertigo, mind concentration. results, as follows, appear to be significantly good in the rr group, also the biggest one. diplopia improved in 262/264 patients (99.2%) (p<0.0001); fatigue in 260/264 (98.5%) (p<0.0001); headache in 205/208 (98.6%) (p<0.0001); balance coordination in 23/26 (88.5%) (p<0.0001); quality of sleep in 55/59 (93.2%) (p<0.0001); vertigo in 30/33 (90.9%) (p<0.0001); mind concentration in 142/144 (98.6%) (p<0.0001). other results regarded: upper limb numbness and mobility in 20/24 (83.3%) (p=0.0002); lower limb numbness and mobility 13/15 (86.7%) (p=0.0087); thermic sensibility 3/4 (75%) [p: not significant (n.s.)]; bladder control 2/3 (66.6%) (p: n.s.). in contrast in the progressive cases results are quite different where, nevertheless, some useful considerations were collected and statistically significant, too. in addition, venous angioplasty appears to be safe, side effects were observed only in seven patients (0.19%) that grew a monolateral jugular thrombosis but still were regularly controlled and above all did not suffer worsening of the disease. finally, the overwhelming percutaneous transluminal angioplasty results in the rr group lead to say that the correct criteria should be the sooner the better. introduction chronic cerebrovascular venous insufficiency (ccsvi) is perhaps one of the most important new chapters in vascular diseases, often correlated with severe neurologic ones, of the past decade. certainly it is one of the most frequent discussion topics related to venous malformations. moreover, this argument has openly split medical opinions and shaken a worldwide population of patients affected with multiple sclerosis (ms).1 all this turmoil started a few years ago, in 2007, when prof. paolo zamboni first presented his paper regarding the big idea2 that gave fire to the fuse and shortly after exploded with shattering effects inside medical scientific world.3-6 in past, we gave our contribution with two papers,7,8 with the purpose to realize the presence of ccsvi in ms affected patients through duplex exams. in that occasion the purpose of the exams was principally to find out possible presence of haemodynamic vascular irregularities (stenosis and/or valve malfunctions)9-11 regarding venous outflow from the brain stream and cervical medulla. since the beginning of all, the definition for ccsvi and the protocol for carrying out this type of diagnostic exam was defined by menegatti et al.12,13 and still is the main reference in this argument. since 2007 and onwards, hundreds of papers were written on this argument and divided schools of thoughts, and now even some textbooks are introducing the pathology. after having achieved the correct know-how directly from zamboni in mid 2010, the author started in november 2010 to examine ms patients, and is still doing so at present. after four years, and completed exam 2150, the collected results were sorted-out and the present study is addressed in assessing the effect of percutaneous transluminal angioplasty on the more frequent and disabling symptoms coming from the association between ccsvi and ms. materials and methods the work regards 366 ms affected patients, 238 females and 128 males between 18 and 58 years old (mean age 33.3), that were both interviewed and duplex examined between november 2010 and december 2014, growing a totality of 1464 consecutive duplex exams. all duplex control exams were, every time, anticipated by a regular interview with standardized questions with the aim to seek and register eventual changes of symptoms in a certain lapse of time. the first word was therefore given to the patients and their answers allowed to collect objective clinical situations that were later compared with the duplex exam result. the author collected the eleven most frequent symptoms in these groups of patients and described them in another publication.14 all scheduled controls were performed after venous angioplasty of one or both internal jugular veins and, when necessary, also of the azygos vein. in some occasions the venous pta procedure was repeated a second or even third time but follow-ups were still based on the same number of controls within a four-year period. all the patients had a first duplex exam, called exam zero, that was positive to ccsvi according to zamboni’s and the consensus document criteria15 and they autonomously underwent to vein pta, freely choosing their physician, either vascular surgeon or interventional radiologist. the patients were divided into three groups according to the expanded disability status scale classification16 attributed by their neurologists. moreover, on the basis of the latest discharge letters, the patients’ disease was correspondence: pietro m. bavera, vascular surgeon at the university of milano; vascular imaging diagnostician for medick-up vascular lab, milano, italy. e-mail: pietromaria.bavera@fastwebnet.it conflict of interest: the author declares no potential conflict of interest. acknowledgments: the author would like to thank dr. nicolò margaritella for his valuable help in statistical evaluations. key words: chronic cerebrospinal venous insufficiency; multiple sclerosis; jugular veins; venous angioplasty; symptoms. received for publication: 26 june 2015. revision received: 15 september 2015. accepted for publication: 17 september 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright p.m. bavera, 2015 licensee pagepress, italy veins and lymphatics 2015; 4:5400 doi:10.4081/vl.2015.5400 no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:5400] [page 63] sorted into: relapse-remitting (rr), secondary progressive (sp), and primary progressive (pp). these criteria also helped to obtain more homogenous results and comparisons. in the rr group the patients were 264 (72%), in the sp 62 (17%) and in the pp 40 (11%). a demographic table describes each ms group with the clinical course age, expressed as mean and standard deviation and gender, male/female (table 1). the rr patient group was the relatively easiest one to follow-up since 201 (76%) underwent to only one angioplasty and 63 (24%) to a second one, while none had a third procedure. the sp patient group resulted the most articulated and complicated since only 3 (5%) stopped after one angioplasty while 51 (82%) underwent to a second one and 8 (13%) to a third procedure. in the pp patient group none (100%) stopped after the first angioplasty and 37 (92%) had a second one while only 3 (8%) had a third procedure. a peculiarity of the rr group was that the second angioplasty was always performed between 12 and 18 months after the first one while both sp and pp groups had a re-do in average 6 months after the first one and eventually a third procedure in average 9 months after the second one. as a rule for all, the first duplex control was usually carried out within three months after the first procedure. the description of the venous pta was read always after the duplex exam, so to avoid any possible influence on the exam itself, making each time as if it was the first one. moreover, each successive duplex exam was performed without reading the results of previous ones. all patients were first asked if they were willing to answer to standardized questions that regarded the most frequently past and eventually still present disorders in order to check-out for how long and how many benefits or improvements were active or wore-out in time. in order to help the patients and ease them, no particular scores were used from their answers but these were simply limited to catalogue the presence (+) or absence (-) of disorders in between a certain lapse of time after having received the angioplasty and also between the previous duplex control. the timetable for the controls was established after the first angioplasty and then quite flexible: within 3 months, 9/12 months, 18/24 months and lastly 36/48 months. the tables 2,3 and 4 regarding group divisions and duplex exams compared with patient’s answers are given with the results and only include those that underwent to regular duplex controls. this group of ms population established the definitive questionnaire list on the basis of 11 symptoms that were most frequently described. other disorders or disabilities were less frequent and therefore discarded since probably would not have given significant numbers. these symptoms naturally were more persistent or consistent in parallel with the severity of the disease (sp and pp), while often happened to be absent in the less severe (rr) phase. point 0 (zero), as also seen in the tables, was considered as previous to the venous pta. the eleven most frequently complained disorders or disabilities were: diplopia, fatigue, headache, upper limb numbness/ mobility, lower limb numbness/mobility, altered thermic sensibility, bladder control, balance coordination, quality of sleep, vertigo, mind concentration. the working activity, secondary to the most common disabilities was included and influenced their symptomatology. after having collected the information, the duplex exam was performed. usually, good duplex results matched with clinical symptoms, especially in the rr group but did not always occur with the sp and pp figuring out that other situations could cause the disturbs. one among all often was a variable connected with ambulation difficulties and in general the use of devices to help walking. this particular situation apparently caused table 1. patients’ demographic characteristics stratified for multiple sclerosis course. ms course no. age mean (sd) gender f/m rr 264 28.5 (5.3) 179/85 sp 62 47.9 (7.1) 37/25 pp 40 43.0 (4.0) 22/18 total 366 33.3 (9.7) 238/128 ms, multiple sclerosis; sd, standard deviation; f, female; m, male; rr, relapse-remitting; sp, secondary progressive; pp, primary progressive. table 2. results on the relapse-remitting group of patients. rr patients (264) disturbs and results in time zero 0/3 9/12 18/24 36/48 months months months months qol improved mcnemar’s bonferroni’s χ² test with p-values continuity correction correction diplopia +264 −263 −99.6% −263 −99.6% −263 −99.6% −262 −99.2% 262 99.2% χ²=260 p<0.0001 fatigue +264 −264 −100.0% −264 −100.0% −262 −99.2% −260 −98.5% 260 98.5% χ²=258 p<0.0001 headache +208 −208 −100.0% −208 −100.0% −205 −98.6% −205 −98.6% 205 98.6% χ²=203 p<0.0001 upper limb numbness/mobility +24 −20 −83.3% −20 −83.3% −20 −83.3% −20 −83.3% 20 83.3% χ²=18.05 p=0.0002 lower limb numbness/mobility +15 −11 −73.3% −12 −80.0% −13 −86.7% −13 −86.7% 13 86.7% χ²=11.08 p=0.0087 thermic sensibility + 4 −4 −100.0% −4 −100.0% −4 −100.0% −3 −75.0% 3 75.0% ns ns bladder control +3 −3 −100.0% −3 −100.0% −3 −100.0% −2 −66.6% 2 66.6% ns ns balance coordination +26 −19 −73.1% −21 −80.8% −22 −84.6% −23 −88.5% 23 88.5% χ²=21.04 p<0.0001 quality of sleep +59 −48 −81.4% −50 −84.7% −56 −94.9% −55 −93.2% 55 93.2% χ²=53.01 p<0.0001 vertigo +33 −30 −90.9% −29 −87.9% −30 −90.9% −30 −90.9% 30 90.9% χ²=28.03 p<0.0001 mind concentration +144 −121 −84.0% −129 −89.6% −141 −97.9% −142 −98.6% 142 98.6% χ²=140 p<0.0001 working activity +264 −251 −95.1% −260 −98.5% −262 −99.2% −260 −98.5% 260 98.5% χ²=258 p<0.0001 rr, relapse-remitting; qol, quality of life; ns, not significant. no n c om me rci al us e o nly article [page 64] [veins and lymphatics 2015; 4:5400] an abnormal muscular fatigue of the neck, often with a sort of muscle hypertrophy, and in some cases to unnatural extrinsic compression of blood vessels. lastly, regarding tables 2-4, statistical analyses were conducted using mcnemar’s test to determine whether the number of patients within each disorder or disability significantly changed between baseline (zero) and the last follow-up (36/48 months). continuity correction to mcnemar’s test was applied to cope with disturb categories within which a low number of subjects were showed. p-values were multiple comparisons corrected using bonferroni’s procedure. results the results, updated to the end of december 2014, regard a four-year follow-up. all controlled subjects underwent to venous angioplasty, no stentings were observed. the duplex exams were always well accepted, appeared obviously safe and had an important role in the evaluation of the venous haemodynamic situation,17 combined with the purely ccsvi symptoms questionnaire as described by the patients themselves. firstly, after having clearly identified the presence of ccsvi in a considerable majority of patients affected by ms, there seems to be a frequent parallelism between some disturbs and the vein abnormalities: they usually improve or even disappear when the outflow is corrected. secondly, both the clinical and blood flow improvements appear to be long lasting when they are not yet so severe and apparently the neurological damage is not so widely distributed. this could explain why better and perjuring results appear to occur in the rr group of patients. for the same reason this could be why the results are less stable in the more severe sp and pp patients that, nevertheless, still want to table 3. results on secondary progressive patients. sp patients (62) disturbs and results in time zero 0/3 9/12 18/24 36/48 months months months months qol improved mcnemar’s bonferroni’s χ² test with p-values continuity correction correction diplopia +62 −62 −100.0% −62 −100.0% −53 −85.5% −49 −79.0% 49 79.0% χ²=47.02 p<0.0001 fatigue +62 −60 −96.8% −42 −67.7% −15 −24.2% −4 −6.5% 4 6.5% χ²=2.25 p>0.9 headache +53 −53 −100.0% −52 −98.1% −51 −96.2% −50 −94.3% 50 94.3% χ²=48.02 p<0.0001 upper limb numbness/mobility +62 −61 −98.4% −58 −93.5% −46 −74.2% −35 −56.5% 35 56.5% χ²=33.03 p<0.0001 lower limb numbness/mobility +62 −62 −100.0% −31 −50.0% −18 −29.0% −10 −16.1% 10 16.1% χ²=8.1 p=0.0531 thermic sensibility +62 −62 −100.0% −55 −88.7% −41 −66.1% −12 −19.4% 12 19.4% χ²=10.08 p=0.018 bladder control +56 −55 −98.2% −54 −96.4% −53 −94.6% −46 −82.1% 46 82.1% χ²=44.02 p<0.0001 balance coordination +62 −61 −98.4% −31 −50.0% −25 −40.3% −15 −24.2% 15 24.2% χ²=13.07 p=0.004 quality of sleep +56 −56 −100.0% −50 −89.3% −50 −89.3% −50 −89.3% 50 89.3% χ²=44.02 p<0.0001 vertigo +52 −51 −98.1% −48 −92.3% −26 −50.0% −25 −48.1% 25 48.1% χ²=23.04 p<0.0001 mind concentration +62 −62 −100.0% −58 −93.5% −57 −91.9% −50 −80.6% 50 80.6% χ²=48.02 p<0.0001 working activity +62 −62 −100.0% −27 −43.5% −14 −22.6% −5 −8.1% 5 8.1% χ²=3.2 p=0.884 sp, secondary progressive; qol, quality of life. table 4. results on primary progressive patients. pp patients (40) disturbs and results in time (*after one or more pta) zero 0/3 9/12 18/24 36/48 months months months months qol improved mcnemar’s bonferroni’s χ² test with p-values continuity correction correction diplopia +40 −40 −100% −40 −100.0% −16 −40.0% −5 −12.5% 5 12.5% χ²=8.1 p=0.884 fatigue +40 −38 −95% −26 −65.0% −8 −20.0% −2 −5.0% 2 5.0% χ²=0.5 p>0.9 headache +33 −33 −100% −33 −100.0% −30 −90.9% −30 −90.9% 30 90.9% χ²=28.03 p<0.0001 upper limb numbness/mobility +40 −40 −100% −20 −50.0% −23 −57.5% −6 −15.0% 6 15.0% χ²=4.17 p=0.495 lower limb numbness/mobility +40 −40 −100% −10 −25.0% −12 −30.0% −2 −5.0% 2 5.0% χ²=0.5 p>0.9 thermic sensibility +40 −40 −100% −15 −37.5% −18 −45.0% −5 −12.5% 5 12.5% χ²=8.1 p=0.884 bladder control +40 −40 −100% −38 −95.0% −36 −90.0% −34 −85.0% 34 85.0% χ²=32.03 p<0.0001 balance coordination +40 −40 −100% −12 −30.0% −20 −50.0% −4 −10.0% 4 10.0% χ²=2.25 p>0.9 quality of sleep +38 −38 −100% −33 −86.8% −35 −92.1% −28 −73.7% 28 73.7% χ²=26.04 p<0.0001 vertigo +32 −31 −97% −29 −90.6% −30 −93.8% −18 −56.3% 18 56.3% χ²=16.06 p=0.0007 mind concentration +40 −40 −100% −38 −95.0% −35 −87.5% −35 −87.5% 35 87.5% χ²=33.03 p<0.0001 working activity +40 −37 −93% −13 −32.5% −14 −35.0% −15 −37.5% 15 37.5% χ²=13.07 p=0.0036 pp, primary progressive; pta, percutaneous transluminal angioplasty; qol, quality of life. no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:5400] [page 65] try one or two re-do procedures. besides this, in these two latter groups of patients, mostly pp, the presence of external vein compression appears to influence the pta and, in this group of examined patients, seems principally to occur on males. the most important aspect, that regards the clinical disturbs, is that there is a matching duplex exam: an improved bloodstream outflow corresponds with a better clinical situation while, on the other hand, one or more severe venous outflow problems meet with symptomatic disturbs that gradually return to a situation prior venoplasty. tables 2-4 are descriptive for disturbs and results. under a statistical point of view, the venous outflow problems re-occur most frequently in the sp and pp patients, usually found at the brachial cephalic junction and, most commonly, on the left side (72%) otherwise bilaterally (21%) while apparently less frequent is the monolateral right side alone (7%). valve leaflet restenosis alone appear to be more frequent in rr patients (91%), while conjunct valve defects and vein stenosis mostly occur with sp (63%) and pp (87%) patients. working activities after three months in rr patients improved in 95.1% of cases and showed to be even better at the end of the survey (98.5%). in seven progressive patients, in this case always after control of the second procedure, a thrombosis of the internal jugular vein was observed, in six cases on the left side. these veins were all hypoplasic since before any whatsoever procedure and probably for this reason important haemodynamic changes never occurred. it was not therefore so strange, that the opposite side appeared to be giving a satisfactory compensation. therefore, the left jugular district appeared to be most vulnerable, in this series of controlled patients. in this series, symptomatology usually was the reason that leads these patients to submit themselves to venous angioplasty, more than a real attitude against traditional medical therapy. disturb symptoms appear considerably improved in rr patients, as clearly evident in table 2. symptomatology appeared to be more complicated in the two progressive groups, as shown in tables 3 and 4, where the amount of disturbs were already more present since starting point. motion problems associated with extreme tiredness and quick exhaustion were the principal problems that lead to the venous angioplasty. peculiarity of the majority of this group was, in both cases of progressive forms, an extraordinary benefit that came in reduced symptoms (99.08% for the sp and 99.27% for the pp) immediately after the venoplasty. most of the improvements in these two groups of patients unfortunately lasted for a short lapse of time, between two weeks and three months. veins and valve leaflets most probably recovered a sort of memory effect and this gradually overtook the venous angioplasty. moreover a general poor mobility and tremendous muscular stress required to keep sufficient balance during ambulation, usually with the help of devices, gradually developed and could be in some cases the cause of muscular hypertrophy of the neck and consequent extrinsic vein compression. discussion this is an independent four-year study carried out on 366 ms patients with a regular follow-up plan. there is not the will to convince that ccsvi is the therapy for ms. in this series it is quite evident that the positive results are observed in almost totality of relapse-remitting population and appear more persistent. again, the majority of progressive ms patients experienced, perhaps only for a short period, symptom improvements and for this reason submitted themselves to a second or even third procedure hoping to re-establish them. anyhow, it is a matter of fact that both duplex and clinical improvements were established in a sufficient number of treated patients with balloon angioplasty, enough to make this type of treatment as sufficiently safe, considering the low number of sideeffects observed or described in my series and confirmed in literature.18,19 finally, as described in the most recent consensus document,20 parallelism between poor cephalic venous outflow and a list of symptoms, either neurologic or motor are confirmed. symptoms appear to improve with a better venous outflow and the patients were very precise on this topic. this work is autonomous, free from economical interests, based on the responsible help of all those patients that helpfully answered in the past four years to questions collected at duplex exams or controls, before and after venoplasty. for obvious reasons they are all kept anonymous but they were all informed that their voluntary help would become useful for this purpose. references 1. zamboni p, menegatti e, occhionorelli s, et al. the controversy on chronic cerebrospinal venous insufficiency. veins and lymphatics 2013;2:e14. 2. zamboni p. the big idea iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. j r soc med 2006;99:5. 3. zamboni p, galeotti r. the chronic cerebrospinal venous insufficiency syndrome. phlebology 2010;25:269-79. 4. zamboni p, menegatti e, weinstockguttman b, et al. the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis is related to altered cerebrospinal fluid dynamics. funct neurol 2009;24:133-8. 5. zamboni p, morocic s, menegatti e, et al. screening for chronic cerebrospinal venous insufficiency (ccsvi) using ultrasound recommendations for a protocol. int angiol 2011;30:571-97. 6. simka m, kostecki j, zaniewski m, et al. extracranial doppler sonographic criteria of chronic cerebrospinal venous insufficiency in the patients with multiple sclerosis. int angiol 2010;29:109-14. 7. bavera pm, mendozzi l, cavarretta r, et al. venous extracranial duplex ultrasound and possible correlations between multiple sclerosis and ccsvi: an observational study after 560 exams. acta phlebologica 2011;12:109-13. 8. bavera pm, agus gb, alpini d, et al. results from 823 consecutive duplex exams for ccsvi in a vascular centre. acta phlebologica 2012;13:14-48. 9. simka m, kostecki j, zaniewski m, et al. extracranial doppler sonographic criteria of chronic cerebrospinal venous insufficiency in the patients with multiple sclerosis. int angiol 2010;29:109-14. 10. menegatti e, tessari m, gianesini s, et al. human internal jugular valve m-mode ultrasound characterization. curr neurovasc res 2013;11:149. 11. zamboni p, tisato v, menegatti e, et al. ultrastructure of internal jugular vein defective valves. phlebology 2014 [epub ahead of print]. 12. menegatti e, genova v, tessari m, et al. the reproducibility of colour doppler in chronic cerebrospinal venous insufficiency associated with multiple sclerosis. int angiol 2010;29:121-6. 13. menegatti e, galeotti r, gianesini s, et al. echo-color-doppler criteria for diagnosis of chronic cerebrospinal venous insufficiency. xvi world congr uip 2009. int angiol 2009;28:36. 14. bavera p. the most frequent symptoms and disturbs from ccsvi. behav neurol 2015 [in press]. 15. lee bb, bergan j, gloviczki p, et al. diagnosis and treatment of venous malformations. consensus document of the international union of phlebology (uip) 2009. international union of phlebology (uip) int angiol 2009;28:434-51. no n c om me rci al us e o nly article [page 66] [veins and lymphatics 2015; 4:5400] 16. kurtzke jf. rating neurologic impairment in multiple sclerosis: an expanded disability status scale (edss). neurology 1983;33:1444-52. 17. dolic k, siddiqui ah, karmon y, et al. the role of noninvasive and invasive diagnostic imaging techniques for detection of extra-cranial venous system anomalies and developmental variants. bmc med 2013;11:155. 18. hubbard d, ponec d, gooding j, et al. clinical improvement after extracranial venoplasty in multiple sclerosis. vasc interv radiol 2012;23:1302-8. 19. zamboni p, galeotti r, weinstock-guttman b, et al. venous angioplasty in patients with multiple sclerosis: results of a pilot study. eur j vasc endovasc surg 2012;43:116-22. 20. lee bb, baumgartner i, berlien p, et al. diagnosis and treatment of venous malformations consensus document of the international union of phlebology (iup): updated 2013. int angiol 2015;34:97-149. no n c om me rci al us e o nly hrev_master veins and lymphatics 2016; volume 5:5986 [veins and lymphatics 2014; 3:5986] [page 13] compression in mixed ulcers giovanni mosti angiology department, barbantini clinic, lucca, italy peripheral arterial occlusive disease (paod) is reported in about 15-20% of patients with venous leg ulcers (vlu). in such cases compression therapy is considered a contraindication when ankle-brachial pressure index (abpi) is <0.8.1 aim of this short paper is to briefly refer about the literature data and summarize our personal experience in applying compression therapy in patients with mixed ulcers and moderate paod. despite the fact that arterial recanalization is often recommended as first therapeutical step in patients with leg ulcers and arterial impairment,2,3 there are some reports on clinical effectiveness of compression in favoring the healing of mixed ulcers with a not critical arterial disease. ghauri4 applying compression in patients with mixed moderate arterial/venous ulcers achieved healing rates comparable with venous ulcers, although nurse-led surveillance was required. humphreys5 managed patients with leg ulcers due to mixed moderate arterial/venous disease (abpi above 0.5 up to 0.85) with supervised modified compression and considered for revascularization these patients only if their ulcer did not heal. he reported a 68% healing rate at 36 weeks in patients with mixed moderate arterial/venous disease and 87% in patients without arterial impairment. georgopoulos6 treated patients with moderate paod (0.5<abi<0.75) conservatively with modified compression and considered patients with not-healing ulcers for revascularization. he reported a 64.7% healing rate at 24.7±3.1 weeks with modified, reduced compression therapy. marston reported two different studies on patient with paod treated just by compression without any surgical procedure for paod. in the first one7 he compared the outcomes of patients with mixed ulcers and moderate paod with patients affected by venous ulcers without any paod. he reported a fast healing time (57% of the ulcers healed at 10 weeks) although paod was a delaying factor. in the second paper he treated patients with pure paod ulcers8 and reported that compression therapy was effective even if the healing time was very slow (25% at 6 months and 52% at 12 months). also in experimental setting compression was shown to be not harmful in patients with paod. top9 measured the toe pressure with and without short stretch bandages in patients with mixed leg ulcers and was able to show that compression did not significantly reduce toe pressure. interface pressure was not measured. our group10 reported that inelastic compression in patients with mixed and arterial ulcers does not reduce but even increase periwound flow, toe pressure and tcpo2 measured distally to the bandage provided that compression pressure is <40 mm hg and that the perfusion pressure corresponding to the systolic ankle pressure is >60 mm hg. similar data were published by junger,11 who reported that, after application of an inelastic multicomponent compression system in subjects with moderate paod, laser doppler fluxmetry indicated significant improvements of the microcirculation. taking into consideration these data, we wanted to check the outcomes of patients with mixed ulcers with moderate paod treated by compression. we retrospectively analyzed the records of 180 outpatients (43 men and 137 females; mean age was 74±11.5 years; age ranged between 31-92 years) with recalcitrant venous leg ulcers (vlu with ulcer surface up to 100 cm2 showing no healing tendency after a 6 months therapy) who had been treated between january 2011 and july 2014. in this case series we compared the clinical outcome of patients with mixed leg ulcers (mlu) with that of patients affected by pure vlu (pvlu). paod in mixed ulcers was considered moderate when abpi was <0.8 and >0.5 patients with small ulcers lower that 15 cm2 or lasting less than 6 months, which cannot be defined as recalcitrant were excluded, as also patients affected by severe paod with abpi <0.5 who need to be referred for arterial revascularization as first therapeutical step. seventy-one out of 180 patients were affected by mlu with moderate paod and 109 by pvlu. all patients received the same local dressing (debridement with saline or light antiseptic solution and foam absorbing dressing). when clinical signs of infection occurred cadexomer® powder was added until signs of infection disappeared. in addition to the same local wound dressing, the patients received foam sclerotherapy (sodium tetradecyl sulfate 3%) of the superficial veins with reflux directed to the ulcer area and inelastic compression therapy (ct). in patients with pvlu ct was applied with a strong pressure higher than 60 mm hg and patients with mlu received short stretch bandages with a reduced pressure lower than ≤40 mm hg. no patient was referred for arterial revascularization. the patients were followed until complete ulcer healing and healing rate was recorded. patients with mlu and pvlu showed comparable demographic characteristics in terms of sex, age, venous pathophysiology, ulcer surface, duration, wound-bed conditions and recurrence. twenty-five patients were lost at follow-up and were excluded from final analysis. the outcomes were analyzed in the remaining 155 patients [93 patients with pvlu (85.4%) and 62 patients with mlu (87.4%)]. the maximal time for complete healing was 48 weeks in pvlu group and 52 weeks in mlu (p=0.009). the median healing time of patients with pvlu (23 weeks) was significantly shorter than that of patients with mlu (25.5 weeks) (p=0.03). multiple linear regression analysis showed the factors which influenced the healing time: deep venous disease (p<0.001), ulcer surface (p<0.001), arterial disease (p=0.002), and ulcer duration (p<0.01). pain ulcer-related rapidly disappeared. pain cessation required an average of four weeks (in patients with vlu) and up to eight weeks in patients with mixed ulcers. compression device-related pain or discomfort were minimal and tended to disappear when the patients got used to compression therapy. in conclusion patients with mixed ulcers and moderate arterial disease may be effectively and safely treated with reduced, modified compression therapy characterized by short stretch material applied with reduced interface pressure (<40 mmhg) and close surveillance. the vein disease treatment may be completed by foam sclerotherapy of refluxing veins. this treatment protocol may heal the mixed ulcers even if in a longer time period compared to pure vlu. we suggest this conservative treatment protocol to patients with mixed ulcers not complicated by severe arterial disease restricting arterial revascularization procedures mainly to cases with critical ischemia (abpi <0.5). references 1. o’meara s, cullum na, nelson ea. compression for venous leg ulcers. cochrane database syst rev 2009;1: cd000265. 2. lantis jc, boone d, lee l, et al. the effect of percutaneous intervention on wound healing in patients with mixed arterial venous disease. ann vasc surg 2011;25:79-86. correspondence: giovanni mosti, angiology department, barbantini clinic, via del calcio, 55100 lucca, italy. e-mail: giovanni.mosti10@gmail.com this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright g. mosti, 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5986 doi:10.4081/vl.2016.5986 no n c om me rci al us e o nly conference presentation [page 14] [veins and lymphatics 2016; 5:5986] 3. hafner j, schaad i, schneider e, et al. leg ulcers in peripheral arterial disease (arterial leg ulcers): impaired wound healing above the threshold of chronic critical limb ischemia. j am acad dermatol 2000;43: 1001-8. 4. ghauri as, nyamekye i, grabs aj, et al. the diagnosis and management of mixed arterial/venous leg ulcers in communitybased clinics. eur j vasc endovasc surg 1998;16:350-5. 5. humphreys ml, stewart ah, gohel ms, et al. management of mixed arterial and venous leg ulcers. br j surg 2007;94:1104-7. 6. georgopoulos s, kouvelos gn, koutsoumpelis a, et al. the effect of revascularization procedures on healing of mixed arterial and venous leg ulcers. int angiol 2013;32:368-74. 7. marston wa, carlin re, passman ma, et al. healing rates and cost efficacy of outpatient compression treatment for leg ulcers associated with venous insufficiency. j vasc surg 1999;30:491-8. 8. marston wa, davies sw, armstrong b, et al. natural history of limbs with arterial insufficiency and chronic ulceration treated without revascularization. j vasc surg 2006;44:108-14. 9. top s, arveschoug ak, fogh k. do shortstretch bandages affect distal blood pressure in patients with mixed aetiology leg ulcers? j wound care 2009;18:439-42. 10. mosti g, iabichella ml, partsch h. compression therapy in mixed ulcers increases venous output and arterial perfusion. jvs 2012;55:122-8. 11. junger m, haase h, schwenke l, et al. macroand microperfusion during application of a new compression system, designed for patients with leg ulcer and concomitant peripheral arterial occlusive disease. clin hemorheol microcirc 2013;53:281-93. no n c om me rci al us e o nly hrev_master veins and lymphatics 2017; volume 6:6627 [page 10] [veins and lymphatics 2017; 6:6627] an innovative compression system providing low, sustained resting pressure and high, efficient working pressure josefin damm,1 torbjörn lundh,2 hugo partsch,3 giovanni mosti4 1presscise ab, herrljunga, sweden; 2chalmers university of technology, gothenburg, sweden; 3medical university of vienna, austria; 4angiology department, clinica md barbantini, lucca, italy introduction chronic venous insufficiency (cvi) can cause considerable morbidity and reduced quality of life.1 compression therapy, such as bandages and stockings, is the cornerstone and golden standard in the prevention and treatment of cvi today.2 it is also shown that compression used after the healing of ulcers, reduces the rate of recurrence.3 it has been found that compression products with a stiff, non-elastic material, are essential for an improved haemodynamic effect, indicating that low resting pressure and high working pressure is vital, in order to achieve the most effective and well tolerated compression treatment.4 however, one great challenge is that by applying a stiff bandage, either as a single component or as a part in a multi-component product, one always adds, a not so easily quantified, resting pressure. in order to achieve the most effective treatment it is easy to apply the bandage in a too tight and uneven manner, often resulting in painful resting pressures.4 in earlier studies, it has been shown that common for todays practice is that the compression treatment is dependent on the applier and that only about 10% of the healthcare personnel managers to apply a pre-defined target bandage pressure.5 it has also been shown that the applied pressures decrease in effectiveness, only after a couple of hours, due to e.g. oedema reduction, resulting in poor compression treatment over time.6 aim the goal is to find a method to provide a well-defined resting pressure and a method that increases the working pressure without changing the pre-defined resting pressure, as well as maintaining the pressure over time. materials and methods first, an elastic compression bandage (lundatex® medical by presscise) providing and maintaining a certain pressure level was applied on the leg. the bandage is based on laplace’s law, where the pressure is a product of the force, times the overlap, times the curvature. the bandage is provided with visual guidelines for correct stretch per each turn and correct overlap. due to the specific elastic properties in the material the force is adjusted to the changes in curvature when the guidelines are followed. this results in a well-defined pressure, with minimal variability. several patches (presspatch™ by presscise ab) made in a hook and loop material and with an optimal shape, were attached over the elastic bandage, creating a multicomponent compression system (lundatex® system by presscise ab). the patches adhere directly to the bandage material without any force being added; hence there is no increase of resting pressure. in the front of the leg a special patch was added (fixpatch™ by presscise ab). this patch can be opened easily e.g. every morning, in order to maintain the pressure level over time. in one pilot-study interface pressures were measured on point b1 and c on patients with severe venous reflux in the great saphenous vein (ceap c2-c5), during lying and standing (n=18). three consecutive measurements where done: 1) the elastic bandage applied to the leg with a pressure of 20 mmhg, 2) the elastic bandage applied to the leg with a pressure of 30 mmhg and 3) after attaching the stiff patches to the elastic bandage. in a second pilot-study the pressure was measured on one healthy volunteer at b1, over seven days. measurements were taken in supine, at dorsal flex and standing position, twice a day. the pressure-measuring device used was picopress® (by microlab italia). results the elasitc bandage provides a welldefined pressure, independent of placement or position. the patches add the stiffness to the underlying material and increase only the working pressure. with the patches, resting pressure is close to the same pressue as before, however working pressure increases significantly. as expected, there were a significant drop of working pressure in the evening day one in the 2nd pilot-study, due to some odema reduction. the correction of the fixpatch™ correspondence: josefin damm, presscise ab, herrljunga, sweden. e-mail: josefin@presscise.com conflict of interest: two of the authors have commercial interest to declare. josefin damm and torbjörn lundh are co-inventors of the patches. the authors are also co-founders of the start-up company presscise ab. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright j. damm et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6627 doi:10.4081/vl.2017.6627 figure 1. pressure measurements on b1, in supine (resting) and standing position with the bandage providing 20 mmhg and 30 mmhg (baseline) and pressure measurements in supine and standing position with the patches added over the bandage (patches). (n=18). no n c om me rci al us e o nly conference presentation [veins and lymphatics 2017; 6:6627] [page 11] each morning, however, maintained the working pressure level over seven days. conclusions the presented device is of considerable practical interest in order to achieve a quantified compression treatment. it may also be especially essential for those patients who should have a low controlled resting pressure, as e.g. patients with mixed arterial venous disease and for whom hemodynamically active pressures are desirable as soon the patient is active. the easy way to maintain the pessure level over time may also be of great benefit for self-management. references 1. moffatt cj, franks pj, doherty dc, et al. psychological factors in leg ulceration: a case-control study. br j dermatol 2009;161:750-6. 2. partsch h. understanding the pathophysiology of compression. understanding compression therapy: ewma position document; 2003. 3. o’meara s, cullum n, nelson ea, dumville jc. compression for venous leg ulcers. cochrane database syst rev 2012;11:cd000265. 4. partsch h, clark m, bassez s, et al. measurement of lower leg compression in vivo: recommendations for the performance of measurements of interface pressure and stiffness. dermatol surg 2006;32:224-33. 5. protz k, heyer k, dörler m, et al. compression therapy: scientific background and practical applications. j dtsch dermatol ges 2014;12:794-801. 6. protz k, heyer k, verheyen-cronau i, augustin m. loss of interface pressure in various compression bandage systems over seven days. dermatology 2014. figure 2. pressure measurement over seven days, on one subject. correction of the front patch (fixpatch™) was done daily, before bed rise no n c om me rci al us e o nly hrev_master veins and lymphatics 2016; volume 5:5979 [veins and lymphatics 2016; 5:5979] [page 1] cinderella indications for compression therapy giovanni mosti,1 hugo partsch2 1angiology department, barbantini clinic, lucca, italy; 2department of dermatology and angiology, medical university of vienna, vienna, austria cinderella is the poor, underestimated girl in the fairy tale whose beauty stays unrecognized till the time when a clever prince discovers her. there are many indications for compression therapy outside the phlebo-lymhological area. they are also forgotten, underestimated and unrecognized but deserve to be newly discovered. this may also shed light on our principle to understand the mechanisms of action and exceed our conventional hemodynamic ideas about how compression works. the tradition of compression, which is one of the oldest management procedures in medicine, dates back thousands of years and is obviously based on the experience that applying pressure to a painful part of the body helps in relieving symptoms. already prehistoric rock paintings show the simplest form of compressive hands but also of bandages applied to the extremities, obviously used after trauma and bleeding.1 this demonstrates that traumatic lesions were much more frequent and important for the ancient healers than our present phlebo-lymphological indications. the present issue basically contains the collection of extended abstracts presented at the annual scientific meeting of the international compression club (icc), held in bari (italy) on october 2015. the first three presentations deal with the effects of compression on inflammatory symptoms. after a general introduction by ligi et al.,2 valentina dini reports her positive experience in treatment of different kind of vasculitis by compression therapy.3 alberto macciò underlines the anti-inflammatory effect of compression in dermato-lymphangio-adenits commonly named erysipelas or cellulitis. this condition is usually considered a contraindication for compression, while with his presentation alberto macciò demonstrates that, thoroughly applied zinc paste, bandages are very effective in reducing inflammation and painful swelling.4 mieke flour presents a series of completely unusual indications both on polytrauma patients and endocrinopaties including myxedema and diabetes mellitus.5 again, flour et al.6 present interesting data on another very unusual indication represented by burns and scars. venous leg ulcers are the classical indication for compression treatment. less known is the fact that wounds of the leg due to other pathologies respond also quite nicely to good compression. this is shown by enzo fracchia7 for hematological ulcers, by giovanni mosti,8 for mixed, arterial-venous ulcers, by patricia senet,9 for the hypertensive ulcer and by rolf jelnes,10 for posttraumatic ulcers. oscar maleti refers his positive experience in applying compression to the leg after venous hervesting for aorto-coronary by-pass.11 brorson et al.,12 pioneer in reducing lymphoedema by liposuction show in their very practice-orientated presentation that additional compression is indispensable before and after surgery. hugo partsch emphasizes the importance of compression therapy in deep vein thrombosis and in prevention of post-thrombotic syndrome despite of some recent papers with negative report on this topic.13 compression seems to have positive effects also in healthy people practicing sports. these aspects are underlined in the paragraphs by jean patrick benigni14 and helmut lötzerich.15 finally, bender and co-authors present interesting data on a completely obscure indication for compression represented by the restless leg syndrome.16 it seems very clear from all the following reports that what was considered a cinderella indication or even a contraindication for compression therapy is actually a true indication. references 1. gardon-mollard c. 10.000 years of history of medical support bandaging. paris: elsevier masson; 2011. 2. ligi d, croce l, mannello f. inflammation and compression: the state of art. veins and lymphatics 2016;5:5980. 3. dini v. compression in vasculitis. veins and lymphatics 2016;5:5981. 4. macciò a. compression in dermato-lymphangio-adenits. veins and lymphatics 2016;5:5982. 5. flour m. compression treatment following polytrauma and in endocrinopathies. veins and lymphatics 2016;5:5983. 6. flour m, anthonissen m, van den kerckhove e. pressure therapy for postburn scars: does it work? veins and lymphatics 2016;5:5984. 7. fracchia e, cantello c, gori a, et al. ulcers in congenital anemia. veins and lymphatics 2016;5:5985. 8. mosti g. compression in mixed ulcers. veins and lymphatics 2016;5:5986. 9. senet p. compression in hypertensive leg ulcer (martorell’s ulcer). veins and lymphatics 2016;5:5987. 10. jelnes r. compression after trauma. veins and lymphatics 2016;5:5988. 11. maleti o. compression after vein harvesting for coronary bypass. veins and lymphatics 2016;5:5989. 12. brorson h, svensson b, ohlin k. role of compression after liposuction. veins and lymphatics 2016;5:5990. 13. partsch h. compression and deep vein thrombosis. veins and lymphatics 2016;5:5991. 14. benigni jp. compression and sports. veins and lymphatics 2016;5:5992. 15. lötzerich h. effects of compression on performance and regeneration. veins and lymphatics 2016;5:5993. 16. bender d, kuhn pj, olson dj, sullivan jp. adjustable topical compression foot wrap, is more effective than a dopamine agonist, ropinirole, in reducing the symptoms of moderate to severe restless leg syndrome. veins and lymphatics 2016;5:5994. correspondence: giovanni mosti, angiology department, barbantini clinic, via del calcio, 55100 lucca, italy. e-mail: giovanni.mosti10@gmail.com this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright g. mosti, 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5979 doi:10.4081/vl.2016.5979 no n c om me rci al us e o nly hrev_master veins and lymphatics 2016; volume 5:5687 [page 28] [veins and lymphatics 2016; 5:5687] bridging the gap between chronic cerebrospinal venous insufficiency and ménière disease dario c. alpini,1 pietro m. bavera,2 federica di berardino,3 stefania barozzi,1 piero cecconi,4 mario farabola,4 valentina mattei,1 laura mendozzi,5 luigi pugnetti,6 antonio cesarani4 1ear nose throat-otoneurology service, irccs s. maria nascente don carlo gnocchi foundation, milano; 2vascular imaging diagnostician for medick-up vascular lab, milano; 3department of clinical and community sciences, university of milan and audiology unit, irccs foundation, ca’ granda ospedale maggiore policlinico, milano; 4neuro-radiology, irccs s. maria nascente don carlo gnocchi foundation, milano; 5department of neurologymultiple sclerosis, irccs s. maria nascente don carlo gnocchi foundation, milano; 6neurophysiology service, irccs s. maria nascente don carlo gnocchi foundation, milano, italy abstract ménière disease (md) is a chronic illness of the inner ear that affects a substantial number of patients every year worldwide. because of a dearth of well-controlled studies, the medical and surgical management of md remains quite empirical. the main reason is that it is very difficult to investigate patients affected with certain md due to the post-mortem criterion necessary for this diagnostic grade. although endolymphatic hydrops (eh) is the worldwideaccepted mechanism of md, the causes that induce it are still not clear. in fact md has been correlated mostly to a wide and different disturbances ranging from trauma to sleep disorders. it is nowadays sufficiently demonstrated that chronic cerebrospinal venous insufficiency (ccsvi) is very frequent in md. even if ccsvi may potentially induce eh through a pure hydraulic mechanism ccsvi, per se does not explain how the various disorders correlated with md may interact with ccsvi and provoke eh. the aim of this review is an attempt to approach md into the context of the more recent findings about the global brain waste clearance system, to which inner ear is anatomically and functionally connected, in order to build a reasonable model of md pathogenesis. the major part of the diseases correlated to md may act on the inner ear disturbing the glymphatic (gs) and/or brain lymphatic system (bls) activity. the venous system interplays with gs and bls. in this model ccsvi is considered more than a direct cause of md rather the anatomical predisposition to develop the disease. in this model eh, and then md, is the consequence of a failure of the compensation of the congenital venous abnormalities, anatomical compensation as collateral pathways and/or functional compensation as gs and bls. in this model the major part of the disturbances correlated to md and the various treatment proposed find their appropriate placement. introduction ménière’s disease (md) is a chronic illness of the inner ear that affects a substantial number of patients every year worldwide. in europe the incidence is about 50-200/100,000 a year.1 the disease is characterized by intermittent episodes of vertigo lasting from minutes to hours, with sensorineural, usually fluctuating, hearing loss, tinnitus, and aural pressure. attacks of vertigo may come on suddenly or after a short period of tinnitus or muffled hearing. inner ear diseases, including md, are usually considered as peripheral diseases but, especially for the reasons that this paper concern, it is necessary to highlight at least three aspects that oblige the clinicians, at least under the therapeutic point of view, to approach the inner ear as a central organ: inner ear structures are deeply embedded into the petrous part of the temporal bone, the unique ivory bony part of the skull: i) inner ear vascularization is provided by a long slender branch of the anterior inferior cerebellar artery (>85% cases) or basilar artery (<15% cases) through the labyrinthine artery (also named auditory artery or internal auditory artery), that accompanies the vestibulo-cochlear nerve through the internal acoustic meatus; ii) inner ear drainage is formed by the labyrinthine veins that accompany the branches of auditory artery from the vestibule and semicircular canals via the inferior petrous sinus into the internal jugular veins (ijvs). md may be classified according to the worldwide still accepted guide-lines published in 1995 by the committee on hearing and equilibrium of the american academy of otology head and neck surgery, into different grades of certainty (table 1).2 because of a dearth of well-controlled studies, the medical and surgical management of md remains quite empirical. the main reason is that it is very difficult to investigate patients affected with certain md due to the postmortem criterion necessary for this diagnostic grade. therefore every research is substantially conducted on patients with a lower diagnostic grade due to the impossibility to conduct control studies on certain md. every research on md is thus conditioned by this bias. for this reason, in our opinion, every research substantially has to be considered as a high level speculation with a reasonable certainty grade. the aim of this paper is an attempt to approach md into the context of the more recent findings about the global brain waste clearance system to which inner ear is anatomically and functionally connected in order to build a reasonable model of md pathogenesis. ménière disease and chronic cerebrospinal venous insufficiency md is substantially characterized by three symptoms, vertigo, hearing loss and tinnitus, it is generally correlated to a lot of causes and it is sustained by only one worldwide accepted correspondence: dario carlo alpini, ear nose throat-otoneurology service, irccs s. maria nascente don carlo gnocchi foundation, vertigo school, via lomellina 58, 20133 milano, italy. e-mail: dario.alpini@fastwebnet.it key words: ménière disease; chronic cerebrospinal venous insufficiency; glymphatic system; brain lymphatic system; hearing loss; multiple sclerosis; jugular veins; vertigo. conflict of interest: the authors declare no potential conflict of interest. contributions: dca and pmb conceived and designed the paper; sb and vm selected the appropriate definite md patients; fdb analyzed the data regarding md patients; dca and ac drafted the article; pc and mf analyzed the data regarding mri in md patients; lm and lp critically revised the paper for important intellectual content. paper partially presented at 35th congress of società italiana audiologia e foniatria (siaf, italian society of audiology and phoniatry), milano, italy, december 16th 2015. poster presented at 6th annual isnvd meeting, new york city, usa, april 29th 2016. received for publication: 15 december 2015. revision received: 10 may 2016. accepted for publication: 11 may 2016. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright d.c. alpini et al., 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5687 doi:10.4081/vl.2016.5687 no n c om me rci al us e o nly review [veins and lymphatics 2016; 5:5687] [page 29] hydraulic pathogenetic mechanism: the endolymphatic hydrops (eh). paparella3 used the notion of lake-river-pond to explain the occurrence of malabsorption of endolymph leading to hydrops. this notion describes the endolymphatic sac (es) as a pond, with the vestibular aqueduct (the river) connecting it to the endolymphatic fluid space that is like a lake. when there is an obstruction near the es or duct, a backlog of endolymphatic fluid is created, leading to hydrops. the causes of this kind of malabsorption of endolymph leading to hydrops are still debated. at the beginning of our personal experiences on chronic cerebrospinal venous insufficiency (ccsvi) we observed, quite incidentally, a possible correlation between ccsvi and inner ear disorders.4 in fact, comparing echocolor doppler (ecd) findings in multiple sclerosis (ms) and in a controlled group of patients affected with different disorders we found only three controls out of sixty showing venous flow abnormalities: all of them had been affected by sudden hearing loss. thus, we begun to extensively investigate ccsvi in a large sample of subjects affected with audiovestibular disorders, including md. in 2013 alpini and colleagues described a patient affected with5 bilateral ccsvi and bilateral sudden sensorineural hearing loss (sshl). in 2013 alpini and colleagues6 compared ecd arterial and venous tests in patients affected with cochleo-vestibular disturbances subdivided into three groups: definite unilateral md, non-md cochleo-vestibular impairment and patients affected with benign paroxysmal positioning vertigo with cochlear hearing loss. this paper showed that asymmetrical venous flow was more frequent in md patients than in others. successively di berardino and colleagues7 investigated ccsvi in md using both ecd and magnetic resonance imaging (mri) confirming the high correlation between ccsvi and md. this correlation is further supported by filipo and colleagues.8 bruno and colleagues9 performed percutaneous transluminal angioplasty (pta) in 20 md ccsvi-positive patients obtaining at six-months follow-up significant improvement of symptoms (hearing loss and acute vertigo spells) in 19. in 2015 bavera and colleagues presented at the 5th isnvd annual meeting in naples a comparison of ccsvi characteristics into three groups of patients: md, ms and other non-md cochleo-vestibular disturbances. incidence of ccsvi in md and ms was, as expected, high, according to previous literature findings.10 comparing ccsvi findings in ms vs md, the authors showed that the level of venous abnormalities was different: j1 in ms and j3 in md (figure 1). venous alterations are differently distributed according to the kind of disease. distribution is expressed in % of abnormal examinations. j3i is the most involved level in md (27 definite ménière patients); j1 is the most involved level in ms (70 clinically definite patients); in the group other vestibular disorders (51 patients) venous alterations are rare but j3 is still the most represented level. this figure has been redrawn from that presented by bavera and colleagues at the 5th isnvd meeting. also filipo and colleagues8 observed that md patients showed the prevalence of proximal venous abnormalities with 76% of unidirectional venous return in the petrosal sinuses. petrosal sinuses are directly involved in the drainage of the inner ear. in 2016 vannini and colleagues at the 6th isnvd meeting11 presented a comparison between sshl and md patients regarding presence and characteristics of ijvs valves showing substantial differences in the two groups confirming, in this way, a certain disease-specificity of ccsvi. hence, it seems nowadays reasonable to state that ccsvi may be the anatomical background to develop eh in md, at least in definite and probable md patients. model of brain circulation in chronic cerebrospinal venous insufficiency and its correlation with ménière disease the mechanism leading from ccsvi to md is still debated. both di berardino and colleagues7 and filipo and colleagues8 proposed a hydraulic disorder, or venous vasculitis or the microangiopathic changes usually associated with chronic venous insufficiency. the blood-labyrinth barrier is impaired in association with the eh.12 the luminal compartment of the inner ear, the endolymphatic space, is separated by the abluminal compartment, the perilymphatic space, by highly specialized epithelial cells with tight junctions. the endolymphatic space contains luminal fluid with high potassium (k+) concentration and low sodium (na+) concentration, which provides the ionic milieu needed to sustain transduction of sound and head acceleration into viii cranial nerve impulses. the fluid volume within the bony labyrinth remains constant. changes in the volumes of the endolymphatic and perilymphatic compartments are responses to osmotic gradients between the compartments themselves.13 perilymph is connected fairly directly to spinal fluid pathways via the cochlear canaliculus. when spinal fluid pressure changes, perilymph pressure changes within about 10 s. the composition of endolymph is maintained by stria vascularis, that is the seat of k+ secretion. stria vascularis table 1. the worldwide accepted and used diagnostic ménière disease guidelines. it is interesting to highlight that the grade of certainty is established to be possible only with post mortem confirmation. the american academy of otolaryngology head and neck surgery criteria for diagnosis of ménière’s disease the definition of the disease requires the combination of 1. recurrent spontaneous and episodic vertigo. a definitive spell of vertigo lasting at least 20 min, often prostrating, accompanied by disequilibrium that can last several days; usually nausea or vomiting, or both; no loss of consciousness. horizontal rotatory nystagmus is always present 2. hearing loss (not necessarily fluctuating) 3. either aural fullness or tinnitus, or both the classification of the disease is graded as follows certain ménière’s disease definite disease plus post mortem confirmation definite ménière’s disease two or more definitive episodes of vertigo plus audiometrically confirmed sensorineural hearing loss, plus tinnitus, aural fullness, or both probable ménière’s disease one definitive episode of vertigo plus audiometrically confirmed sensorineural hearing loss plus tinnitus, aural fullness, or both; other causes excluded possible ménière’s disease episodes of vertigo with no associated hearing loss or hearing loss with non-definitive disequilibrium; other causes excluded no n c om me rci al us e o nly review is densely vascularized compared with the avascular reissner’s membrane and singlevessel metabolic supply of the outer sulcus. reissner’s membrane is thought to be primarily responsible for na+ homeostasis of cochlear endolymph. outer sulcus epithelium is located in the lateral cochlear wall, it is capable of absorbing na+ and provides a parasensory shunt for k+ efflux.14 endolymph is coupled more indirectly to cerebrospinal fluid (csf) pressure and air pressure, through membranes. one pathway is via the endolymphatic duct, to the sac, and the dural membrane. another is via the membranes that separate the endolymphatic and perilymphatic compartments. normally, there is little flow of endolymph either radially or longitudinally. if endolymphatic volume becomes excessive it is reabsorbed back into the stria vascularis by means of radial flow. when there is a largest volume increase endolymph move longitudinally into the es. the es is a blind pouch, its epithelial cells consist primarily of two types: mitochondria-rich cells and ribosome-rich cells but little is known about the ion transport properties of each cell type. es is placed on the posterior surface of the petrous portion of the temporal bone, where it is in contact with the dura mater and perform both absorptive and secretory, as well as phagocytic and immunodefensive, functions. in this way the underlying mechanism of eh is still debated, with some researches in favor of a purely hydraulic mechanism and others hypothesizing a control mechanism of ionic balance. hydraulic hypothesis supports es surgery, while control hypothesis pharmacologic treatments. on the other hand, several studies analyzing the temporal bone anatomy in md patients have found consistent alterations in the arrangement of the sigmoid sinus, anteriorly or medially displaced, and jugular bulb abnormalities (jba).15 for these reason sac-vein decompression16 seems to be more effective that sac decompression alone. if the role of intracranial veins in causing abnormalities of inner ear metabolism and then labyrinth function is easy to understand, more difficult is to correlate alterations of neck vein structures on cerebral venous hemodynamics. müller and toro17 described a mathematical model for the cardiovascular system in order to describe the complex interaction between intracranial pressure and cerebral vasculature and the starling-resistor like behavior of the intracranial veins. the cranial cavity is a space of fixed volume containing parenchyma, the brain, and fluids, csf and blood, fluids functionally connected: variations in intracranial blood volume produce fluctuations of intracranial pressure and, consequently, exchange of csf between the intracranial and spinal subarachnoid spaces. in this way18 blood volume may regulate glimphatic system.19 furthermore, variations in intracranial blood volume20 may potentially influence on brain lymphatic system.21 intracranial veins are flexible tubes that drain into the various dural sinuses, located in the dura madre and therefore more rigid than cerebral veins. starling resistor is a an experimental device in which a collapsible tube, like an intracranial vein or ijv, is connected to two rigid tubes, like the dural sinuses, at its extremities and located in a chamber of fixed volume with variable ambient pressure, like the cranial cavity. the pressure difference that regulate cerebral blood flow (cbf) both to feed brain parechima and to drain waste products of the brain parenchima metabolism, is depending on the difference between arterial and intracranial pressure, so called cerebral perfusion pressure. cbf is considered as a flow phenomenon governed by a sterling resistor.18 csf filtration from the subarchnoid space towards the dural sinuses varies linearly with the difference between intracranial pressure and superior sagittal sinus pressure. the model proposed by the authors indicates that the leading mechanism of starlingresistor like behavior of intracranial veins is at the point where they join dural sinuses. structural, like jba, or functional, like in ccsvi, abnormalities of the cervico-cephalic veins may impair drainage of the inferior petrosal sinuses through increased pressure or blood reflux into the sinuses.8 in this way, labyrinth drainage into the petrosal sinuses through endolymphatic radial flow, by means of the cochlear and the vestibular aqueduct veins, and longitudinal flow, by means of es, is impaired. these phenomena increase inner ear pressure, leading to eh, and/or induce alteration in k+/na+ balance in the inner ear fluids, provoking md attacks. furthermore, since many of the venous vessels in the scala tympani have little or no bony covering and are essentially exposed to the perilymphatic space,22 the venous system cold become a route of entry for the cells participating in the inner ear inflammatory process especially if slowing or refluxing of venous flow as observed in ccsvi, prolong the persistence of toxins, autoantibodies or pathogens into the inner ear like viruses23-25 free radicals26 and cochlear autoantibodies, like hsp 70.27 md has been correlated also to migraine28,29 but ccsvi has been described also in chronic migraine patients.30 since, generally speaking, venous flow may be depending also on global circulating blood volume, it is possible that hyperidric diet31 frequently proposed to md patients, may act directly facilitating braininner ear venous drainage. some aspects of md may be explained also without considering ccsvi. for example, lifestyle changes and hypertension32 treatment, including salt restriction,33 one of the most popular treatment regimen in md and continuous positive airway pressure in obstructive figure 1. distribution of levels of detected venous abnormalities in three groups of patients. md, ménière disease; ms, multiple sclerosis; ovd, other vestibular disorders. figure 2. distribution of side of ménière disease (md) in relation with gender. [page 30] [veins and lymphatics 2016; 5:5687] no n c om me rci al us e o nly review [veins and lymphatics 2016; 5:5687] [page 31] sleep apnea syndrome (osas),34 may act directly on inner ear vascularization35 and therefore on endolymph production, frank hypoglycemia36 and hyperinsulinemia, rather than diabetes,37-39 it is known to alter na+/k+ inner ear pump, the same pump on which is supposed acts proton pump inhibitors.40 since md has been correlated mostly to a wide and different diseases and treatments in addition to those mentioned above,41 ccsvi may be considered more than a cause of md per se, rather the anatomical predisposition to develop the disease. the role of ijvs in md has been extensively investigated and ijvs abnormalities are substantially considered the main alteration that may condition the onset of the disease. on the other hand, ijv it is known to be main route of venous drainage when supine. the extracranial venous circulation is strongly influenced by posture as demonstrated by gadda and colleagues42 that correlated, in a simulated model, the cross-sectional area and the perimeter of joint vibration analysis during the cardiac cycle. authors showed that ijv is completely distended in supine position and collapsed when standing. in both postures vertebral veins drain the brain, in general, and, particularly, the brainstem and the cerebellum. a retrospective review of mri performed in the md patients that we studied for the previous paper on ccsvi in md,6,7,10 showed compensatory hypertrophy of vertebral plexus or vertebral veins or both in all the patients that presented ijvs abnormalities. the complex connection between the inner ear and the neck43 support the idea that a disturbed labyrinth leads to a disturbance of headto-neck position control and neck function increasing drainage difficulties through deep cervical muscles compression of the vertebral plexus. furthermore, the idea that ijvs do not compensate primarily impaired vertebral drainage dysfunction had to be taken in account. mülle and toro observed17 flow distribution asymmetry between right and left transverse sinuses and, consequently, between left and right ijv. it is interesting to note that simka and colleagues44 showed that in ms venous malformations were more commonly found on the left side. the prevalence of left internal jugular vein malformations was 81.7% vs 64.0% on the right side. similarly, blockages were found only in the left and not in the right brachiocephalic vein. same findings in ms have been recently reported by bavera.45 herman,46 in 1993 reported predominance of left ear in md, sudden deafness, and inner ear damage. successively, in 2014 reiss and reiss47 confirmed the prevalence of left sshl at least in females. we conducted a retrospective evaluation of 135 patients (mean age 43±6 years) affected with definite unilateral md. md affected the right side in 57 and the left side in 78 with the slight left expected prevalence (57%). but, right md regarded 29 females (51%) while left md regarded only 17 males with a prevalence of 78% of females (figure 2). in our experience the correlation between the md side and prevalent venous abnormalities side is 87%. therefore, our experience confirms the left prevalence either of ccsvi or md. ccsvi is considered to be a congenital venous malformation. in adults, the ijvs that drain the brain develops from precardinal veins in the embryo.48 these precardinal veins mostly join the common cardinal veins, in the area where, in an adult, the jugular valve is found. as stated by simka and colleagues44 it is plausible to imagine that this process could not always be perfect, especially on the left side, where part of the left common cardinal vein naturally involutes. even the left prevalence is not so high as in ms this fact is at least intriguing. left md present a slight prevalence (57%) but it is to highlight that the distribution of females is highly prevalent in left md while in right md genders are equally represented. however, despite the side, md has been correlated to a very wide range of very different disorders: herpetic neuropathy,25 autoimmune not cochlear pathologies,49,50 metabolic disorders,37 sleep disorders,51 water/salt imbalance,52 cervical disorders,53 allergies54 and food intolerance with special regard to gluten sensitivity.55,56 subject to the foregoing, it is our opinion that there is a gap between the so wide and so different disturbances connected to md and a unique specific pathogenetic mechanism (eh). the stagnation per se due to jugular stenosis and/or intratemporal reflux or persistence of pathogens into the inner ear veins precisely due to venous stagnation does not seems to us enough. bearing in mind the venous cervico-cephalic drainage system into the context of the most complex waste brain clearance apparatus, constituted also by the glymphatic and the lymphatic systems, may bridge this gap. ménière disease, chronic cerebrospinal venous insufficiency and glymphatic system the veins of the vestibule and semicircular canals accompany the arteries, and, receiving those of the cochlea at the base of the modiolus, join to form the internal auditory veins (or veins of labyrinth) which end in the posterior part of the superior petrosal sinus or in the transverse sinus. the common modiolar vein enters the bony channel immediately adjacent to the aqueduct to become the vein of the cochlear aqueduct, which in turn drains via the inferior petrous sinus into the ijvs. the cochlear aqueduct and the internal auditory canal communicate with the subarachnoid space57 from where the csf is driven into the virchow-robin spaces by a combination of arterial pulsatility, respiration, slow vasomotion and csf pressure gradients.58 the forces that drives csf towards brain parenchyma are the same that regulates venous cervico-cephalic drainage.59 as it is known, the clearance system that utilizes perivascular tunnels formed by astroglial cells is the glymphatic system (gs).19 consequently, due to the anatomy of its structures, the inner ear is therefore connected both to the cervico-cephalic venous system and the gs. the gs also facilitates brain-wide distribution of glucose, amino acids, lipids and neuromodulators.60 in the same way, through the internal auditory canal, the same substance may reach the perilymphatic space. acetazolamide, an inhibitor of carbonic anhydrases, is widely used in the treatment of md61 to reduce eh. however, acetazolamide is known to have a strong effect in reducing csf formation. we think that the connection between inner ear and gs may explain the therapeutic effects of acetazolamide in md: the reduction of csf may induce a retrieval of perilymph reducing inner ear pressure. the csf movement into the parenchyma drives convective interstitial fluid fluxes within the tissue towards the perivenous spaces surrounding the large deep veins. the interstitial fluid is collected in the perivenous space from where it drains out of the brain towards the cervical lymphatic system. gs functions mainly during sleep and it is largely disengaged during wakefulness.62 nakayama and colleagues51 found in 35 definite md that total sleeping time was significantly higher than in controls. nevertheless, they also showed, for the first time, a poor quality of sleep with decreased deep sleep and an elevated arousal index. yet, major sleep disorders like osas were rare and not md specific: 4 cases in md group and 3 in controls. hence, it is unlikely that md is due to reduced brain oxygenation or vascular disturbances as observed in osas, while, in our opinion, these data support the role of a gs disturbance in md pathogenesis, at least in patients affected with a poor quality of sleep. in the same way the role of stress, that is considered as a trigger of md attacks,63,64 may be interpreted: stress increase brain levels of norepinephrine that is known to be responsible for suppression of gs.65 the supposed gs disturbance may not to be, for example, the reactive gliosis of aging because there is an inverse correlation between age and md prevalence:66 md typically starts between the ages of 20 and 50. in addition, md is not a neurodegenerative disease. consequently, the expected gs disorders are no n c om me rci al us e o nly review [page 32] [veins and lymphatics 2016; 5:5687] unlikely to be linked to glia and astrocytes. it is more reasonable the involvement of the aquaporins (aqp): they regulate the production both of csf and endolymph. aqp are membrane proteins also known as water channels that form pores in the membrane of biological cells. aqp selectively conduct water molecules in and out of the cell, while preventing the passage of ions and other solutes. some of them, known as aquaglyceroporins, also transport across the membrane other small-uncharged solutes, such as urea, co2, ammonia and glycerol, depending on the size of the pore. the so-called glycerol test (gt) is a still worldwide employed test for the diagnosis of md.67 ingestion of glycerol, 1.5 g/kg body weight, causes a transient reduction of the hearing loss in the early stage of md. in some cases improvements occur with considerable speech discrimination gain. no glycerol effect is seen in normal or cases of cochlear deafness of other types. the gt has been recently re-visited using the vestibular evoked potentials68 instead of the pure tone audiometry in order to have a more objective test. the action of glycerol is purely osmotic and the effect in md is due to a reduction of intralabyrinthine pressure by means of specific aqp. it is interesting to note though, that aqp1 is expressed both in the choroid plexuses, that produce csf, and in the stria vascularis of cochlea, that produce endolymph69 in the rats. in humans aqp1 is localized to fibrocytes and blood vessels of the underlying stroma and trabecular perilymphatic tissue:70 venous vessels are connected to the perilymphatic space, thus it is more probable that glycerol acts on endolynphatic pressure through the functional connections between venous system and gs than directly on inner ear. in hypertension, another putative cause of md32 vasopressine dysregulation71 may be claimed and the anti-diuretic hormone results to be involved both in gs72 and in eh.73 in conclusion, we can state that a defective venous system as in ccsvi interferes with regular function of gs. when another factor of gs dysfunction occurs, like stress or hypertension or sleep/awakness cycle dysregulation, inner ear may become unable to clear waste products of its metabolism either through the subarachnoid space and gs and the river-lake-pond system blocks leading to the endolymphatic hydrops. ménière disease, chronic cerebrospinal venous insufficiency and lymphatic system a true lymphatic vascular system (ls) draining brain interstitial fluids and macromolecules has been very recently described.21,74 generally speaking, ls is constituted by a network of lymphatic vessels in the dura mater of the cns that drains out of the skull via the foramina of the base of the skull itself alongside arteries (the major branches of the middle and anterior meningeal arteries and the pterygopalatine artery), cranial nerves (i, v, ix, x and xi) and veins. lymphatic vessels have been observed in the dural lining of the cribriform plate, where some vessels passe through the skull into the nasal mucosa. dura mater lymphatic vessels drains brain isf into deep cervical lymp nodes and experiments conducted in mice60 showed that impairment of ls compromises cns macromolecule clearance. as stated also by zamboni75 the interconnection of brain lymphatics with both the nasal mucosa and the deep cervical lymph-nodes allows t-cells and viruses to easily circulate into the brain and therefore in the inner ear too. in md either virus infections by herpes viruses76 or autoimmune viral activation77 or autoimmune diseases as thyroiditis78 have been considered as probable causes of the disease. the lymphatic vessels run down toward the base of the skull along the transverse sinus, the sigmoid sinus, the retrosigmoid vein and the rostral rhinal vein. the es, the pond into paparella’s model, is placed on the posterior surface of the petrous portion of the temporal bone, where is in contact with the dura mater. the endolymphatic duct and es perform absorptive and secretory, as well as phagocytic and immunodefensive functions: the es is capable of antigen recognition and processing for initiation of an immune response.79,80 reflux of venous blood flow into the petrous veins, and, as a consequence along modiolar veins, may alter the capability of the endolymphatic sac to drain via the lymphatic dura vessels with an alteration of its immunocompetence of the es inducing recurrent flogistic eh episodes.81 another group of diseases claimed as md cause are allergies, in general, food allergies, in particular. for almost a century inhalant and food allergies have been linked with md symptoms.82 the prevalence of allergy in patients with md is almost three times than in the general population.83 wheat is one of the most common food allergens found in patients with md, 68.2% according to derebery and colleagues.84 in 2010 derebery and colleagues85 defined the relation between allergy and md. in 2012 di berardino and cesarani55 confirmed the relation between immune response to the acid proteins fraction of gliadin in md and in 2013 di berardino and colleagues56 reported recovery of md after gluten-free diet. recently, di berardino and colleagues86 in a group of 116 definite md patients (52 male 49.5±12 years 63 female 49.8±13 years) showed an incidence of 96% of atopic subjects by means of an allergo-immunologic battery including skin tests (prick test, prick by prick and/or intradermo reaction) intestinal permeability test and nasal mucociliary clearance (nmc).87 in md nmc was significantly slowed. it is well known the correlation between md and nose disorders, generally read as to be sustained by eustachian tube disturbances.88 in our opinion, the correlation between nose and eh pass through the ls: slowing of nmc in atopic patients may lead to slowing of allergens clearance in cervical lymphnodes and therefore a sensitization of the inner ear that become a hypersensitive target of the immune response to antigens.89,90 venous disturbances may hamper inner ear lymphatic drainage through the perivenous lymphatic vessels. the putative correlation between cervico-cephalic venous regulation and nasal function may be sustained because the nose is not only a clearance organ but also a sophisticated conditioning system of the breathed air. it regulates both humidity and temperature of the inhaled air in order to maintain enough constant the physical characteristics of the air that reach the lungs despite the environmental conditions. this conditioning is due to the regulation of blood flow of the like-erectile tissue contained into each turbinate (three each side). as in corpus cavernosum, swelling of turbinate depends on arterial inflow and venous outflow. congestion of the nose is also linked to body position, to be maximum on the side on which the subject is lying, head angle with respect to the trunk when supine, to be maximum when it is lower than 20°, and eventual pressure exerted on axillar vein with swelling of the same side.91 lifting the head more than 20° when sleeping on one hand facilitate nasal patency, on the other hand, it is usually suggested to a patient affected with ccsvi (so called inclined-bedtherapy). furthermore, eustachian tube exercises using a small balloon to be inflate using the nose is usually suggested in md patients in order to relieve aural fullness: this is nothing but repeated valsalva maneuver that de facto facilitates venous drainage from the brain to the thorax. in conclusion, we can state that a defective venous system as in ccsvi interferes with regular function of ls. when another factor of ls dysfunction occurs, like virus infections or allergic reactions or autoimmune diseases, es may become unable to clear throughout the lymphatic vessels, the river-lake-pond system blocks leading to the inflammatory eh. bridging the gap the presence of venous disturbances in a high percentage of patients affected with definite md has been established. these abnorno n c om me rci al us e o nly review [veins and lymphatics 2016; 5:5687] [page 33] malities seem to be disease specific due to the specific anatomic11 and functional7,8 findings observed. furthermore, it seems that venous disturbances are also and organ specific interpreting bavera and colleagues10 experience that, although the number of positive cases was very low, found j3 as the most represented dysfunctional level also in non-md vestibular diseases. obviously, this last observation needs to be confirmed in a largest number of patients. this paper represents a putative model of interpreting the effects of ccsvi on inner ear under the light of brain gs and lf. from an epistemological point of view, a theory is a series of logical steps that are as valid as they are true while a model, the form of presentation we have chosen, is a series of logical steps as valid as useful. the helpfulness of our model is to allocate the various disorders and pathologies considered to be involved in md in a logic and unitary explanation and, consequently, to facilitate therapeutic planning. ccsvi may lead to endolymphatic hydrops through a pure hydraulic mechanism and therefore both an accurate case history and a complete evaluation of the patient are necessary in order to identify which compensatory circuits have been blocked to cause failure of compensation of the congenital abnormalities. on the basis of the literature we think that the most probable blocked circuits in md are the vertebral plexus,92 the thyroid veins78 and the anterior condylar confluent.93,94 failure of compensation may regards also the gs and/or the ls. again, an accurate case history and a complete evaluation of the patient are necessary in order to identify why gs and/or ls are not able to compensate the venous clearance. on the basis of the literature we think that the most probable causes of a blocked gs in md are sleep disorders, stress,95 nicotine95 and excitants abuse96 water/salt balance dysregulation,97 intestinal disorders.98 on the basis of the literature we think that the most probable causes of a blocked ls in md are virus infections,99 viral reactivations,100 activation of viral inner ear epitopes,101 systemic autoimmune diseases,102 middle ear diseases,103-105 allergies,106 nasal disturbances,107 food intolerances.108 in conclusion, md therapy requires accurate identification and treatment of each structural, metabolic ear, nose, throat and general diseases of the specific patient according to a model that we can define as a glocal model of ménière disease. this glocal model suggest to subdivide md in two main groups: i) structural md, in which a structural jba may directly act impairing inner ear metabolism; ii) combined md, in which two out of three brain drainage systems are impaired or compensatory venous pathways are impaired in ccsvi-positive md patients. considering that pta induces immediately a significant relief of symptoms in ms patients but requires at least three months109 to obtain hearing improvement and vertigo attacks reduction in md patients, further researches on the correlation between ccsvi and md had to taken in account the possible causative role of the vertebral veins per se on inner ear disorders. references 1. james a, thorp m. ménière disease. bmj clin evid 2007;2007. 2. committee on hearing and equilibrium. guidelines for the diagnosis and evaluation of therapy in ménière’s disease. american academy of otolaryngology-head and neck foundation, inc. otolaryngol head neck surg 1995;113:181-7. 3. paparella mm. the cause (multifactorial inheritance) and pathogenesis (endolymphatic malabsorption) of ménière’s disease and its symptoms (mechanical and chemical). acta otolaryngol 1985;99:445-51. 4. bavera pm, agus gb, alpini d, et al. results from 823 consecutive duplex exams for ccsvi in a vascular centre. acta phlebol 2012;13:141-6. 5. alpini d, bavera pm, di berardino f, et al. bilateral sudden sensorineural hearing loss and chronic venous cerebrospinal insufficiency: a case report. phlebology 2013;28:231-3. 6. alpini d, bavera pm, hahn a, mattei v. chronic venous cerebrospinal insufficiency (ccsvi) in ménière disease. case or cause? science med 2013;4:9-12. 7. di berardino f, alpini dc, bavera pm, et al. chronic cerebrospinal venous insufficiency in ménière disease. phlebology 2015;30:274-9. 8. filipo r, ciciarello f, attanasio g, et al. chronic cerebrospinal venous insufficiency in patients with ménière’s disease. eur arch otorhinolaryngol 2015;272:77-82. 9. bruno a, califano l, mastrangelo d, et al. chronic cerebrospinal venous insufficiency in ménière disease: diagnosis and treatment. veins and lymphatics 2014; 3:77-80. 10. bavera pm, cecconi p, alpini d, di berardino f. venous abnormalities in ménière disease. veins lymphat 2015;4:7. 11. vannini me, menegatti e, tessari m, et al. high resolution m-mode characterization of jugular veins valves in healthy volunteers and in patients with neurological disorders. proc. 6th annual isnvd meeting, 2016 apr 29, new york, ny, usa. 12. tagaya m, yamazaki m, teranishi m, et al. endolymphatic hydrops and bloodlabyrinth barrier in ménière’s disease. acta otolaryngol 2011;131:474-9. 13. merchant sn, adams jc, nadol jb jr. patophysiology of ménière syndrome: are symptoms caused by endolymphatic hydrops? otol neurotol 2005;26:74-81. 14. kim su, marcus dc. regulation of sodium transport in the inner ear. hear res 2011;280:21-9. 15. redfern re, brown m, benson ag. high jugular bulb in a cohort of patients with definite ménière’s disease. j laryngol otol 2014;128:759-64. 16. gianoli gj, larouere mj, kartush jm. sacvein decompression for intractable ménière’s disease: two-year treatment results. otolarygol head neck surg 1998; 118:22-9. 17. müller lo, toro ef. enhanced global mathematical model for studying cerebral venous blood flow. j biomech 2014;17: 3361-72. 18. toro ef, zhang q, contarino c. progress towards a global circulation mathematical model, incorporating detailed csf and lymphatics dynamics. proc. 6th isnvd annual meeting, 2016 april 30, new york, ny, usa. 19. jessen na, finmann munk as, lundgaard i, nedeergaard m. the glymphatic sistem: a beginner’s guide. neurochem res 2015;40:2583-99. 20. contarino c, toro ef. a first step towards a mathematical model for the human lymphatic system. proc. 6th isnvd annual meeting, 2016 april 30, new york, ny, usa. 21. louveau a, smirnov i, keyes tj, et al. structural and functional features of central nervous system lymphatic vessels. nature. 2015;523:337-41. 22. ciuman rr. communication routes between intracranial spaces and inner ear: function, pathophysiologic importance and relations with inner ear diseases. am j otolaryngol 2009;30:193-202. 23. vrabec jt. herpes simplex virus and ménière’s disease. laryngoscope 2003; 113:1431-8. 24. gartner m, bossart w, linder t. herpes virus and ménière’s disease. orl j otorhinolaryngol relat spec 2008;70:28-31. 25. gacek rr. ménière’s disease is a viral neuropathy. orl j otorhinolaryngol relat spec 2009;71:78-86. 26. raponi g, alpini d, volontè s, et al. the role of free radicals and plasmatic antioxidant in ménière’s syndrome. int tinnitus j 2003;9:104-8. 27. di berardino f, cesarani a, hahn a, alpini d. viral infection and serum antibodies to heat shock protein 70 in the acute phase of ménière’s disease. int tinnitus j 2007; 13:90-3. 28. rassekh ch, harker la. the prevalence of migraine in ménière’s disease. laryngoscope 1992;102:135-8. no n c om me rci al us e o nly review [page 34] [veins and lymphatics 2016; 5:5687] 29. ibekwe ts, fasunla ja, ibekwe pu, et al. migraine and ménière’s disease: two different phenomena with frequently observed concomitant occurrences. j natl med assoc 2008;100:334-8. 30. koerte ik, schankin cj, immler s, et al. altered cerebrovenous drainage in patients with migraine as assessed by phase-contrast magnetic resonance imaging. invest radiol 2011;46:434-40. 31. sammartano am, cassandro c, giordano p, et al. medical therapy in ménière’s disease. audiol med 2012;10:171-7. 32. warninghoff jc, bayer o, ferrari u, straube a. co-morbidities of vertiginous diseases. bmc neurol 2009;9:29. 33. coelho dh, lalwani ak. medical management of ménière’s disease. laryngoscope 2008;118:1099-108. 34. nakayama m, masuda a, ando kb, et al. a pilot study on the efficacy of continuous positive airway pressure on the manifestations of ménière’s disease in patients with concomitant obstructive sleep apnea syndrome. jcsm 2015;11:1101-7. 35. foster ca, breeze re. the ménière attack: an ischemia/reperfusion disorder of inner ear sensory tissues. med hypotheses 2013;81:1108-15. 36. weille fl. hypoglycemia in ménière’s disease. arch otolaryngol 1968;87:555-7. 37. d’avila c, lavinsky l. glucose and insulin profiles and their correlations in ménière’s disease. int tinnitus j 2005;11: 170-6. 38. brookler kh. ménière’s syndrome, otosclerosis, and insulin resistance syndrome. ear nose throat j 2006;85:82-3. 39. lavinsky j, wolff ml, trasel ar, et al. effect of hyperinsulinism on sensorineural hearing impairment in ménière’s disease: a cohort study. otol neurotol 2014; 35:155-61. 40. pirodda a, modugno gc, mannari l, et al. ménière’s disease and the use of proton pump inhibitors. swiss med wkly 2010;140:w13104. 41. sajjadi h, paparella mm. ménière’s disease. lancet 2008;372:406-14. 42. gadda g, taibi a, sisini f, et al. a simulation model to study the role of the extracranial venous drainage pathways in intracranial hemodynamics. conf proc ieee eng med biol soc 2015;2015:7800-3. 43. franz b, altidis p, altidis b, collis-brown g. the cervicogenic otoocular syndrome: a suspected forerunner of ménière’s disease. int tinnitus j 1999;5:125-30. 44. simka m, latacz p, ludyga t, et al. prevalence of extracranial venous abnormalities: results from a sample of 586 multiple sclerosis patients. funct neurol 2011;26:197-203. 45. bavera pm. may symptoms of chronic cerebrospinal venous insufficiency be improved by venous angioplasty? an independent 4-year follow up on 366 cases. veins lymphat 2015;4:62-6. 46. heermann j. predominance of left ear in ménière’s disease, sudden deafness, inner ear damage, tinnitus and abnormally patent eustachian tube. ear nose throat j 1993;72:205-8. 47. reiss m, reiss g. laterality of sudden sensorineural hearing loss. ear nose throt j 2014;93:318-20. 48. lee bb, laredo j, neville r. embryological background of truncular venous malformation in the extracranial venous pathways as the cause of chronic cerebrospinal venous insufficiency. int angiol 2010;29: 95-108. 49. gazquez i, soto-varela a, aran i, et al. high prevalence of systemic autoimmune diseases in patients with ménière’s disease. plos one 2011;6:e26759. 50. greco a, gallo a, fusconi m, et al. ménière’s disease might be an autoimmune condition? autoimmun rev 2012; 11:731-8. 51. nakayama m, suzuki m, inagaki a, et al. impaired quality of sleep in ménière’s disease patients. j clin sleep med 2010;6: 445-9. 52. perlman hb, goldinger jm, cales jo. electrolyte studies in ménière’s disease. laryngoscope 1953;63:640-51. 53. bjorne a, berven a, agerberg g. cervical signs and symptoms in patients with ménière’s disease: a controlled study. cranio 1998;16:194-202. 54. di berardino f, barozzi s, cesarani a. allergy and ménière disease. eur ann aller clin immunol 2005;37:299-300. 55. di berardino f, cesarani a. gluten sensitivity in ménière’s disease. laryngoscope 2012;122:700-2. 56. di berardino f, filipponi e, alpini d, et al. ménière disease and gluten sensitivity: recovery after a gluten-free diet. am j otolaryngol 2013;34:355-6. 57. schuknecht hf, pathology of the ear. philadelphia, pa: lea & febiger; 1993. 58. ruız dsm, gailloud p, rufenacht da, et al. the craniocervical venous system in relation to cerebral venous drainage. ajnr am j neuroradiol 2002;23:1500-8. 59. sisini f, toro e, gambaccini m, zamboni p. the oscillating component of the internal jugular vein flow: the overlooked element of the cerebral circulation. behav neurol 2015;2015:170756. 60. yang l, kress bt, weber hj, et al. evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of csf tracer. j trans med 2013; 11:107. 61. brookes gb, hodge ra, booth jb, morrison aw. the immediate effects of acetazolamide in ménière’s disease. j laryngol otol 1982;96:57-72. 62. xie l, kang h, xu q, et al. sleep drives metabolite clearance from the adult brain. science 2013;342:373-7. 63. söderman ach, möller j, bagge sjöbäck d, et al. stress as a trigger of attacks in ménière’s disease. a case crossover study. laryngoscope 2004;114:1843-8. 64. juhn sk, li w, kim jy, et al. effect of stress-related hormones on inner ear fluid homeostasis and function. otol neurotol 1999;20:800-6. 65. berridge cw, waterhouse bd. the locuscoreleus-noradrnergic system: modulation of behavioural state and state-dependent cognitive processes. brain res rev 2003; 42:33-7. 66. tyrrell js, whinney dj, ukoumunne oc, et al. prevalence, associated factors, and comorbid conditions for ménière’s disease. ear hearing 2014;35:e162-9. 67. klockhoff i, lindblom u. glycerol test in ménière’s disease. acta otolaryngol 1966:224:449. 68. murofushi t, matsuzaki m, takegoshi h. glycerol affects vestibular evoked myogenic potentials in ménière’s disease. auris nasus larynx 2001;28:205-8. 69. sawada s, takeda t, kitano h, et al. aquaporin-1 (aqp1) is expressed in the stria vascularis of rat cochlea. hearing res 2003;181:15-9. 70. lopez ia, ishiyama g, lee m, et al. immunohistochemical localization of aquaporins in the human inner ear. cell tissue res 2007;328:453-60. 71. hoffman we, phillips mi, schmid pg, et al. antidiuretic hormone release and the pressor response to central angiotensin ii and cholinergic stimulation. neuropharmacol 1977;16:463-72. 72. thrane as, thrane vr, nedergaard m. drowning stars: reassessing the role of astrocytes in brain edema. trends neurosci 2014;37:620-8. 73. kumagami h, loewenheim h, beitz e, et al. the effect of anti-diuretic hormone on the endolymphatic sac of the inner ear. pflügers arch 1998;436:970-5. 74. aspelund a, antila s, proulx st, et al. a dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. j exp med 2015;212:991-9. 75. zamboni p. the discovery of the brain lymphatic system. veins lymphat 2015;4:58. 76. welling db, daniels rl, brainard j, et al. detection of viral dna in endolymphatic sac tissue from ménière’s disease patients. otol neurotol 1994;15:639-43. 77. arnold w, niedermeyer hp. herpes simplex virus antibodies in the perilymph of patients with ménière disease. arch otolaryngol head neck surg 1997;123:53-6. no n c om me rci al us e o nly review [veins and lymphatics 2016; 5:5687] [page 35] 78. fattori b, nacci a, dardano a, et al. possible association between thyroid autoimmunity and ménière’s disease. clin exp immunol 2008;152:28-32. 79. møller mn, kirkeby s, vikeså j, et al. gene expression demonstrates an immunological capacity of the human endolymphatic sac. laryngoscope 2015;125:e269-75. 80. harris jp. immunology of the inner ear: response of the inner ear to antigen challenge. otolaryngol head neck surg 1983;91: 18-23. 81. harris jp, fukuda s, keithley em. spiral modiolar vein: its importance in inner ear inflammation. acta otolaryngol 1990;110: 357-65. 82. duke ww. specific tests in the diagnosis of allergy. arch int med 1923;32:298-304. 83. derebery mj, berliner ki. prevalence of allergy in ménière’s disease. otolaryngol head neck surg 2000;123:69-75. 84. derebery mj. allergic management of ménière’s disease: an outcome study. otolaryngol head neck surg 2000;122: 174-82. 85. derebery mj, berliner ki. allergy and its relation to ménière’s disease. otolaryngol clin north am 2010;43:1047-58. 86. di berardino f, soi d, alpini d, et al. gluten sensitivity and ménière disease. proc. 7th symposium on ménière disease and inner ear disorders, 2015 oct, rome, italy. 87. sleigh ma, blake jr, liron n. the propulsion of mucus by cilia. am rev respir dis 1988;137:726-41. 88. hall cm, brackman de. eustachian tube blockage and ménière’s disease. arch otolaryngol 1977;103:355-7. 89. endicott jn, stucker fj. allergy in ménière’s disease related fluctuating hearing loss preliminary findings in a double�blind crossover clinical study. laryngoscope 1977;87:1650-7. 90. hsu l, zhu xn, zhao ys. immunoglobulin e and circulating immune complexes in endolymphatic hydrops. ann otol rhinol laryngol 1990;99:535-8. 91. ko jh, kuo tb, lee gs. effect of postural change on nasal airway and autonomic nervous system established by rhinomanometry and heart rate variability analysis. am j rhinol 2008;22:159-65. 92. bjorne a, berven a, agerberg g. cervical signs and symptoms in patients with ménière’s disease: a controlled study. cranio 1998;16:194-202. 93. bjorne a, agerberg g. craniomandibular disorders in patients with ménière’s disease: a controlled study. j orofac pain 1995;10:28-37. 94. bjorne a, agerberg g. symptom relief after treatment of temporomandibular and cervical spine disorders in patients with ménière’s disease: a three-year follow-up. cranio 2003;21:50-60. 95. siirala u, gelhar k. further studies on the relationship between ménière, psychosomatic constitution and stress. acta otolaryngol 1970;70:142-7. 96. ledesma all, barreto madsc, bahmad f jr. caffeine effect in vestibular system. int tinnitus j 2014;19:77-81. 97. golding-wood ph. water and salt balance in ménière’s disease. j laryngol otol 1960;74:480-8. 98. collins sm, surette m, bercik p. the interplay between the intestinal microbiota and the brain. nature rev microbiol 2012; 10:735-42. 99. arnold w, niedermeyer hp. herpes simplex virus antibodies in the perilymph of patients with ménière disease. arch otolaryngol head neck surg 1997;123:53-6. 100.gacek ra. a perspective on recurrent vertigo. orl j otorhinolaryngol relat spec 2013;75:91-8. 101.platt m, dillwall s, elackattu a, et al. mining immune epitopes in the inner ear. otolaryngol head neck surg 2014; 150:160-9. 102.gazquez i, soto-varela a, aran i, et al. high prevalence of systemic autoimmune diseases in patients with ménière’s disease. plos one 2011;6:e26759. 103.harner sg, blakey bw, blakey je. smoking and middle ear disease: are they related? a review article. otolaryngol head neck surg 1995;112:441-6. 104.nadol jb. positive hennebert’s sign in ménière’s disease. arch otolaryngol 1977;103:524-30. 105.sadé j, ar a. middle ear and auditory tube: middle ear clearance, gas exchange, and pressure regulation. otolaryngol head neck surg 1997;116:499-524. 106.endicott jn, stucker fj. allergy in ménière’s disease related fluctuating hearing loss preliminary findings in a double�blind crossover clinical study. laryngoscope 1977;87:1650-7. 107.eccles r, eccles ks. asymmetry in the autonomic nervous system with reference to the nasal cycle, migraine, anisocoria and ménière’s syndrome. rhinology 1981; 19:121-5. 108.shambaugh ge jr, wie rj. the diagnosis and evaluation of allergic disorders with food intolerance in ménière’s disease. otolaryngol clin north am 1980;13:671-9. 109.bruno a. ccsvi prevalence in ménière disease and preliminary results of balloon venous angioplasty. proc. 6th isnvd annual meeting, 2016 apr 30, new york, ny, usa. no n c om me rci al us e o nly 429 too many requests you have sent too many requests in a given amount of time. hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: the chemical mediators of some sclerotherapy complications (les médiateurs chimiques dans certaines complications de la sclérothérapie) by ferrara f, ferrara g. phlébologie 2012;65:27-31. alessandro frullini studio medico flebologico – figline valdarno florence, italy e-mail: info@venevaricose.it abstract to evaluate the chemical reaction of the venous wall to different sclerosing agents, the authors studied the level of blood histamine concentration before and 8-10 min after sclerotherapy injection into large 3-6 mm subcutaneous varices. a total of 45 sessions were studied: a solution of iodine 2% was used in 15 (group a), liquid 2% polidocanol in 15 (group b), polidocanol 0.5% foam in 15 (group c). histamine basal level was 4.49, 4.48 and 4.52 µg/100 ml, respectively, while after injection an increase was found of 4.50 (102%), 4.42 (99%) and 4.46 (100%) µg/100 ml, respectively. no significant relationship was found between agents and reactions. in c group, 2 cases had visual symptoms, both showing an 150% increase in histamine. migraine with aura seems to be associated with high hematic levels of histamine. high histamine levels caused by sclerotherapy may explain the visual symptoms frequently reported after treatments. in fact, histamine is a vessel vasoconstrictor (venous spasm) but also a small artery vasodilator (hypotension). it could, therefore, mediate these minor sclerotherapy complications. for this reason, an antihistaminic pre-medication could be justified. the recently suggested endotheline hypothesis could support this. comment by alessandro frullini this paper by francesco ferrara has clear merit in that it confirms that sclerotherapy is not simply the closure of a vein. instead, it has to be considered as a complex phenomenon in which a particular reaction is elicited in the target vein. this includes release of mediators and probably other products from the vein or from the blood inside the vein itself. furthermore, the venous spasm that sclerotherapy provokes introduces a strong variable in revealing side effects: a partial spasm means the presence of a flux in the irritated vein and this could be a key point when withdrawing mediators with consequent systemic side effects. the release of histamin after sclerotherapy is a well-known phenomenon for the experienced sclerotherapist. indeed, after sclerotherapy for teleangectasias, wheal formation is a clear sign of histamin release. dr ferrara’s demonstration and measurement of this deserves recognition. in my opinion, there is a balance between vasodilator and vasospastic mediator release after sclerotherapy. this is made more complex by the presence of receptors that act as antagonists for the same mediators; endothelin has et-a and et-b receptors with different effects. in any case, it is now clear that to explain systemic side effects of foam sclerotherapy by the presence of gas bubbles is too simplistic if not completely wrong. the dramatic onset of a neurological or visual disturbance after sclerotherapy has to be considered the epiphenomenon of a truly complex reaction between an irritant and the vein wall. this includes mediator release and can be affected by many other conditions, such as vasospasm, concomitant drug treatments, width of the treated area, etc. fully understanding this process will hopefully help us to prevent these rare but very annoying complications. [top] hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: mechanochemical tumescentless endovenous ablation: final results of the initial clinical trial by elias s, raines jk. phlebology 2012;27:67-72. stefano ricci abstract a new mechanochemical device, (clariveinw, madison, ct, usa), that does not require a generator or the use of tumescent anesthesia, was developed to achieve venous occlusion utilizing a wire rotating within the lumen of the vein at 3500 rpm that abrades the intima to allow for improve the efficacy of the sclerosant. a liquid sclerosant (sodium tetradecyl sulphate) is concomitantly infused through an opening close to the distal end of the catheter near the rotating wire. the wire tip is positioned 2 cm from the saphenofemoral junction under ultrasound guidance. with the wire rotating and during sclerosant infusion, the catheter is pulled down the vein at a rate of approximately 1–2 mm per second. catheter wire rotation is first activated for 2–3 s at the highest speed setting to create venospasm which minimizes forward flow into the common femoral vein. this is a single-use device that can be inserted through a 4 or 5 french guiding catheter with local insertion site anesthesia only, without the need for tumescence anesthesia. the system includes an infusion catheter, motor drive, stopcock and syringe. our series included 30 veins in 29 patients: 77% were in class 2 (varicose veins), 7% in class 3 (varicose veins and edema), and 16% in class 4a (varicose veins with skin changes). the sclerosant used was 1.5% liquid sodium tetradecyl sulphate (sotradecol®). for this study, all treated veins received 12 cc of 1.5% sclerosant. the average diameter of the treated gsv was 8.1 mm (range 5.5-13 mm). average treatment length was 37.5 cm (range 24-47 cm). average total procedure time was 14 min. no other concomitant procedures were performed. a compression bandage was applied to the treated limb from the foot to the groin remaining in place for 24 h. the patients then applied a 15-20 mmhg thigh-high compression stocking continuously for the next 48 h, except whilst showering. during the procedure, no patient complained of pain. three minor thigh ecchymoses were observed at levels where the rotating wire may have caught on a valve cusp or vein wall. average follow up is 260 days with only one vein recanalized, corresponding to a primary closure rate of 96.7%. no adverse events of any grade were recorded. in conclusion, mechanochemical ablation utilizing the clarivein® device has a good safety profile and appears to have good efficacy. these two modalities, mechanical and chemical, achieve venous occlusion results equal to those from endothermal methods. clariveinw comment by stefano ricci some questions have been raised by this interesting report: what is the destiny of the largely mobilized endothelium into the venous stream? when two modalities are combined, how can you say that the final result is due to the combination of the two or only to one of the methods? have you carried out a trial with abrasion alone, for example? why did you choose to use liquid sclerosant instead of foam (which has a better performance, but also better visualization on us)? did you ever observe any adverse events during initial device development? did you use animal models? could you study histological gsv evolution? what will be the average cost of the device, compared to the low costs of foam sclerotherapy? what is the appearance of the closed vein at 260 days? is there any difference between this and a foam-sclerosed vein? reply by the author these questions were put to the author but we have not yet received a reply. [top] 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2016; volume 5:5981 [page 4] [veins and lymphatics 2016; 5:5981] compression in vasculitis valentina dini department of dermatology, university of pisa, italy cutaneous vasculitis is a pathological process characterized by inflammation of the skin blood vessel wall leading to an alteration of the blood flow, ischemia and tissue damage. the most important histopathologic feature is an inflammatory cell infiltration with fibrinoid necrosis and destruction of blood vessels. the heterogeneous group of vasculitic disorders has been classified not only by primary and secondary causes but also by the size of the affected vessel. the diagnosis is based on clinical features and tissue and laboratory evaluation. vasculitis affecting small vessels is the most common type in dermatology, also known with the histologic term of leukocytoclastic vasculitis. the distribution of skin lesions often starts on dependent areas (e.g., feet, lower legs, buttocks) before becoming generalized. this is due to the effect of hydrostatic forces on the post capillary venules leading to the preferential deposition of immune complexes at these sites. the major cutaneous manifestation is represented by a palpable purpura. the evolution of skin lesions depends on the etiology and can be acute resolving, within several days to weeks, or chronic persisting, from months to years. the clinical presentation is characterized by increasing crops, evolving from palpable purpura to papules and nodules, leading to a significant post-inflammatory hyperpigmentation. the lesions are commonly palpable and non-blanching, often demonstrated by applying pressure with a glass tumbler. purpura is due to extravasation of red blood cells and can be associated with vesicles, bullae and ulcers. small vessels vasculitis are idiophatic in the 50% of the cases or associated with drugs, infections, in particular hepatitis, wegener’s granulomatosis, churg strauss syndrome and henoch-schonlein purpura. the major pathogenetic mechanism is an immune complex reaction with a leukocytoclastic vasculitis with predominantly neutrophilic infiltrate. the treatment depends on the cause of the cutaneous vasculitis. if the underlying pathology is a primary vasculitis, treatment is based on the disease severity and systemic involvement. if the vasculitis involves only the skin, conservative measures can be undertaken. they include corticosteroids and immunosuppressive drugs while, when associated, skin ulcer local treatment can include moist wound dressings and bandaging. in addition, patients can receive basic instructions on self-care, including recommendations about diminish the factors known to exacerbate vasculitis such as excessive standing, cold exposure, wearing tight-fitting cloths, and promote rest as the legs elevated. compression by bandages has not yet shown to be useful in vasculitic skin lesions, so far. in the department of dermatology of the university of pisa we have treated 31 patients (female:male = 3:1) in the age range between 26-65 years. the eco color doppler did not show significant findings in 28 patients and was positive for venous insufficiency in 3 patients. 15 patients were affected by small or medium vessels vasculitis, 3 by rheumatoid arthritis, 2 by churg strauss syndrome, 4 by cryoglobulinaemia, 1 by sjögren syndrome and behçet disease and 1 by necrotizing vasculitis. we have evaluated the patients attending our clinic together with the rheumatologists. during the first clinical manifestation of skin lesions we started systemic drug and compressive short stretch bandaging. in case of relapse we applied compression by bandages before increasing the dose of systemic therapy or switching to a new drug. only in a few cases we applied an ultraportable negative pressure therapy. in our experience compression therapy by short stretch bandages in vasculitic ulcers with or without venous insufficiency, was very useful in order to improve the healing time, relieve the burning sensation and pain, due to the reduction of inflammation of blood vessels. in our opinion the compression therapy can be used in the inflammatory phase of vasculitis with or without leg ulcers in order to reduce the administration of systemic steroids. correspondence: valentina dini, department of dermatology, university of pisa, via savi 10 56126 pisa, italy. e-mail: valentina.dini@unipi.it this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright v. dini, 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5981 doi:10.4081/vl.2016.5981 hrev_master veins and lymphatics 2015; volume 4:5559 [veins and lymphatics 2015; 4:5559] [page 61] reply to: saphenous sparing laser modern options (comment to gianesini et al., veins and lymphatics 2013;2:e21 and veins and lymphatics 2015;4:5246) sergio gianesini vascular disease center, university of ferrara, cona (fe), italy dear editor, i really enjoyed dr. ferracani interest in saphenous sapring innovations.1 as a matter of fact modern phlebology is constantly offering us brand new tools to improve our outcomes. nevertheless, these better outcomes regard just a better mini-invasiveness, that is not followed by a corresponding improvement in the post-procedural recurrence rate. as pointed out by the recent prevait analysis on the recurrence rate in fact traditional stripping, radiofrequency and laser procedure produce overlapping outcomes in terms of recurrences.2 this feature is testified by the modern guidelines recommending endovenous thermal ablation over surgery not because of a better recurrence rate performance, but because of their mini-invasiveness.3 at the same time, this year a cochrane review reported a varicose veins recurrence reduction following a saphenous sparing surgical strategy rather than a traditional ablative one.4 whenever dealing with saphenous sparing options a great attention must be paid. it has been demonstrated that a hemodynamic procedure performed in not well trained centres leads to outcomes that are worse than a traditional ablative procedure.5 for this reason i hope dr. ferracani will soon produce a paper with a clear indication of the hemodynamic types that are eligible for his procedure, specifying the required learning curve for such an elegant and interesting therapeutic option. once again a clear distinction must be made among the strategy and the technique. along these last decades phlebology has moved its therapeutic army endowing it with always brand new technical devices. nevertheless the strategy has always remained ablative. previous surgical papers demonstrated the competitiveness of a saphenous sparing therapeutic, so forcing our discipline to evaluate the feasibility and performance of the new devices not only as ablative tools. in conclusion, looking for a recurrence rate reduction, it’s desirable to explore the performance not just of new tools in an old strategy, rather innovative tools for innovative strategies. only in this way i think we’ll be able to appreciate the new devices at their best, finally improving not just our mini-invasiveness, but also the recurrence rate. references 1. ferracani el. saphenous sparing laser modern options (comment to gianesini et al., veins and lymphatics 2013;2:e21 and veins and lymphatics 2015;4:5246). veins and lymphatics 2015;4:5531. 2. perrin m. presence of varices after operative treatment: a review. phlebolympho logy 2014;21:1. 3. gloviczki p, comerota aj, dalsing mc, et al. the care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the society for vascular surgery and the american venous forum. j vasc surg 2011;53:2s48s. 4. bellmunt-montoya s, escribano jm, dilme j, martinez-zapata mj. chiva method for the treatment of chronic venous insufficiency. cochrane database syst rev 2015;6:cd009648. 5. milone m, salvatore g, maietta p, et al. recurrent varicose veins of the lower limbs after surgery. role of surgical technique (stripping vs. chiva) and surgeon’s experience. g chir 2011;32:460-3. correspondence: sergio gianesini, vascular disease center, university of ferrara, via aldo moro 8, 44128 cona (fe), italy. e-mail: sergiogianesini@hotmail.com key words: letter to editor; saphenous sparing procedures. received for publication: 30 september 2015. accepted for publication: 30 september 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s. gianesini, 2015 licensee pagepress, italy veins and lymphatics 2015; 4:5559 doi:10.4081/vl.2015.5559 no n c om me rci al us e o nly stefano ricci comment to: anatomy of the veno-muscular pumps of the lower limb by uhl jf, gillot c. phlebology 2014 jan 10 [epub ahead of print] stefano ricci abstract the authors studied 400 limbs of 200 non-embalmed cadaveric subjects (mean age of 84). after ligation of the femoral vein, green neoprene latex was injected (about 120 to 150 ml per limb), over 30 min. dissection was started the next day; in some cases, an iodine contrast agent was added to the latex injection and, prior to dissection, a multislice helical ct performed. the medial and mostly lateral plantar veins converge into the plexus-shaped calcaneal crossroad, where the blood is ejected upwards into the two posterior tibial veins. in addition, several medial perforators of the foot directly connect the deep system (medial plantar veins) to the superficial venous system (medial marginal vein). a venous reservoir of 25 ml of blood is mobilized upwards with each step during walking. the calf veno-muscular pump is the most important pump in the limb. it consists on the leg pump, located in the veins of the soleus, and the popliteal pump located in the gastrocnemius muscle. the gastrocnemius and soleus together form a muscular mass that is occasionally described as the triceps suræ; its tendon of insertion is the tendo calcaneous (tendo achillis). it is the thickest and strongest tendon in the body. the drainage of the veins of the soleus is divided into two parts: the medial veins horizontally oriented into the posterior tibial veins and the lateral veins, vertically into the fibular veins. the gastrocnemius is the most superficial muscle, and forms the greater part of the calf. it arises by two heads, which are connected to the condyles of the femur by strong, flat tendons. the muscular veins of gastrocnemius (mainly the medial ones) have two main characteristics: they consist of several pedicles of longitudinal veins appearing at the lower part of the muscle as a continuation of the polar perforators of the calf. they join upwards in a unique collector ending into the popliteal vein. the medial gastrocnemial veins are the larger ones, with two to four pedicles of one or two veins. the pedicles originate from a network of veins connected to several calf perforators. when present, the medial gastrocnemial collector frequently makes a common trunk (about 30%) with the ssv. the power of the pump is explained by the unique collector draining into the popliteal vein, producing a high-speed ejection of blood during the contraction of the gastrocnemius muscle. concerning the thigh pumps, posteriorly, the biceps and particularly the semimembranosus muscles have important venous arcades in shape of a plexus. the semimembranosus muscle is located at the posterolateral aspect of the thigh. a number of the venous arcades are located inside the muscle, which constitutes the main pump of the posterior thigh; they have a number of anastomoses with the popliteal axis and drain proximally into the deep femoral vein, a safety valve on the femoral vein axis, shunting the narrowed part created by the hunter’s outlet. in fact, the flush of the gastrocnemial pump is so powerful that the popliteal vein cannot accommodate the whole flux of the blood if there is a stenosis or a simple narrowing of the hunter’s canal. in such cases, a part of the outflow can be absorbed by the semimembranosus pump, and drained via the deep femoral vein. the quadriceps femoris includes four muscles on the front of the thigh. the muscular veins of this big mass drain mainly into a big trunk ending at the root of the thigh into the common femoral vein. the synchronization of the different veno-muscular pumps during walk is crucial: foot, then leg, popliteal and finally thigh pumps. the dynamic effect of the venous pumps is closely related to the anatomy of the venous valves. the anatomical knowledge of the veno-muscular pumps, and particularly the calf pump, is crucial to better understand their major role in venous return. this knowledge helps explain the impact of ankle stiffness, which impairs the calf pump activation. comment by stefano ricci all phlebologists should deserve special gratitude to this anatomy school (gillot-uhl) that has, nowadays, no comparable examples. it is impossible to make a summary of such an important paper, the details of the limb veins description being more important than the general aspects. moreover, the text is correlated to an exceptionally rich iconography that needs to be directly explored to be enjoyed. while some concepts are not new (leg pumps), special interest is related to the analysis of the muscle veins orientation (vertical for medial/horizontal for lateral), which should correspond to a special hemodynamic mechanism that is still not clear. thigh pumps are a new input in our knowledge, in particular the one concerning the semimembranous muscle as a safety valve when hunter’s canal is unable to receive the powerful ejection of the calf pump. this event (virtual femoral obstruction) could also concern the giacomini vein (gv) development or, more, the transmission of a systolic sapheno-popliteal reflux via the gv into the gsv stream to join the femoral vein. there are however two limitations in this excellent paper: the complete absence of a correlation between anatomy and ultrasound imaging, not allowing a more complete application of the given data to the clinical everyday experience. limited hemodynamic evidences of pumps mechanisms (pressures measurements) to accompany the anatomy findings. finally, it would be interesting to understand the foot pump function: being stated that the most powerful pump is the one of the calf, how the foot pump insufficiency (ankle stiffness) condition the limb venous return? [top] hocaoglu c. clozapine-induced rabbit syndrome: a case report cyanoacrylate glue for saphenous ablation nick morrison abstract although surgical treatment of saphenous vein incompetence is still the most adopted approach worldwide, endovenous thermal ablation of superficial truncal veins is firmly established in the armamentarium of phlebologists in some countries for the ablation of saphenous and non-saphenous veins. reported results are equal to or better than surgical treatment in terms of postoperative pain and return to full activities. 1 one of the technical challenges of the thermal ablation procedure is the instillation of tumescent anesthesia into the saphenous sheath under ultrasound guidance. this promotes patient comfort allowing the procedure to be carried out in an ambulatory setting. ultrasound guided tumescent anesthesia is arguably the most difficult hurdle for operators who are new to the procedure. it also represents the most painful part of thermal ablation for the patient. while there is no high-level scientific evidence to support the use of compression following thermal ablation, in practice, nearly everyone utilizes some form of compression for up to several weeks following the procedure because anecdotal evidence suggests that patients are significantly more comfortable and enjoy better postoperative recovery. tumescent anesthesia instillation under ultrasound guidance is challenging and postprocedural compression is considered to be a standard requirement. given this, even less invasive techniques for venous ablation are being developed. among these is the instillation of cyanoacrylate glue (cag) into the target vein. cyanoacrylate glue has been used effectively as a tissue adhesive, a vascular closure agent, and as an intracranial embolic agent for arteriovascular malformations. cyanoacrylates are synthetic glues that rapidly polymerize on contact with water or blood. n-butyl-2-cyanoacrylate (histoacryl; b braun, melsungen, germany) has been used extensively in surgery for a decade. another n-butyl-2-cyanoacrylate (glubran, gem srl., viareggio, italy) was recently approved for endoscopic use in europe. 2-octyl-cyanoacrylate (dermabond, ethicon, inc., somerville, nj, usa), approved by the federal drug administration for superficial wound closure, is widely used in the us, particularly by emergency room physicians, dermatologists and surgeons. substances such as plasma, blood or saline stimulate polymerization of the adhesive upon contact, leading to occlusion of the vessel. the resultant polymerization damages the vascular intima and induces an immunological response. after polymerization is complete, gradual resorption of the occlusive polymer takes place. within approximately one month, the response progresses to a granulomatous process with foreign body giant cells and eventual fibrosis. sapheon inc. (santa rosa, california, usa) has developed a proprietary cyanoacrylate adhesive (sca) for permanent closure of incompetent superficial leg veins in an attempt to eliminate the need for the tumescent anesthesia and postoperative compression used in thermal and surgical ablation procedures. following successful vein occlusion in animal models, 2 the first human study was carried out by an american group (almeida et al. 3). this product received ce approval for use in europe in september 2011. however, since it has not been approved by the us fda for saphenous vein ablation, the studies 4 were conducted outside the us on 38 patients treated with sca of the great saphenous vein (gsv) under only local catheter insertion site anesthesia and without the use of tumescent anesthesia or postoperative compression. the mean maximum gsv diameter was 8 mm and 17 of 38 patients were ceap class 4 or above. the catheter was positioned approximately 4 cm below the saphenofemoral junction (sfj). this was manually compressed and the sca was injected. compression was maintained for 3 min. the adhesive was delivered at 3 cm intervals for the remainder of the treated vein using 30 s of compression for each subsequent delivery (figure 1). figure 1. sapheon inc. (santa rosa, california, usa) has developed a proprietary cyanoacrylate adhesive for permanent closure of incompetent superficial leg veins. the mean length of ablated gsv segments was 33 cm (range 15-52) and the average treatment duration was 20.3 min (range 11-33). the mean volume of sca delivered was a total of 1.3 ml (range 0.63-2.25). thirty-six of 38 (95%) patients were followed for 30 days, including clinical (vcss scores) and duplex evaluations. the procedure was well tolerated by all patients who required no postoperative analgesics (6 of 37 received nsaids). duplex examination documented complete occlusion of the gsv in 35 of 38 patients (92%) with one complete recanalization and 2 partial mid-thigh recanalizations. clinical vcss scores decreased dramatically within 24 h and continued to improve over the follow-up period (mean 6.0-1.9 at 30 days). the problem of post ablation thrombus extension (paste) through the sfj, an infrequent event after thermal or foam saphenous ablation, was seen in 8 of 38 (21%) patients in the study. however, in a preliminary report 5 of a study of 20 patients (escope study in germany, denmark and the uk) this problem appears to have been resolved by moving the first injection to 5 cms below the sfj, as reported by proebstle et al. 5 in conclusion, several innovative methods for saphenous ablation have been developed and are currently undergoing clinical tests. the use of cyanoacrylate glue appears to hold some promise in reducing the two main challenges related to thermal ablation for physicians and patients alike: the need for ultrasound guided tumescent anesthesia and postoperative compression. references 1. rasmussen lh, lawaetz m, bjoern l, et al. randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins. br j surg 2011;98:1079-87.[crossref][pubmed] 2. almeida ji, min rj, raabe r, et al. cyanoacrylate adhesive for the closure of truncal veins: 60-day swine model results. vasc endovascular surg 2011;45:631-5.[crossref][pubmed] 3. almeida j. saphenous trunk closure with glue: data from animal and first-in-man trial. presented: international vein congress, may, 2011. miami beach, fl, usa. 4. almeida j, et al. cyanoacrylate glue great saphenous vein ablation: preliminary 180-day follow-up of a first-in-man feasibility study of a no-compression-no-local-anesthesia technique. presented: american venous forum 24th annual congress, february 2012; orlando, fl, usa. 5. proebstle t. status of cyanoacrylate glue for saphenous ablation. presented: international vein congress, june 2012, miami, fl, usa. [top] stefano ricci comment to: thermal ablation of saphenous veins is feasible and safe in patients older than 75 years: a prospective study (evta study) by hamel-desnos c, desnos p, allaert f-a, kern p; the “thermal group”. phlebology 2014, june 18 [epub ahead of print] raffaele antonelli incalzi department of geriatrics, campus biomedico university, rome, italy r.antonelli@unicampus.it abstract a multicenter, prospective observational study has been conducted under the aegis of the french society of phlebology, with the participation of the swiss society of phlebology and the vein group of the french society of vascular diseases to evaluate feasibility, tolerance, results, and satisfaction of thermal ablation (ta) of saphenous vein (sv) in patients aged more than 75 years. between september 2011 and june 2012, consecutive younger and older patients aged more than 75 years, presenting with an indication to treat sv (great or small) by ta, with ceap clinical class of c2 to c6, were included in 18 participating centers (13 french and 5 swiss). ta could be made with either laser (evla: 810, 980 and 1470 nm; bare tip and radial fibers) or radiofrequency (rfa: closure-fast, or celon-rfitt). ta could be performed under tumescent local, general or epidural anesthesia according to the modalities of treatment inherent to the practitioner. the therapist had to indicate if ta was performed in the hospital, in the hospital but outside of the operating room or in a private office. concomitant or delayed treatment of tributary varicose veins could be made by either phlebectomy or sclerotherapy. seven hundred and seven patients (863 legs) could be included. thirteen per cent (90 patients, 101 legs) of the patients were older than 75 years (group 1). mean age of these elderly patients was 80.3 years (75-92); it was 53.5 (21-74) in the younger population (group 2). in group 1, small saphenous veins (ssv) were treated more frequently (27 versus 17%) than great saphenous veins (gsv) and treatment indication was more often medical instead of only aesthetic (strictly medical indication 86.1 versus 52.1%, only aesthetic 2 versus 6.7%, medical and aesthetic 11.9 versus 41.2%). venous insufficiency was more severe in group 1, with significantly more c4 to c6 of the ceap classification. comorbidities, particularly diabetes, cardiac insufficiency, history of thromboembolic disease (ted) were significantly more frequent in the elderly patients. eighty six per cent of patients were treated with laser. the 1470 nm wavelength was the most used (57%). radial fiber was the most frequent choice (67%). in 75% of cases, the continuous application mode was chosen. fourteen per cent were treated with radiofrequency. significantly more patients older than 75 years were treated in a private office (65 versus 55%), than in an operating room (29 versus 31%) or in the hospital but outside of the operating room (6 versus 14%). most treatments were performed under strict tumescent local anesthesia (tla) (86%). most patients had no concomitant treatments for tributaries in both groups. seventy five per cent of group 1 received lmwh during 5.4 days versus 82% of group 2 during 5.3 days. occlusion rate was excellent and identical in both groups, as well as at one week than at three months (100% complete occlusion in the elderly versus 99.5% complete and 0.5% partial occlusions in the younger). the satisfaction rate was identical and very high in both groups (mean 9.3, median 10/10). the rate of paresthesia was significantly higher when thermal ablation was performed under general anesthesia instead of tla (11.8 versus 2.2%). short-term results at three months, rate of side effects, tolerance and satisfaction are identical for elderly and younger patients. in elderly patients, ta was performed more often in private offices in town outside of an operating room and under tla. in this condition, the operation is very well tolerated and the periand post-operative pain is low. it is also safer, as the rate of post-operative paresthesia is significantly lower than if ta is performed under general anesthesia. comment by raffaele antonelli incalzi this study looks very promising as it shows that the elderly benefit as much as the young adult from thermal ablation (ta) of saphenous veins. given that the reason for ta in the elderly was almost exclusively medical, this finding has special value. however, the authors do not provide any information about whether difficulty in walking, mental impairment, obesity, arterial obstruction, anticoagulation and large gsv diameters impacted patient impacted selection or response to the therapy. thus, the reader remains uncertain about whether the studied population was representative of the elderly population with venous insufficiency or represented a selected one, furthermore, the available data do not allow estimate how much the elderly patients did benefit from ta. indeed, in elderly people the effects of any therapeutic procedure should be assessed in terms of health status and personal independence. unfortunately, no such measures were available. in a context characterized by multimorbidity one might doubt about how treating the venous insufficiency would improve the classical geriatric outcomes. nevertheless, the reported high satisfaction of the elderly patients with ta suggests that at least health status improved. further supporting the importance of ta as an effective procedure in the elderly is the fact that skin lesions are more likely to chronicize in less active and multimorbid patients frequently experiencing arterial insufficiency or hypoxemia due to respiratory problems. this is a major added value of the procedure. finally, that tumescent anesthesia was fully effective is remarkable: even sedation and minor anesthesiological procedures, e g for cataract removal and lens implant, are associated with a notable risk of delirium and cognitive deterioration. curiously, elderly had their procedures performed more commonly in private offices. could this be consequence of the fact that in public hospitals, non-vital operations in elderly may be limited by financial difficulties and risk fear? in conclusion, the authors have to be commended for having shed light on a topic of major interest in geriatric medicine. too frequently, a nihilistic approach results in elderly patients being excluded form procedures able to improve their health status and to reduce the need of care. though purely observational, these findings strongly support a positive and proactive approach to venous insufficiency in the elderly. [top] claude franceschi stefano ermini the evaluation of essential elements defining varicose vein mapping claude franceschi, stefano ermini preliminary notes dus check-up must be done with the patient standing and with the feet resting on the floor. this allows the re-creation of a physiologic movement during dynamic flow activation tests with the patient standing in front of the physician. the detected flow must be put in relation to the kind of activation flow test used, and to its phase (muscle pump contraction/relaxation, valsalva press or release, systole/diastole). great saphenous vein anatomic us check-up record the presence/competence/incompetence of the anterior accessory saphenous vein (pay attention to the alignment sign). record sfj anatomical aberrations (double sfj, superficial femoral artery position, dilations and tributary disposition if in a prominent position). measure the gsv trunk caliber 15 cm below the groin with exclusion of the dilations. record the number of dilations. hemodynamic check-up record competence/incompetence of the saphenous trunk. record the presence of an escape point, specifying the test used. record the presence of one or more pelvic escape point as described by c. franceschi. in case of sfj incompetence, specify the competence/incompetence of the terminal valve, with reference to the tests used and evidencing the incongruences. define gsv length incompetence and any multiple incompetence segments. small saphenous vein anatomic us check-up record the spj height level. record the relationship with the gastrocnemius veins. record the presence or not of the giacomini vein and of the thigh extension vein. measure the ssv trunk caliber below the junction. hemodynamic check-up use only the parana’ maneuver. record the competence/incompetence of the spj terminal valve. record the ssv length incompetence and any multiple incompetence segments. look for the presence of a systolic reflux and define its duration in relation to the muscle pump contraction phase. look for the flow direction in the convexity or concavity arc tributaries. in case of simultaneous popliteal vein incompetence, repeat the check-up associating the ssv trunk finger compression below the junction. perforators (anatomically enlarged) use only dynamic tests (paranà, knee bending). record its role in relation to its hemodynamic pattern, keeping in mind that: diastolic inward flow is typical of a re-entry perforator. diastolic outward flow is typical of an escape point stefano ermini & claude franceschi. systolic outward flow is typical of vicarious (compensative) flow in a shrinking syndrome and is always facilitated by its angle of insertion. a systole refluxing perforator can also represent the escape point of a varicose vein, in absence of deep vein dysfunction. this is due to the perforator angle and is always the consequence of a trauma. in this perforator the diastolic behavior is conditioned by the fact that the gradient level may or may not generate a syphon effect (height of the hydrostatic column interposed between the escape point and the re-entry perforator and possible diastolic muscular choking) and by the competence of the higher venous system. assysto-diastolic outward flow is the typical pattern of an incompetent perforator associated with the absence of orthodynamic pressure fractioning in the deep veins. the absence of flow is due to the absence of gradient and this may be related to the type of valve competence test used, to a simultaneous and deep vein incompetence, or to the fact that the patient has been standing for a long time. g. a gsv perforator placed in a non-terminal area may present a diastolic outward flow that must not be considered pathogenic (please measure the gsv caliber above and below the perforator). this diastolic outward flow inverts its direction closing the gsv below the perforator (finger compression or surgical disconnection). giacomini vein check the flow direction using a paranà maneuver if the flow is centrifugal (towards the spj): find an escape point (if one exists) determine if the centrifugal flow is valsalva positive or negative. if the flow is centripetal (distancing from the spj): check if the systolic shunt is an open derivative or vicarious (if it is sustained or not by a compensative function) check the centripetal flow duration in relation the muscle pump contraction phase (if it occurs only in the early contraction or if it is present during the entire muscle pump contraction phase) compare the right and left calibers of the femoral superficial vein repeat the test with a shoe that has a 4 cm heel points b, c, and d can be considered part of a pre-surgical exam and not a first level doppler us check up. reccomendations superficial veins: it is absolutely useless to measure the reflux time in order to relate it to the presumed gravity of the svi, because reflux time depends on the gradient exhaustion time. this time depends on the kind of valve competence test used and on the filling level of the venous system at the time the test is performed. deep veins: dynamic reflux index proposed by c. franceschi can be used (vmr=average diastolic reflux speed, tmr=average diastolic reflux time, vms= average systolic speed, tms= average systolic time) it is mandatory to identify without hesitation the vicarious circles (compensative circles). their disconnection leads to a huge worsening that is no longer curable (if not by nature). remember that our mission is to cure the patient and not to treat the reflux. use the perthes test to clarify ambiguous situations during dus check-up and to limit unnecessary and extensive phlebectomies in the surgical planning phase. basic venous mapping elements useless to plan a hemodynamic conservative strategy (to add to what is described above) the mission of hemodynamic conservative surgery is to preserve a draining saphenous system. the saphenous drainage after hemodynamic correction can be restored with a centrifugal flow or with a centripetal flow. basic elements to restore a centrifugal non-pathogenic saphenous flow: to convert a closed diastolic shunt in a open diastolic derivative shunt (to treat the escape point n1-­‐>n2, n2-­‐>n3). to restore a physiologic compartment drainage (from n3 to n1). the finger tributary compression test can be used in the definition of re-entry perforators. in case of gsv trunk disconnection below a perforator (<1%), check the saphenous flow with a dynamic test compressing the gsv trunk below the perforator. basic elements to restore a centripetal non-pathogenic saphenous flow: to test centripetal saphenous flow speed and time after finger tributary compression using a dynamic maneuver. this is important when we choose the strategy treatment of a type iib shunt. to test the relation between the incompetent gsv caliber and that of the competent tract as well as the length of both segments. to check gsv trunk multiple incompetences. more information in: https://drive.google.com/file/d/0b9u_duxdrapybuzquzrvelbqzxc/view?usp=sharing http://www.slideshare.net/claudefranceschi/duplex-assessment-of-venous-hemodynamics-3-oct-13th-2011-‐morning-20mn2 [top] 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2016; volume 5:5984 [veins and lymphatics 2014; 3:5984] [page 9] pressure therapy for post-burn scars: does it work? mieke flour,1 mieke anthonissen,2 eric van den kerckhove2 1phlebology and chronic wounds clinic, vascular centre, university hospital, st. raphaël (kuv), leuven; 2department of rehabilitation sciences, catholic university leuven research and development, leuven, belgium several controlled trials have accumulated evidence for the effectiveness of conservative strategies in the treatment of post-burn scars, including compression therapy.1 randomized controlled trials using noninvasive instruments have assessed the effect of pressure on the 6 classical clinical parameters of post-burn scars: thickness, pigmentation, vascularity, pliability, color and overall aspect. there is worldwide acceptance for compression therapy and for silicone gel sheets in this specific indication, although question marks remain regarding most appropriate dosage and about working mechanisms. the most common working hypothesis is that pressure would induce ischemia and thus impair further growth of the scar. it is generally accepted that pressure impacts on the realignment of collagen fibers.2,3 the impact of pressure is most evident of thickness of the scar. the mechanism of action of silicone was postulated as improving skin hydration through occlusion and by reducing fibroblast’s activity and collagen formation.4 this working mechanism supports the effect of silicone on elasticity and redness of a hypertrophic scar. but how much compression pressure is needed? data on a prospective study comparing 2 levels of pressure are presented: 20 vs 15 mmhg, during 3 months of pressure treatment in 76 burn scars, using the chromameter to assess redness and high resolution ultrasound (dermascan™; cortex technology, hadsund, denmark) to measure thickness. results of this study show that the higher pressure (20 mmhg) is more effective than the lower pressure (15 mmhg) and that this effect occurs sooner. this is in accordance with other published research which showed that the higher the amount of pressure, the better the effect on decrease of thickness.5,6 nevertheless, there was no clear consensus about the minimum effective amount of pressure. some authors suggested a pressure of at least 15 mmhg, while others recommended pressure of 24 mmhg to overcome capillary pressure. higher pressure worn for 14 to 23 hours/day was more effective in flattening of burn scars and resulted in thinner scars. a compression pressure greater than 40 mmhg could result in complications such as paresthesia. baseline selection differences between studies could explain the discrepancy of results concerning erythema (intervention time, time after burn injury, and the patient population: e.g. asiatic vs caucasian). since silicone and pressure therapy had complementary modes of action, it appeared to be evident that their combined application would give complementary results. however a review of the literature yields variable outcomes, most probably due to differences in study selection parameters. finally, the authors tested what is the pressure added to the effect of silicone sheets, in several types of scars: post trauma, following surgery or burn injury. results show the value of pressure treatment as a preventive measure against hypertrophy of scars: treated sites are less marked, and early treatment seemed to be more effective than a late start of the same therapy. in their experience, pitfalls of this treatment are the several factors, which interfere with steady pressure: like the anatomical contours e.g., the axilla or the chest, compliance (adherence to treatment), and pressureloss of the garment. therefore (=to counteract pressure loss) custom made pressure pads or 3d-fitted inflatable silicone inserts are used to adapt and to maintain pressure values in concave anatomical areas (figure 1). on the other hand these can limit the mobility when used over a joint, and macerate the skin due to excessive sweating.7 since pressure is more effective if high enough, above 20 mmhg, it is important to regularly check and evaluate pressure garments, using a pressure sensor.8 moreover, pressure loss of pressure garments needs to be taken into account. their advice is to monitor objectively and to adapt pressure treatment if needed in order to maintain the pressure above 20 mmhg (figure 2). sharp et al. very recently published a best evidence statement on pressure therapy in the management of hypertrophic scarring.9 references 1. anthonissen m, daly d, janssens t, van den kerckhove e. the effects of conservative treatments on burn scars: a systematic review. burns 2016;pii:s03054179(15)00396-4. 2. costa m, peyrol s, pôrto c, et al. mechanical forces induce scar remodeling. am j pathol 1999;155:1671-9. 3. kischer c, shetlar m, shetlar c. alteration of hypertrophic scars induced by mechanicorrespondence: mieke flour, schoonzichtlaan 43, b-3020 herent, belgium. tel. +32.478.566780. e-mail: mie.flour@skynet.be this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright m. flour et al., 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5984 doi:10.4081/vl.2016.5984 figure 1. combination of pressure device and custom made inflatable silicone insert system in concave anatomical regions. figure 2. monitor the scar and the interface pressure with objective and reliable tools and adjust the pressure therapy when needed. no n c om me rci al us e o nly conference presentation [page 10] [veins and lymphatics 2016; 5:5984] cal pressure. arch dermatol 1975;111:60-4. 4. li-tsang c, lau j, choi j, et al. a prospective randomized clinical trial to investigate the effect of silicone gel sheeting (cicacare) on post-traumatic hypertrophic scar among the chinese population. burns 2006;32:678-83. 5. van den kerckhove e, stappaerts k, fieuws s, et al. the assessment of erythema and thickness on burn related scars during pressure garment therapy as a preventive measure for hypertrophic scarring. burns 2005;31:696-702. 6. engrav l, heimbach d, rivara f, et al. 12year within-wound study of the effectiveness of custom pressure garment therapy. burns 2010;36:975-83. 7. van den kerckhove e, stappaerts k, boeckx w, et al. silicones in the rehabilitation of burns: a review and overview. burns 2001;27:205-14. 8. van den kerckhove e, fieuws s, massagé p, et al. reproducibility of repeated measurements with the kikuhime pressure sensor under pressure garments in burn scar treatment. burns 2007;33:572-8. 9. sharp p, pan b, yakuboff k, rothchild d. development of a best evidence statement for the use of pressure therapy for management of hypertrophic scarring. j burn care res 2015 [epub ahead of print]. no n c om me rci al us e o nly hrev_master veins and lymphatics 2017; volume 6:6622 [page 2] [veins and lymphatics 2017; 6:6622] compression with the juxta reduction kit ® (medi) in patients undergoing a total knee arthroplasty ad a. hendrickx,1,2 wim p. krijnen,1 robert j. damstra,2 richard bimmel,3 cees p. van der schans2,4 1expert centre of lympho-vascular medicine, nij smellinghe hospital, drachten; 2research and innovation group in health care and nursing, hanze university of applied sciences, groningen; 3department of orthopaedics and traumatology, nij smellinghe hospital, drachten; 4department of rehabilitation medicine, university of groningen, university medical center groningen, the netherlands introduction total knee replacement (tka) is a successful operation in the treatment of osteoarthritis. enhanced recovery programs, with emphasis on early mobilization and optimal analgesics have reduced hospital stay and peri-operative morbidity.1,2 patients undergoing a knee arthroplasty can experience pain, swelling, a decrease in knee-extension strength, loss of range of motion (rom), causing a decline in functional performance.3-6 problems with the activation of the quadriceps, in the early postoperative phase can be related to either the surgical procedure or arthrogenic reflex inhibition of the muscle related to pain and swelling.7 post-operative swelling is mainly caused by intra-articular bleeding and inflammation of peri articular tissues.8 impaired functional performance can delay rehabilitation and affect length of stay and patient-reported outcomes.8 thereby, excessive swelling is associated with increased rates of wound dehiscence and infection in surgical wounds.9 compression therapy is a frequently used modality in the postoperative treatment to reduce swelling. the literature is not consistent about the effects of compression therapy. this is due to the use of various materials, the time frame of application and the different outcome measurements used.8,10,11 our experiences with compression in the treatment of venous ulcers and lymphedema create possibilities to introduce compression technologies in other fields of medicine, such as orthopaedic surgery. regarding the type of bandage, inelastic compression bandages show a low, tolerable resting pressure and a more effective activation of the deep venous system and calf muscle pump with ambulation (working pressure) compared to elastic materials.12,13 the juxta reduction kit® (jrk) is a non-elastic compression device, suitable for self-management, which can be tailored to the circumference of the leg. the device allows full rom, so ambulation and exercise will not be impaired. it is hypothesized that immediate postoperative compression and prolonging the period of use until 6 weeks postoperatively will prevent excessive swelling and initiate an earlier reduction. reduced swelling improves range of motion, knee extension strength, reduces pain, supporting the rehabilitation process. the research questions concern feasibility and effectiveness of the treatment on volume, pain, wound aspects and functional recovery. in this article we will focus on study design and feasibility aspects. materials and methods in nij smellinghe hospital the fast-track principles have been implemented in joint replacement surgery. ambulation and exercise of the patient start 4 hours postoperative and patients are discharged when they are functional independent. table 1 shows the compression and exercise protocols for the control and treatment group. patients are instructed about the use of the jrk prior to the operation and during clinical stay. they are instructed to apply a firm, but tolerable dose of compression. after having signed the inform consent patients are randomly assigned to either the control or the treatment group. inclusion criteria: i) 18 years of age or older; ii) patients undergoing a primary elective total knee arthroplasty; iii) the patient is able to understand the study and is willing to give written informed consent. exclusion criteria: i) allergy against one of the used materials; ii) severe systemic diseases causing peripheral edema; iii) acute superficial or deep vein thrombosis; iv) arterial occlusive disease (stadium ii, iii or iv) abpi<0.8; v) local infection in the therapy area; vi) auto-immunological disorders or vasculitis; vii) use of systemic corticosteroids; viii) inability to don, doff and adjust the device. the local medical ethical committee approved the study. the study was registered under clinicaltrials.gov, nct02375945. measurements and data collection feasibility data are collected about the number of patients recruited and dropped out, time required for the whole process (measurements, preparation of the jrk, instruction of the patient and administration), pain in action (pa) and in rest (pr), the ability to exercise and sort and number of complications. data collection was pre-operative, day 1 and day 2 during hospital stay and at day 14, 42 and 84 after discharge. statistical analyses all data are analyzed with the programming language r version 3.3.0 for statistical computing. a p-value smaller than or equal to 0.05 is considered to be statistically significant. results in total 68 patients were included (32 patients in the control group and 36 patients in the treatment group). 19 patients in the control group (13 drop outs) and 20 patients the treatment group (16 drop outs) completed the study. measurements, preparation of the jrk, instruction and administration demanded 6 hours per patient. pain scores in rest and action are shown in figure 1. figures 2 and 3 show the interaction data plots. the ability to exercise was successful in the first phase of recovery. when the rom comes closer to the 90 degrees of flexion the material strips up at the back of the knee and restricts the possibility to flex the knee. no complications did occur. correspondence: ad a. hendrickx, nij smellinghe hospital, department of physical therapy, compagnonsplein 1, 9202 nn drachten, the netherlands. e-mail: a.hendrickx@nijsmellinghe.nl this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright a.a. hendrickx et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6622 doi:10.4081/vl.2017.6622 no n c om me rci al us e o nly conference presentation [veins and lymphatics 2017; 6:6622] [page 3] conclusions the vas scores for pain in rest and in action showed no significant differences between the two groups. regarding feasibility this is considered positive, because more pain was expected by adding compression in the first phase of recovery. a limitation of this study is that no data were collected about the use of pain-medication. the analgesic influence of compression on the pain cannot be stated. this pilot study demonstrates a feasible concept. regarding outcome on volume the preliminary results show a positive effect in favor of the treatment group, supporting the need for further research. table 1. compression and exercise protocol. control group treatment group • immediately postoperative until 24 hours postoperative compression • immediately postoperative until 6 weeks postoperative, 24/7 with elastic bandages for the knee region with elastomuhl haft® (jobst) compression with the jrk ®+ struva®, class 2 anti-thrombosis stocking • from 24h until 6 weeks postoperative an anti-thrombosis stocking, (medi) comprinet stocking ® (bsn medical) • ambulation and exercise program according to the fast-track principles • ambulation and exercise program according to the fast-track principles figure 1. pain scores in rest and action. figure 2. interaction plot pain in action (pa). no n c om me rci al us e o nly conference presentation [page 4] [veins and lymphatics 2017; 6:6622] references 1. khan sk, malviya a, muller sd, et al. reduced short-term complications and mortality following enhanced recovery primary hip and knee arthroplasty: results from 6,000 consecutive procedures. acta orthop 2014;85:26-31. 2. berend kr, lombardi jr av, mallory th. rapid recovery protocol for perioperative care of total hip and total knee arthroplasty patients. surg technol int 2004;13:239-47. 3. mizner rl, petterson sc, snydermackler l. quadriceps strength and the time course of functional recovery after total knee arthroplasty. j orthop sports phys ther 2005;35:424-36. 4. mizner rl, petterson sc, stevens je, et al. early quadriceps strength loss after total knee arthroplasty. the contributions of muscle atrophy and failure of voluntary muscle activation. j bone joint surg am 2005;87:1047-53. 5. mizner rl, snyder-mackler l. altered loading during walking and sit-to-stand is affected by quadriceps weakness after total knee arthroplasty. j orthop res 2005;23:1083-90. 6. stevens je, mizner rl, snydermackler l. quadriceps strength and volitional activation before and after total knee arthroplasty for osteoarthritis. j orthop res 2003;21:775-9. 7. holm b, kristensen mt, bencke j, et al. loss of knee-extension strength is related to knee swelling after total knee arthroplasty. arch phys med rehabil 2010;91:1770-6. 8. brock tm, sprowson ap, muller s, reed mr. short-stretch inelastic compression bandage in knee swelling following total knee arthroplasty study (sticks): study protocol for a randomised controlled feasibility study. trials 2015;16:87. 9. yu gv, schubert ek, khoury we. the jones compression bandage. review and clinical applications. j am podiatr med assoc 2002;92:221-31. 10. munk s, jensen nj, andersen i, et al. effect of compression therapy on knee swelling and pain after total knee arthroplasty. knee surg sports traumatol arthrosc 2013;21:388-92. 11. andersen lo, husted h, otte ks, et al. a compression bandage improves local infiltration analgesia in total knee arthroplasty. acta orthop 2008;79:806. 12. partsch h, menzinger g, mostbeck a. inelastic leg compression is more effective to reduce deep venous refluxes than elastic bandages. dermatol surg 1999;25:695-700. 13. spence rk, cahall e. inelastic versus elastic leg compression in chronic venous insufficiency: a comparison of limb size and venous hemodynamics. j vasc surg 1996;24:783-7. figure 3. interaction plot pain in rest (pr). no n c om me rci al us e o nly hrev_master veins and lymphatics 2013; volume 1:e10 [page 30] [veins and lymphatics 2013; 2:e10] quantified hemodynamics of compression garments dean j. bender,1 helane fronek,2 ed arkans3 1circaid medical, san diego, ca; 2lajolla vein, lajolla, ca; 3aci medical, san marcos, ca, usa abstract various forms of compression therapy have been utilized for centuries in the treatment of venous disease, with inelastic bandage systems being used in the more acute treatment of severe venous disease and elastic compression stockings used for long-term management of the disease. however, with the advancement in inelastic adjustable compression wraps, we now have the option to consider long-term management of venous disease with an inelastic system and not just elastic systems. the aim of this study was to compare the hemodynamic effect of elastic compression stockings and inelastic compression wraps on venous disease patients when both products are applied to provide the same level of compression. utilizing the apg device (aci medical, san marcos, ca, usa), venous volumes, venous filling indexes and ejection fraction measurements were captured on 10 patients with varying degrees of venous disease. measurements were obtained for each patient at baseline (without compression), with either 30-40 or 20-30 mmhg elastic compression stockings (ecs) and an inelastic compression wrap (icw) (juxta-curestm by circaid medical, san diego, ca, usa). the compression level of the ecs was measured at the b1 point utilizing a picopress® [microlab elettronica sas, roncaglia di ponte san nicolò (pd), italy] and the icw was adjusted to provide the exact compression level as the ecs in order to compare the effects of inelasticity versus elasticity independent of compression differences. as expected, the use of compression therapy significantly improved all measures of hemodynamics although it was found that the icw (average static stiffness 14.3) further improved the measures over ecs (average static stiffness 2.4). average venous volumes were reduced over baseline with ecs by 19% while icw showed a reduction of 35%. average venous filling indexes were reduced with ecs by 25% and 39% with icw. the ejection fractions for both devices, ecs and icw, improved an average of 27%. when applying the same compression level, the stiffness associated with icw can further improve the venous hemodynamics of venous disease patients over ecs. for certain patients, using icw could prove to be a significant benefit in the management of their disease. introduction compression therapy continues to be the principal approach to the management of venous and lymphatic disease around the world. even with the significant amount of research that has been conducted demonstrating the benefits of inelastic or short-stretch compression therapy over elastic compression stockings (ecs)1-5 remain the dominant technology used in the management of chronic venous insufficiency (cvi). however, one main observation of most of these comparisons is that the compression level achieved with inelastic bandaging is significantly higher that that achieved with elastic compression stockings. this is due to the inherent characteristic of inelastic bandages to lose compression over time thus requiring an initial high compression level to provide a therapeutic effect. additionally with bandages there is no reliable method to apply bandages to a known compression level.6 however, now with the advancement of inelastic compression wraps (icw) to provide a reliable method of achieving known levels of compression that can be adjusted over time by the patient to maintain a therapeutic compression level, we can begin to practically consider the benefits of inelastic compression with improved patient compliance and concordance. thus, the purpose of this study is to demonstrate the differences in venous hemodynamics that are provided to venous disease patients when ecs and icw are used eliminating any discrepancy that may arise from variances in actual compression levels applied. materials and methods in this study the venous hemodynamic and compression levels of two compression devices were measured on a total of 10 patients (m/f 2:8; mean age 56.1 years with a standard deviation of 9.2 years). nine of the 10 patients were clinically evaluated to have venous disease while the 10th patient demonstrated mild lymphedema in her lower leg with no evidence of venous disease (table 1). utilizing air plethysmography (apg device from aci medical, san marcos, ca, usa) baseline venous hemodynamic data was collected for each patient. the measures included venous volume (vv), venous filling index (vfi) and ejection fraction (ef). these measures were taken on the leg in which the patient indicated the worse symptomatic condition (r/l 6:4). each patient was then measured and fit with either a knee-high 30-40 mmhg ecs or a 20-30 mmhg ecs. the actual compression level provided by the stocking was captured utilizing a pressure probe [picopress®, microlab elettronica sas, roncaglia di ponte san nicolò (pd), italy] placed under the garment at the b1 position while the patient was in the supine position with their leg slightly elevated. the patient was then asked to stand firmly on both feet and a second compression level reading was captured in order to determine the static stiffness index of the ecs (figure 1). the venous hemodynamic measures were then repeated with the apg device while the ecs remained in place. the stocking was removed and each patient was then fit with an icw (juxta-cures™ from circaid medical products, san diego, ca, usa). the icw was adjusted to provide the same compression level achieved with the ecw (± 1 mmhg) in the supine position and a second compression measured was captured in the standing position. the venous hemodynamic measures were again repeated while the compression wrap remained in place. results with the compression levels of the ecs and the icw essentially equivalent for each patient, we were able to determine the static correspondence:dean j. bender, circaid medical products inc., 9323 chesapeake drive, suite b2, san diego, ca 92123, usa. e-mail: dbender@circaid.com key words: compression, inelastic, elastic, hemodynamics, stockings, juxta-cures, circaid, venous volume, venous filling index, ejection fraction. conference presentation: part of this paper was presented at the international compression club (icc) meeting on stiffness of compression devices, 2012 may 25, vienna, austria (http://www.icc-compressionclub.com/). received for publication: 1 october 2012. revision received: 19 october 2012. accepted for publication: 19 october 2012. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright d.j. bender et al., 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e10 doi:10.4081/vl.2013.e10 no nco mm er cia l u se on ly conference presentation [veins and lymphatics 2013; 2:e10] [page 31] stiffness index exerted by each compression device. static stiffness of a compression device is defined as the difference between the compression exerted at the b1 point in the standing position versus the supine. the results (figure 2) clearly demonstrate that the ecs provided a low static stiffness index with an average of 2.4 mmhg, while the icw produced an average static stiffness of 14.3 mmhg. the results from the apg measurements were as expected with both the ecs and the icw significantly improving all three measures over baseline. furthermore, it was found that the icw provided a significant improvement over the ecs in vv and vfi reduction. the ecs reduced the vv (figure 3) by an average of 19% (baseline avg 135.5 ml and ecs avg 109.0 ml). the icw reduced vv by an average of 35% (icw avg 86.4 ml). similar reductions were seen in the vfi (figure 4) with a baseline avg 2.9 ml/s; ecs avg 2.2 ml/s (25% reduction from baseline) and the icw avg 1.7 ml/s (39% reduction from baseline). ef (figure 5) for both compression devices significantly improved over baseline with both devices averaging an improvement of 27%. discussion and conclusions the effect of compression devices on the venous system depends on two key factors; the pressure exerted on the limb and the stiffness of the materials used in the device. ecs devices are typically elastic in nature and are designed to provide a given compression range (mmhg) in the ankle region as defined by the manufacturer (i.e. 30-40 mmhg). because of the high elasticity in ecs devices the resulting fabric is not stiff and as such stretches with the movements of the limb. ecs devices can be thought to provide static stiffness where the compression level provided is essentially unchanged as the user moves from supine to standing to walking positions. icw have been available for over 20 years and deliver a compression level that is dependent upon the amount of tension applied to the closing straps. not until the past few years has such a device been able to deliver a known level of compression similar to the of ecs devices. this has been achieved by the inclusion of a built-in pressure system, bps™ (circaid medical products), which correlates the tension applied to the closing straps and the circumference of the limb to a known pressure range. as the name indicates, icws are inelastic, stiff in nature. this inelasticity has been demonstrated to provide a dynamic compression under the device where the compression level increases and decreases dramatically as the patient moves from supine to standing to walking positions. because ecs devices are readily available, have known compression levels, are aesthetically pleasing and relatively easy to apply for a patient when compared to bandaging, they have become the dominant technology in the treatment and management of cvi around the world. however, now that icw devices are becoming more prominent, have known compression levels and are easy for the patient to apply, we have the opportunity to consider the effect of stiffness (dynamic compression) in our treatment of cvi. this study was designed to eliminate the variable of compression level from the assessment of the effectiveness of the device by applying equal compression levels at the b1 point. this was achieved by adjusting the icw straps until a near equivalent compression reading was obtained on the pressure monitor. by eliminating the compression variable we are able to compare the effect that stiffness of the compression device exerts on any given patient. our results clearly showed that the icw was stiff and delivered a higher working pressure (14.3 mmhg) when the patients were in the standing position versus supine, while the ecs (2.4 mmhg) resulted in little to no increase in pressure on the same patients. as expected, both compression devices significantly improved the patient’s venous hemodynamics. applying pressure to the tissue of the limb and thus preventing the expansion of the veins during refilling maintains a smaller total volume of the complete venous system. however, due to the inelastic nature of the icw and the fact that the device has limited stretch under movement, the reduction in vv was significantly greater for the icw (36% p=0.008) than that achieved with the ecs (20% p=0.009). similarly, the inelasticity of the icw resulted in a 40% (p=0.028) reduction in vfi versus 23% (p=0.009) for the ecs, compared to baseline measurements without a compression device. interestingly, both ecs and icw improved the ef by 27% on average, although the measures did not achieve statistical significance (icw p=0.110; ecs p=0.055). the results on average were contrary to our expectations in that mosti and partsch7 reported in 2010 higher ef percentages with inelastic bandages versus ecs when measuring with strain-gauge plethsmography, although 7 out of the 10 table 1. patient population. patient ceap gender age limb stocking pressure no. label b1 compression (mm hg) 1 c2 m 52 rt 30-40 26 2 c3 f 65 rt 30-40 37 3 c2 f 60 rt 30-40 29 4 c4 m 52 lt 20-30 24 5 c4 f 64 rt 30-40 40 6 c3 f 65 lt 30-40 33 7 c2 f 57 lt 30-40 29 8 c3 f 56 lt 20-30 28 9 c3 f 32 rt 20-30 28 10 c0 f 58 rt 30-40 47 (lymph) average 56.1 32.1 ceap, clinical-etiology-anatomy-pathophysiology classification; m, male; rt, right; f, female; lt, left. figure 1. compression levels measured at the b1 position. ecs, elastic compression stockings; icw, inelastic compression wrap. no nco mm er cia l u se on ly conference presentation [page 32] [veins and lymphatics 2013; 2:e10] patients did see an improvement in ef with the icw over ecs. when considering this outcome further in view of our assumption that the ef with the icw would be significantly improved versus the ecs, we observed on a patient-by-patient basis for all 3 variables measured (vv, vfi and ef) that patients number 3, 7 and 9 (figure 5) had equivalent or superior results with the ecs versus the icw. this suggests that there was something unique about these patients that allowed the ecs to perform better than the icw in spite of the greater elasticity. unfortunately, we did not observe anatomical characteristics of these patients in order to determine if a correlation exists between anatomy of the limb and the effect of compression garments. one theory is that certain tissue characteristics may be influenced more by the tension applied by an ecs once stretched, resulting in an increased force inward on the limb. in contrast, the lack of elasticity of the icw simply prevents the limb from expanding, but does not reduce limb size based on movement. another thought is that the tissue make-up defuses the compression differently, thus mitigating the expected effect of the inelastic device. regardless, this is a phenomenon that we believe justifies further investigation and recommend that additional work be conducted to determine what variables should be considered in regards to determining when an elastic device should be chosen over an inelastic device. it is our intention to repeat this study including an anatomical and ultrasound evaluation of each patient and to also monitor sub-garment compression levels throughout the various tests. in conclusion, this study confirms that inelastic compression devices provide a superior hemodynamic effect on average and should be considered when the disease state dictates the need for the maximum impact on the circulatory system. references 1. kline cn, macias br, kraus e, et al. inelastic compression legging produces gradient compression and significantly higher skin surface pressures compared with an elastic compression stocking. vascular 2008;16:25-30. 2. spence rk, cahall e. inelastic versus elastic leg compression in chronic venous insufficiency: a comparison of limb size and venous hemodynamics. j vasc surg 1996; 24:783-7. 3. callam mj, harper dr, dale jj, et al. lothian and forth valley leg ulcer healing trial. 1. elastic versus nonelastic bandaging in the treatment of chronic leg ulceration. phlebology 1992;7:136-41. 4. charles h. compression healing of ulcers. j district nurs 1991;4:6-7. 5. partsch h, horakova ma. compression stockings for the treatment of venous leg ulcers [kompressionstrumpfe zur behandlung venoser unterschenkelgesch wure]. wienermedizinewochenschrift 1994;144:242-9. 6. lurie f, kistner r. interface pressure under compression bandages: current practice and a way to consistency. poster presentation american venous forum, february 9th 2012, orlando, fl, usa. 7. mosti g, partsch h. measuring venous pumping function by strain-gauge plethysmography. int angiol 2010;29:421-5. figure 2. static stiffness index (compression level difference between standing and supine at the b1 position measured in mmhg). ecs, elastic compression stockings; icw, inelastic compression wrap. figure 4. venous filling index – rate of venous refilling. ecs, elastic compression stockings; icw, inelastic compression wrap. figure 5. ejection fraction – percentage of venous blood expelled as a result of a single calf flex. ecs, elastic compression stockings; icw, inelastic compression wrap. figure 3. total venous volume. ecs, elastic compression stockings; icw, inelastic compression wrap. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2013; volume 2:e3 [veins and lymphatics 2013; 2:e3] [page 7] the mannequin-leg: a new instrument to assess stiffness of compression materials masafumi hirai,1 hugo partsch2 1department of vascular surgery, tohkai hospital, nagoya, japan; 2private practice, vienna, austria abstract stiffness of compression material, which has major impact on the performance of the used product, has mainly been investigated by clinical in vivo experiments up to now. experimental two-centre study has been performed in japan and in austria. results are presented using a novel leg model, whose circumference can mechanically be extended by 1 cm. the change of the interface pressure measured under a compression device corresponds to its stiffness. inelastic and multi-component bandages show stiffness values which are more than three times higher than those of elastic bandages and of compression stockings. there is a significant correlation between the stiffness values measured with the simple mannequin-leg and those obtained from extensometer measurements (hohen stein-method) on one hand, and also with data on the human leg (static stiffness index) on the other hand. the average variation coefficient with repeated measurements is 5.4%. the absolute values differ with the used pressure probes. the newly developed mannequin-leg offers a simple method to measure and to compare the stiffness of compression stockings and bandages, including the combination of such devices. introduction in the last years several experimental studies have clearly shown that stiffness is an important parameter determining the performance and efficiency of a compression product. in patients with chronic venous insufficiency higher stiffness is associated with a stronger effect concerning reduction of venous reflux,1 improved venous pumping function2,3 and edema reduction.4 measurements of the interface pressure of compression products on the leg in the lying and standing position allowed us to assess stiffness of a specific device in vivo and to correlate the so-called static stiffness index, which is the difference of standing minus lying pressure with the efficacy of the venous calf pump.5,6 laboratory tests using different extensometers are used by compression hosiery manufacturers mainly to check the pressure range of the products in relation to the leg size. however, the relationship between stretch and force (the slope of the hysteresis curve), characterizing the elastic property of the product, is not declared to the consumer. the used methodologies (hosy, hatra, instron, itf, mst-professional),7 are elaborate, which may be the reason why up to now the stiffness of a specific compression stocking is not declared by the producers. also the air-filled drum device developed by r. stolk8 is too sophisticated to be widely used.9 a report will be given on first experiences coming from japan (m.h.) and from europe (h.p.) achieved with a newly developed leg-model, specifically designed to assess stiffness in an easy manner.10 materials and methods this report combines results obtained in the laboratory of the inventor in japan (m.h.) with data measured in austria (h.p.). pressure was measured by air-filled transducers, 1 cm diameter, in japan (air-pack type analyzer, model ami3037®, ami co., tokyo, japan), and by picopress® probes, 4.5 cm diameter [microlab elettronica sas, roncaglia di ponte san nicolò (pd), italy], in austria. following the definition in the european committee for standardization document11 stiffness may be defined by the increase of the interface pressure of a compression device on the leg when the circumference increases by 1 cm. this induced hirai and coworkers to develop an artificial model, the socalled mannequin-leg, whose circumference can be enlarged by 1 cm (figure 1).10 flat, air-filled pressure probes are attached to measuring points marked on the model (points b1 and c). (point b1 on the human leg is characterized by the transition of the medial gastrocnemius muscle into the tendon; point c corresponds to a medial point at the level of the largest calf circumference). the pressure is registered immediately after application of the compression device and the model is enlarged by pushing down the lever three times. the difference between the highest-pressure increase after the third extension of the model and the following resting pressure is defined as the static stiffness index (si) (figure 2). results comparison compression stockings versus bandages compression stockings and elastic bandages show significantly reduced stiffness values compared to inelastic bandages (figure 3).10 as can be seen from figure 4 compression stockings differ from multi-component bandages more concerning the stiffness than the exerted pressure. all stockings tested were in a pressure range between 10 and 40 mmhg at b1 (picopress®), double stockings achieved pressures between 40 and 50 mmhg. their stiffness (si) did not exceed 10 mmhg. the tested bandages were in a comparable pressure range, but their stiffness values were all higher than 30 mmhg. elastic tubes wrapped over by elastic bandages (t+e in figure 4) showed si values between 10 and 15 mmhg, which were slightly higher than the corresponding values of the stockings. reproducibility thirteen different compression stockings were applied three times to the mannequin leg and pressure and stiffness were measured. figure 5 shows that the variation coefficients (vc) were small (3.9-5.4% in average), only applying double stockings over each other resulted in an increase of the vc to correspondence: hugo partsch, steinhäusl 126, 3033 altlengbach, austria. tel. +436641437274. e-mail: hugo.partsch@meduniwien.ac.at key words: compression therapy, stockings, bandages, stiffness, leg-model. conference presentation: part of this paper was presented at the international compression club (icc) meeting on stiffness of compression devices, 2012 may 25, vienna, austria (http://www.icc-compressionclub.com/). contributions: mh, instrument (mannequin-leg) design, results providing; hp, personal experiences reporting, manuscript writing. this work is dedicated to dr. masafumi hirai who started the research but unfortunately passed away. dr. hugo partsch concluded the project which is published in his honor and memory. conflict of interests: the authors declare no potential conflict of interests. received for publication: 25 august 2012. revision received: 15 october 2012. accepted for publication: 29 november 2012. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright m. hirai and h. partsch, 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e3 doi:10.4081/vl.2013.e3 no nco mm er cia l u se on ly conference presentation [page 8] [veins and lymphatics 2013; 2:e3] more than 20%. this shows clearly that the main cause for the variability is the changeable pressure distribution along the leg by donning the stockings several times. correlation with other in vitro measuring devices a comparison of stiffness values measured by the mannequin-leg and the hohenstein method performed in japan gave a significant correlation between the two methods10 (figure 6). correlation with in vivo assessment of stiffness forty custom made, small sized compression stockings between compression classes i and iii tested on the mannequin leg were applied to one and the same human leg (ankle circumference 22 cm) in which the pressure was measured in the lying and standing position at b1 by the same picopress® probe, and the static stiffness index was calculated by subtracting lying pressure from standing pressure.5 the same procedure was performed by applying elastic and then an inelastic bandage over a class ii stocking. figure 7 shows an excellent correlation between the pressures measured at b1 at the mannequin leg and the corresponding measuring point on the human leg in the lying position (r=0.91). there was also a statistically significant correlation for the stiffness values (r=0.75). discussion the clinical efficacy of compression devices depend mainly on the interface pressure and the stiffness of the product in use.1-4 for compression hosiery we rely on the pressure range in relation to the prescribed stocking-size given by the producers who, up to now, do not give us any information on the stiffness of their products. the pressure exerted by a bandage depends on the strength of application and the amount of layers. the stiffness of bandages is a rather complex parameter, relating mainly to the elasticity of the textile and to internal and external friction of the fibers. by adding several elastic layers over each other the final bandage is getting stiffer, mainly due to an increase of friction between the layers.12 these characteristics of different types of bandages could only be elucidated by examinations performed on human legs during the last few years.13,14 in vivo assessment of stiffness is based on the changes of interface pressure induced by changes of the circumference of the leg by standing up (static stiffness index)13 or by exercise (dynamic stiffness index).15 the preferred measuring point is b1corresponding to the site where the medial gastrocnemius muscle turns into the tendious part6 because this leg segment shows the biggest increase of circumference by standing up and by walking.8 in addition at this point the gastrocnemius tendon will protrude by contraction of the muscle so that the radius at the corresponding leg segment will get smaller contributing to an increase of local pressure due to laplace’s law. it is very obvious that such changes of the leg configuration will vary between single individuals being less pronounced especially in pathological cases like lymphoedema, or lipodermatosclerosis compared to normal legs. this explains the high variability of the reported stiffness values, so that comparisons of compression devices by in-vivo testing only may be problematic.16 in contrast the mannequin leg offers a well-standardized procedure for comparing different compression products always under the same anatomical condition in a resting position and after stretch of the textile by an increase of the leg circumference by 1 cm. the dimension of the air-filled pressure probes and its deformation under a compression device has an important impact on the numeric outcome. this fact explains the differences between the results achieved with the ami® transducer and the picopress® device. as a consequence one should be careful by figure. it shows a picture of the model, which is commercially available (ami techno, tokyo, japan). the model, made of plastic material has an ankle circumference of 20.5 cm and a calf circumference of 34.5 cm. there is a lengthwise transversal cut, which can be extended medially and laterally by 5 mm by pushing down a lever so that the circumference of the model will increases by 1 cm at each level. figure 4. characterization of several compression stockings and multi-component bandages concerning pressure (x-axis) and stiffness values (y-axis). the application of a second stocking over the first in 6 cases increases the stocking pressure to values over 40 mmhg. [t+e=tubular device (tubulcus®) + elastic bandage wrapped over]. all multi-component bandages (in the upper rectangle) showed stiffness indices over 30 mmhg (picopress®). figure 2. a ready made compression stocking, size small, achieves a pressure of 33 mmhg at the b1 point of the model. this pressure drops to 30 mmhg after stretching the model by 1 cm three times. si=3 mmhg (picopress® probe). figure 3. comparison of stiffness values (mean+standard deviation) between elastic stockings (left), long stretch bandages (middle) and short stretch bandages (right), resting pressures 23-46 mmhg (ami-3037®). the difference between elastic and inelastic material is significant (p<0.001). no nco mm er cia l u se on ly conference presentation [veins and lymphatics 2013; 2:e3] [page 9] comparing absolute values. based on the experiences by measuring the static stiffness index on the human leg it has been proposed to take the value of 10 as a reasonable borderline to differentiate elastic (<10) from inelastic material (>10).12 this same cut-off could also be accepted for the mannequin-leg when a picopress® sensor is used (figure 4). using the ami transducer® the cut-off value is lower and comes closer to the results of the tests performed with the hohenstein-method which may be considered as the gold-standard method (figure 6). however, in contrast to the picopress® probe17 accuracy and variability of the ami® probe has not yet been clearly established in clinical studies. preliminary comparisons of custom-made stockings between mannequinresults using picopress® and different kinds of extensometers (hosy, instron) showed also excellent correlations. previous investigations had also shown a good correlation between pressure and stiffness values on human legs with extensometer data.18 methodological flaws of the mannequin leg compared to the in vivo situation are the rigid consistency of the model leading to slightly higher pressure values than those measured over soft, yielding tissue and the relatively flat local radius at b1 which does not change when the model is extended. another draw-back is the fact that up to now only one small sized model is available. larger models or even forms containing a thigh part could be useful in order to obtain stiffness data also from usual european sized and thigh high stockings. as shown in this report the obtained data will depend on the dimensions of the pressure probes so that comparisons of absolute data between will only be possible when the same kind of pressure monitoring system is used. conclusions the presented concept of the extensible mannequin leg is a practically important step forward to assess the stiffness of different compression products and their combinations by a simple and reproducible technique. references 1. partsch h, menzinger g, mostbeck a. inelastic leg compression is more effective to reduce deep venous refluxes than elastic bandages. dermatol surg 1999;25:695700. 2. partsch h. improving the venous pumping function in chronic venous insufficiency by compression as dependent on pressure and material. vasa 1984;13:58-64. figure 6. correlation of stiffness measured by the hohenstein method (x-axis) and by the mannequin-leg (y-axis) in 17 stockings (ami-3037®). figure 7. correlation for pressure at b1 (left) and stiffness (right) between the mannequin leg (x-axis) and a human leg (y-axis). encircled are the values obtained after wrapping elastic and inelastic bandages over a class ii stocking. figure 5. measurement of pressure at b1 (left) and of stiffness (right) on the mannequin leg of 13 different compression stockings, three times repeated (picopress® probe). no nco mm er cia l u se on ly conference presentation [page 10] [veins and lymphatics 2013; 2:e3] 3. mosti g, mattaliano v, partsch h. inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous reflux. phlebology 2008;23:287-94. 4. van geest aj, veraart jc, nelemans p, neumann ha. the effect of medical elastic compression stockings with different slope values on edema. measurements underneath three different types of stockings. dermatol surg. 2000;26:244-7. 5. partsch h. the use of pressure change on standing as a surrogate measure of the stiffness of a compression bandage. eur j vasc endovasc surg 2005;30:415-21. 6. partsch h, clark m, bassez s, et al. measurement of lower leg compression in vivo: recommendations for the performance of measurements of interface pressure and stiffness: consensus statement. dermatol surg 2006;32:224-32. 7. partsch h, rabe e, stemmer r. compression therapy of the extremities. paris: editions phlebologiques francaises; 2000. 8. stolk r, wegen van der-franken cp, neumann ha. a method for measuring the dynamic behavior of medical compression hosiery during walking. dermatol surg 2004;30:729-36. 9. van der wegen franken k. medical elastic compression stockings. thesis, university of rotterdam, the netherlands; 2009. 10. hirai m, niimi k, miyazaki k, et al. development of a device to determine the stiffness of elastic garments and bandages. phlebology 2011;26:285-91. 11. european committee for standardization (cen). non-active medical devices. working group 2 env 12718: european prestandard “medical compression hosiery” cen/tc 205. brussels, cen; 2001. 12. mosti g, mattaliano v, partsch h. influence of different materials in multicomponent bandages on pressure and stiffness of the final bandage. dermatol surg 2008;34:6319. 13. partsch h, clark m, mosti g, et al. classifi cation of compression bandages: practical aspects. dermatol surg 2008;34:600-9. 14. hirai m, niimi k, iwata h, et al. a comparison of interface pressure and stiffness between elastic stockings and bandages. phlebology 2009;24:120-4. 15. van der wegen-franken k, tank b, neumann m. correlation between the static and dynamic stiffness indices of medical elastic compression stockings. dermatol surg 2008;34:1477-85. 16. schuren j. compression unravelled. thesis, university of rotterdam, the netherlands; 2011. 17. partsch h, mosti g. comparison of three portable instruments to measure compression pressure. int angiol 2010;29:426-30. 18. partsch h, partsch b, braun w. interface pressure and stiffness of ready made compression stockings: comparison of in vivo and in vitro measurements. j vasc surg 2006;44:809-14. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2017; volume 6:6626 [page 8] [veins and lymphatics 2017; 6:6626] experimental and numerical approach for the investigation of interface pressure applied by compression bandages fanette chassagne,1-4 pierre badel,1-3 reynald convert,4 pascal giraux,5 jérôme molimard1-3 1ecole nationale supérieure des mines de saint-etienne, cis-emse, sainbiose, f-42023 saint etienne, france; 2inserm, u1059, saint-etienne, f-42000, france; 3université de lyon, sainbiose, f-42000 saint etienne, france; 4thuasne, bp243, 92307 levalloisperret, france; 5department of physical medicine and rehabilitation, faculty of medicine, university jean monnet, saint-etienne, france introduction compression bandages are a common treatment for some venous or lymphatic pathologies, whose efficacy is admitted.1 the bandage applies a pressure on the external surface of the leg which is then transmitted to the internal tissues. this interface pressure depends on several parameters such as: i) the bandage components, the application technique, their mechanical properties and stretch; ii) the patient’s morphology and soft tissue mechanical properties; iii) other parameters like friction for example. various bandages are proposed by manufacturers and their study requires reliable methods to predict interface pressure applied by these bandages. for now, the only method for interface pressure computation is laplace’s law: p = nt / r , t > 0 , r > 0 (1) with p the pressure (n * mm–2), n the number of layers of the bandage, t the bandage tension (ratio between the force needed to stretch the bandage and the bandage width) (n * mm–1) and r the local radius of curvature (mm). however, this equation is questioned in the community.2,3 this work aims to propose an original point of view on this problem. we propose an experimental and numerical approach for the investigation of interface pressure applied by compression bandages. materials and methods interface pressure measurements pressure measurements were performed on 30 healthy subjects (15 males 15 females) in order to evaluate the impact of bandage mechanical properties, application technique and subject’s morphology on the interface pressure applied by elastic compression bandages. these measurements were performed on the medial part of the leg at the heights of measurement point b1 and c thanks to pressure sensors picopress® (microlab elettronica, nicolò pd, italy). two elastic bandages were used in this study: the biflex® 16 (b16) and biflex® 17 (b17) (manufactured by thuasne), which were applied on the leg in a spiral pattern with 2 or 3 layers (i.e. 50% and 66% overlap) and with a 1.3 stretch (following manufacturer’s recommendations). these bandages have a similar structure but differ in their elastic moduli (which links the bandage tension to its stretch), respectively equal to 0.232 and 0.444 n/mm for the b16 and the b17.4 numerical simulation whitin the aim to predict interface pressure applied by compression bandages, a patient-specific numerical simulation was designed for 5 female subjects. for this, their leg geometries were obtained with a 3d optical scanner (artec 3d® scanner) and the bandage geometry was built in matlab®, in order to fulfil the 1.3 stretch requirement. bandage model was inflated then relaxed around the subject’s leg model. the simulation was run for four bandages: b16 and b17 applied in a spiral pattern with 2 and 3 layers (figure 1). interface pressure given by the numerical simulations was then confronted to the experimental values and to those computed with laplace’s law. results interface pressure measurements the interface pressure measurements showed a very strong correlation between pressure and bandage tension (p<0.00001) and between pressure and bandage overlapping (p<0.00001). moreover interface pressure tends to decrease when leg circumference increases. however, these results highlighted the fact that interface pressure is not directly proportional to bandage elastic moduli and so not proportional to bandage correspondence: fanette chassagne, ecole nationale supérieure des mines de saintetienne, cis-emse, sainbiose, f-42023 saint etienne, france. e-mail: fanette.chassagne@emse.fr this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright f. chassagne et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6626 doi:10.4081/vl.2017.6626 figure 1. pressure distribution over a leg for 4 different bandages. no n c om me rci al us e o nly conference presentation [veins and lymphatics 2017; 6:6626] [page 9] tension nor to the leg circumference and consequently to a global estimate of the radius of curvature. these results question the use of laplace’s law for interface pressure computation and support the need to develop new tools for interface pressure computation. numerical simulation numerical model differs significantly from laplace law, with differences up to 19.6%. the main difference between the two models being the mechanical behaviour of the leg, it is proposed that the leg shape variation due to compression plays an important role in pressure generation through changes in curvature radii. nevertheless, significant discrepancy between numerical model and experiments are reported. it is likely that the model relevance would be increased by improving the simulation of bandage application technique. besides, the presence of the pressure sensors might locally change the pressure by modifying the local curvature. discussion and conclusions laplace’s law does not take into account the mechanical effects involved in bandage application. more specifically, it has been shown that changes in the leg geometry influence the applied pressure. this study demonstrated that, using an appropriate surrogate model, such a simulation could be an efficient tool for interface pressure prediction. future works will be focused on improving the simulation and investigating possible errors due to the pressure sensors. references 1. amsler f, willenberg t, blättler w. in search of optimal compression therapy for venous leg ulcers: a meta-analysis of studies comparing divers bandages with specifically designed stockings. j vasc surg 2009;50:668-74. 2. schuren j, mohr k. the efficacy of laplace’s equation in calculating bandage pressure in venous leg ulcers. wounds 2008;4:38-47. 3. thomas s. the production and measurement of sub-bandage pressure: laplace’s law revisited. j wound care 2014;23:234-6, 238-41, 244. 4. chassagne f, martin f, badel p, et al. experimental investigation of pressure applied on the lower leg by elastic compression bandage. ann biomed eng 2015;43:2967-77. no n c om me rci al us e o nly 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2016; volume 5:5994 [veins and lymphatics 2016; 5:5994] [page 27] adjustable topical compression foot wrap, is more effective than a dopamine agonist, ropinirole, in reducing the symptoms of moderate to severe restless leg syndrome dean bender,1 phyllis j. kuhn,1 daniel j. olson,2 john p. sullivan3 1lake erie research institute, inc., girard, pa; 2baycity associates in podiatry, inc., erie, pa; 3neurology associates of erie, erie, pa, usa the objective was to measure the reduction of symptoms with an adjustable topical compression device (restiffictm brand pressure application system; lake erie research institute, inc., girard, pa, usa) of the foot in patients suffering with moderate to severe willis-ekbom disease [restless leg syndrome (rls)]. we designed an experimental study: a single arm, open label single center clinical trial with a repeated measures design conducted from april 2009 to august 2012. follow-up averaged 1.3 years. forty-seven patients were enrolled, 11 were excluded, 7 withdrew, one with usable results. 30 otherwise healthy adults, 22 women and 8 men, mean age 51.5 years, (range 30 to 75 years) diagnosed with moderate to severe primary rls met eligibility criteria. each patient was provided a pair of the restiffictm devices that applies targeted compression to the abductor hallucis and the flexor hallucis brevis muscles in the foot when worn during rest and sleep. main measure, patient-generated international rls study group (irlss) rating scale; secondary measure, physician-generated clinical global impression (cgi) scale. patients were surveyed at period 1: baseline (no device) day 1-7, 3 times per period; period 2: with device days 8-28, 8 times per period; period 3: without device days 29-35, 3 times per period; period 4: with device days 36-56, 8 times per period. meta-analysis used to compare restiffictm to historic reports of ropinirole and placebo pill. demographics, disease severity assessment tools are similar among studies. restiffictm irlss score decreased from 25.05±5.33 (a mean baseline on the day 1) to 7.83±6.33 (a mean score on day 56), overall reduction of 17.22±6.16 (p=0.0001) representing two levels of improvement from severe to mild. change in mean irlss scores were significantly greater for restiffictm, 17.22, compared with historic reports of ropinirole, 12, and its placebo, 8.9 (p<0.05). cgi responders were significantly increased for restiffictm, 90% (27/30), compared with ropinirole 63% (293/464) (p<0.05). only minimal, transient side effects were reported that were relieved by loosening the straps. restiffictm was 1.44 times as effective as historically reported ropinirole in reducing irlss scores. restiffictm represented a marked improvement over current pharmaceutical solutions in both efficacy and safety. correspondence: dean bender, lake erie research institute, inc., 8770 brooks road, girard, pa 16417, usa. e-mail: dbender@mediusa.com this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright d. bender et al., 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5994 doi:10.4081/vl.2016.5994 no n c om me rci al us e o nly paolo zamboni symptoms of ccsvi in multiple sclerosis paolo zamboni correspondence: paolo zamboni, e-mail: paolozamboni@icloud.com in the current issue of veins and lymphatics, pietro bavera publishes an article where he assesses the more frequent symptoms of ccsvi mostly in a multiple sclerosis (ms) population.1 he revises almost 400 cases of ccsvi patients who underwent venous pta with a long follow up of 4 years. his conclusion is that endovascular therapy seems a proper treatment for the more frequent symptoms reported by ms patients. briefly after the publication the article is now the more popular article of our journal, with thousands of downloads. curiously, today, professor juurlink publishes a commentary on the journal of neurology and neurosciences where he strongly claims for non-pharmacological treatments capable to seriously reduce the ms symptoms. among them, special interest is given to all treatments capable to improve venous outflow from the brain.2 again, cerebral venous return is considered among responsibles of specific brain symptomatology actually orphan of effective pharmacological treatment. references bavera p. may symptoms of chronic cerebrospinal venous insufficiency be improved by venous angioplasty? an independent 4-year follow up on 366 cases. veins and lymphatics 2015;4:5400. [crossref] juurlink bhj. time to revisit non-pharmacological research approaches to ameliorate mul ple sclerosis symptoms. j neurol neurosci 2015;6:52. [abstract] [top] hrev_master veins and lymphatics 2016; volume 5:5990 [veins and lymphatics 2016; 5:5990] [page 19] role of compression after liposuction håkan brorson, barbro svensson, karin ohlin department of plastic and reconstructive surgery, malmö university hospital, sweden introduction liposuction, which is a very effective treatment modality to reduce lymphedema, can be performed as soon as the pitting component had been corrected by a phase of initial compression (figure 1). just like after conservative treatment, the use of compression garments after liposuction is very important to maintain the outcome. garments should be prescribed in such numbers so that the edema does not recur. a common mistake is that the patient receive one, or if lucky two, garments, after treatment. when the arm or leg is swollen again the patient comes back to the therapist and treatment starts again, and so on. instead the patient must be followed up at his needs in order to prevent recurrence. this means that treatment must be individualized. an elderly woman may need two garments every 6 months, while a young active patient with a heavy work may need two garments every month. one can draw a parallel to the dosage of insulin to a patient with diabetes that in the same way must be individualized. nobody prescribes two vials of insulin for 6 months, when the patient needs that same amount for one month. the purpose of compression therapy is to increase the interstitial pressure so that the capillary filtration is decreased. when treated with standard compression garments a study showed a reduction of the excess volume (1680 ml; range 670-3320) after two weeks with 20% (range 5-37) corresponding to 338 ml (range 95-1225).1 studies of treatment for 6 months have shown a reduction of excess volume of 17% (range 16-52), corresponding to a volume of 139 ml (range 150-345).2 compression garments can be used at the onset of symptoms to possibly prevent the development of lymphedema. garments that are used throughout the day (15 years’ followup)3 as well as only daytime (6 months followup)2 prevent the edema to recur. compression garments must be ordered by a qualified and experienced lymphedema team, consisting of a lymph therapist with a basic education in physiotherapy or occupational therapy and a physician. the team should have vast knowledge regarding various compression trademarks and how to take measurements for ordering of garments. in order to increase compliance and feedback, the team should never let the patient have the measurements for ordering of garments taken by a retailer outside of the team. ordering of garments when ordering for compression garments the following must be considered: i) compression class; ii) material; iii) size; iv) design; v) the patient’s ability to take on/off the garment and the ability to care for it. compression class the compression classes (ccl) provisionally adopted by the european standardization committee are summarized in table 1.4 compression garments for the arm and hand are usually ordered in ccl 2. in case of incipient symptoms ccl 1 can be sufficient. garments for the leg often require ccl 3 or more. if the lymphedema requires higher compression, a combination with an additional garment on top on the first one can be used. this increases the compression further and can be easier to put on than just one garment in very high compression class. in severe cases another leg long garment may be needed, either a round knitter or a flat knitted. materials and methods materials and production methods vary between different manufacturers. there are circular knitted garments without a seam and flat knitted with a seam. the higher compression classes are usually flat knitted. it should be noted that each class is within a compression interval, and within the compression class different materials may have higher or lower compression. verify how long the manufacturer guarantees that the garment lasts for the specified compression. garments in softer materials have a shorter durability and must be replaced more often, even though the compression is the same as that of a more rigid garment. patients with sensitive skin may need to try different brands. if the patient encounters irritation at the elbow or at the back of the knee a soft lining can be sewn into the sock. there are also modifications in the knitting technique that decreases skin irritation at these locations. there are also different brands of silicone or hydrogel plates, to be put under the garment that will relieve irritated skin. size compression stockings are produced in different standard sizes or made to measure: standard size garments: i) advantage: the patient receives the garment at once; measuring is simpler; ii) disadvantage: do not have enough widths and lengths to suit all; smaller selection of materials; smaller selection of models. made to measure garments: i) advantages: optimal fit; greater possibility when re-measuring in order to gradually reduce the size of the garment as the edema is reduced; ii) disadvantages: more extensive measuring; delivery time; the cost. if made to measure is selected after treatment, the patient must either use a standard garment or bandage the extremity until the custom made garment has been delivered. later on, when measuring for the next garment, the measurements must be compared with the previous order to check that the garment gives the intended effect. the technique when measuring varies from brand to brand. see the instructions of each manufacturer. design compression stockings are available in various models. you can also choose various fasteners, such as silicone ribbon at the top of the garment or a band around the waist. each manufacturer provides information about the different varieties available. which one you choose depends on: i) edema location; ii) the patient’s body constitution; iii) the patient’s wishes; iv) how compression stocking works in daily activities. taking on and off the garment and maintenance of the garment. check that the patient can maintain and manage to take on and off the garment. if the patient has problems one must arrange for someone to help out, such as a relative or home care/district nurse, who also may need instructions. at follow-up, check that this has worked. the manufacturers provide different types of aids that facilitate the procedure. use the various alternatives depend on the severity of the edema: i) continuously throughout the day; ii) continuously during daytime correspondence: håkan brorson, department of plastic and reconstructive surgery, malmö university hospital, se-205 02 malmö, sweden. e-mail: hakan.brorson@med.lu.se this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright h. brorson et al., 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5990 doi:10.4081/vl.2016.5990 no n c om me rci al us e o nly conference presentation [page 20] [veins and lymphatics 2016; 5:5990] (the garment must be taken on in the morning); iii) only use it when performing strenuous work (prolonged static or heavy work, where patients experience that the extremity gets swollen) and at long journeys by plane or car. after a few weeks, it is important to verify that compression stockings have the intended effect. rash after use may be due to an allergic reaction to detergents, or to the garment material, which is very uncommon. if the excess volume has increased at follow-up, this can be due to several factors: i) bad patient compliance; check the patient’s motivation and every day routines; ii) the patient has not understood how the garment must be taken care of or has taken it on in the wrong way (for example not pulled it high enough); iii) incorrect measurements have been taken check them; iv) insufficient compression class increase compression class at the next order; v) progress of underlying malignancy. costs the life span of a compression garment varies between 3 and 6 months, provided that the patient has two garments to switch between. two garments are required so that the patient every day can take on a newly washed garment. at the first time only one garment is ordered to evaluate the fit and to be able to make any corrections. then the second garment is promptly ordered. henceforth two garments should be ordered at each occasion. the minimum amount of compression garments for an arm lymphedema is two every 6 months. if gloves/gauntlets are needed, 2-3 garments every 6 months may be needed since they wear out faster. for legs new garments may need to be reordered every 3-6 months depending on activity level. very active patients and children may need up to 6 stockings every six months. there should be no upper limit to how many garments that need to be ordered. additional garments may be needed at the start of treatment. funds must be set aside anyway so that patients can obtain sufficient numbers of compression garments as described above. controlled compression therapy gradually increasing compression when an untreated edema is subjected to compression, the excess volume is reduced and compression must be adapted continuously. this can be done with bandaging or controlled compression therapy. the methods can be used individually or in combination. it is very important that treatment outcome is checked regularly with excess volume measurements and that treatment continues until there is minimal or no pitting (figure 1). no manual lymph drainage is needed so the treatment is less time consuming and the patient does not need to be on sick leave. also manual lymph drainage lacks evidence in reduction of the excess volume.5-7 how can compression be increased? there are several ways to increase compression pressure: i) decrease circumferential measurements of garments; ii) increase compression class; iii) multilayer; iv) amount of garments; v) take in existing garments. as long as the extremity shows pit on pressure the garment can be reduced in size by using a sewing machine. the circumference can be decreased at 0.5-1 cm increments at regular controls and can also be easily made by the patient when necessary. after 3-4 times the patient needs new garments in a smaller size. every time new garments are ordered they are ordered in a smaller size than last time, if ordering made to measure garments. the method is an alternative to bandaging in connection with the initial edema reduction.1 controlled compression therapy can be used as the only treatment. it can also be used while waiting for other physical-medical methods or surgical treatment as may be indicated. treatment and results for arm lymphedema ccl 2 is mostly used. occasionally ccl 3 may be necessary. the glove can be made of the same material or thinner material (glove for burns) if the patient’s hand edema is not as pronounced. at follow-up, measurements for garments are taken much tighter than the recommendations specified by the manufacturer in order to increase compression and to get sufficient compression for a longer time. for leg lymphedema ccl 3 (leg long) and ccl 2 (knee long) are used. this particular measuring requires an experienced therapist. further follow-up and reduction of the compression garments is made when needed and at scheduled visits at 1 and 3 months. up to the table 1. compression classes as per the european standardization committee. class no. description value ccl i: mild 15-21 mm hg* ccl ii: moderate 23-32 mm hg ccl iii: strong 34-46 mm hg ccl iv: very strong 49mm hg ccl, compression class. *compression at the ankle. the values indicate the compression exerted by the compression garments at an hypothetical cylindrical ankle. figure 1. transforming a pitting lymphedema to a non-pitting one. if the remaining excess volume is still a problem for the patient liposuction can be performed to get complete reduction. no n c om me rci al us e o nly conference presentation [veins and lymphatics 2016; 5:5990] [page 21] 3-month control, when new garments are ordered in smaller size, the patient made 3-4 reductions (using a sewing machine), when he/she notices that the compression decreases. further follow-up with ordering of new garments is done every 3 months until the maximum edema reduction is achieved, i.e., when there is no minimal pitting (3-4 mm for arms and 5-6 mm for legs). this is usually achieved after 6-12 months of treatment. the excess volume is measured at each control. if the excess volume is stable at 1 year, the patient is provided with garments for the next 6 months. if still stable at 1.5 years the patients is seen at 2 years. then, if stable, the patient needs only to be seen once a year and is provided with all the garments for the following year, and so on. controlled compression therapy with compression garments shows an excess volume reduction of 47% (range 2-80) after one year. already after two weeks with a standard garment a reduction of 20% (340 ml) is achieved. the results are permanent after 2 years. these results have been achieved with excess volumes of on average 1.7 liters (0.7-3.3 l), the relative volume of 1.6 (range 1.3 to 2.7) and long duration (mean duration 8 years, range 119).1,8 lymphoscintigraphy shows signs of increased mobilization of lymph after 3 months of compression therapy. after 12 months there is no difference compared with values before treatment.9 this is consistent with findings from combined physiotherapy.10 follow-up (summary) initial follow-up visits are made with a few weeks apart and can then, at steady state, be reduced to 1-2 times per year. treatment is lifelong. the control procedures must be included: i) measurement and calculation of absolute and relative excess volume; ii) review of the compression garments’ fit and elasticity. when necessary it is reduced in size by the use of a sewing machine and/or new garments are ordered; iii) at steady state with persistent troublesome excess volume and minimal or no pitting liposuction can further reduce the excess volume. conclusions all five strategies of increasing compression can be combined to treat leg lymphedema. three of the strategies are useful also when you want to shape specific parts of the leg. you localize the parts needing extra compression by comparing circumferences and by estimating pitting. finally most important is to involve the patient in the decisions. it is the patient that has to do the job, putting on the garments every day and keep them on day and night. if they feel they have a choice in which way to go they will most likely do their part. we used different combinations of increasing compression, the patients needed different amount of garments and different intervals between checkups, but the important thing is to help them never loose control over their lymphedema and help them back on track if the edema temporarily gets worse. advice to the patient the patient should be advised about: i) taking on the garment; ii) seeing the manufacturers’ instructions; iii) rubber gloves can be used for better grip; iv) easy slide (bsn medical, kent, wa, usa) is a simple pull-on tool for both leg and arm; v) anti-slip mat on the floor can make it easier to brace against and herd up the sock over the heel; vi) the material should be distributed evenly over the limb so that pleats are avoided. pleats lead to folds and increased pressure; vii) it is important that the arm garment is pulled high enough so that the elbow marking is at the right level. the elbow and the terminations need to be at the correct level. poorly fitted garment leads to lower pressure and risk of chafing. care to maintain the garment’s properties during 3-6 months it must be handled according to the manufacturer’s instructions. the garment is washed daily to restore its compression and shape and to remove the salt precipitations from perspiration. the salt dries the skin and increases the risk of skin irritation. the garment should be left to dry horizontally to avoid stretch. it dries faster if you first roll it in a towel and gently squeeze the water. soaking, use of fabric softener and tumbling harm the compression garments. fat, oil based skin creams should not be used because they can dissolve the rubber thread in rubber-based garments. use moisturizing lotions instead. miscellaneous skin rash after using the garment may be due to allergic reaction to detergent or the material used. if a new garment feels too tight, it can be stretched over an object while drying after washing, for example a bottle that is somewhat wider the extremity for a few hours. taking in the garment can be made between scheduled visits if it is too loose or as part of the treatment for controlled compression therapy. the patient can be instructed to do it by him/herself. thick seams, for example on the fingers, may need to be stretched somewhat before use, to prevent chafing. during hot summer days, it is wise to bathe or shower with compression garment on and let it dry on the skin. this provides a cooling effect. references 1. brorson h, svensson h. liposuction combined with controlled compression therapy reduces arm lymphedema more effectively than controlled compression therapy alone. plast reconstr surg 1998;102:1058-67. 2. swedborg i. effects of treatment with an elastic sleeve and intermittent pneumatic compression in post-mastectomy patients with lymphoedema of the arm. scand j rehabil med 1984;16:35-41. 3. brorson h. from lymph to fat: liposuction as a treatment for complete reduction of lymphedema. int j low extrem wounds 2012;11:10-9. 4. european committee for standardisation (cen/tc 205wg2). medical compression hoisery. european standard cen/env 12718, 2001. 5. andersen l, hojris i, erlandsen m, andersen j. treatment of breast-cancerrelated lymphedema with or without manual lymphatic drainage--a randomized study. acta oncol 2000;39:399-405. 6. dayes is, whelan tj, julian ja, et al. randomized trial of decongestive lymphatic therapy for the treatment of lymphedema in women with breast cancer. j clin oncol 2013;31:3758-63. 7. javid sh, anderson bo. mounting evidence against complex decongestive therapy as a first-line treatment for early lymphedema. j clin oncol 2013;31:3737-8. 8. brorson h, svensson h. complete reduction of lymphoedema of the arm by liposuction after breast cancer. scand j plast reconstr surg hand surg 1997;31:137-43. 9. brorson h, svensson h, norrgren k, thorsson o. liposuction reduces arm lymphedema without significantly altering the already impaired lymph transport. lymphology 1998;31:156-72. 10. ketterings c, zeddeman s. use of the cscan in evaluation of peripheral lymphedema. lymphology 1997;30:49-62. no n c om me rci al us e o nly hrev_master veins and lymphatics 2017; volume 6:6533 [page 40] [veins and lymphatics 2017; 6:6533] chronic cerebro-spinal insufficiency in multiple sclerosis and meniere disease: same background, different patterns? pietro maria bavera,1,2 federica di berardino,3 piero cecconi,2 laura mendozzi,2 valentina mattei,2 dario carlo alpini2,4 1vascular imaging diagnostician for medick-up vascular lab, milan; 2department of clinical sciences, university of milan, and audiology unit, fondazione irccs ca’ granda ospedale maggiore policlinico, milan; 3irccs s. maria nascente don carlo gnocchi foundation, milan; 4vertigo school, milan italy abstract multiple sclerosis (ms) is a chronic disease of the central nervous system characterized by demyelinating lesions with acute phases and progressive loss of sensorimotor functions. mèniére disease (md) is a disorder of the inner ear characterized by acute spells of vertigo and hearing loss and progressive loss of cochleo-vestibular function. both the diseases have a multifactorial pathogenesis and quite the same chronic cerebro-spinal insufficiency (ccsvi) frequency. however, as far as author’s knowledge concerns, no patients affected with both diseases are described so far. the aim of this paper is to investigate whether ms and md present different ccsvi patterns. three groups of patients were enrolled: 60 definite ms 27 definite unilateral md (men) 41 with other no-mèniére, audiovestibular disorders (ovd). all subjects underwent magnetic resonance venography (mrv) and venous duplex (ecd) and only patients that satisfied both mrv and ecd ccsvi diagnostic criteria were considered. j1 was normal in 57% of ms, 88% of men and 95% of ovd. stenosis (st) were detected, respectively, in 30% of ms and 2% in men and ovd. j2 was normal in 78% of ms, 64% of men and 95% of ovd. at this level alterations of the trunk (at) were detected in 17% in ms and 26% in men; j3 was normal in 74% of ms, 64% of men and 86% of ovd. at were found in 15% of ms, 26% of men and 8% of ovd. hyperplasia of the vertebral veins was observed in 35% of ms, 40% of men and in 15% of ovd. other compensatory collaterals were detected in 25% in ms and only in 5% in men and ovd. our results indicate that the ms pattern is characterized by j1 stenosis, j2 trunk alterations, a prevalence of j1-j2 medial-distal alterations, compensatory collaterals besides vertebral venous system. md pattern is characterized by trunk alteration in j3, a prevalence of j3j2 medial-proximal alterations and vertebral veins hyperplasia without other detectable collaterals. although the group of patients with venous alterations is very small, ovd patients show a ccsvi pattern that is more similar to md than ms pattern. the difference between ms and md patterns indicates that ccsvi is not a unique entity and it could be an explanation of the fact that subjects affected with both the diseases are not reported. introduction multiple sclerosis (ms) is a chronic disease of the central nervous system characterized by demyelinating lesions. typical course is alternating of acute phases followed by unpredictable periods of remission but, usually, with a progressive loss of sensorial-motor functions. a multifactorial pathogenesis is nowadays accepted1 even if a unique final autoimmune mechanism is usually considered. mèniére disease is a disorder of the inner ear characterized by acute spells of vertigo, tinnitus and hearing loss followed by unpredictable period of remission but, usually, with a progressive loss of vestibular and cochlear function. a multifactorial pathogenesis is accepted2 even if a unique final hydraulic mechanism, the so called endolymphatic hydrops (eh), is usually considered.3 both ms4-6 and md7-9 presents quite the same frequency of cerebro-cervical venous abnormalities as evaluated by means of magnetic resonance venography (mrv) or duplex exam (ecd) adopting the criteria for the diagnosis of chronic cerebro-spinal insufficiency (ccsvi).10 despite this, as far as author’s knowledge concerns, no patients affected with ms and md are reported in literature, so far. the aim of this paper is to investigate if ms and md present different ccsvi patterns. materials and methods three groups of patients were enrolled: 60 definite multiple sclerosis (ms, 43 females and 17 males, mean age 43.7 yy); 27 definite unilateral ménière disease (men, 17 females and 10 males, mean age 41.5 yy);11 41 other vestibular disorders (ovd, 28 females and 13 males, mean age 43.3 yy). these subjects presented unilateral hearing loss and vestibular hypofunction due to different cases: 8 otosclerosis, 3 acoustic neuroma in the othologic phase, 9 inner ear vascular disorders (so called lyndasy-hemenway syndrome), 21 vestibular neuritis.12 multiple sclerosis diagnoses were performed by a trained neurologist (ml). diagnosis of men or ovd were based on clinical and audio-vestibular investigations by the same audiologist (mv) that was unaware of the mrv and ecd results. the exclusion criteria comprised, for all three groups of patients: retro cochlear lesion or other known anatomic/structural lesions of the ear, temporal bone or head trauma, syndrome features or congenital othologic abnormalities. furthermore in men and ovd groups any known central nervous system disease. the work was carried out in accordance with the declaration of helsinki, including, but not limited to there being no potential harm to participants, guaranteed anonymity correspondence: dario carlo alpini, vertigo school, via lomellina 58, 20133 milan, italy. fax: +39.02.70105197. e-mail: vertigoschool5@gmail.com key words: chronic cerebro-spinal insufficiency; vertebral veins; multiple sclerosis; mèniére disease. contribution: pmb designed the experiment and performed duplex evaluations; pc designed the experiment and analyzed, mrv data; vm performed oto-neurological tests to select audio-vestibular patients; dca designed the experiment and wrote the manuscript, mendozzi l designed the experiment and selected multiple sclerosis patients; fdb analyzed the data, wrote the manuscript and critically revised the paper for important intellectual content. all the authors contributed to the preparation of the paper conflict of interest: the authors declare no potential conflict of interest. received for publication: 3 january 2017. revision received: 12 february 2017. accepted for publication: 14 february 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright p.m. bavera et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6533 doi:10.4081/vl.2017.6533 no n c om me rci al us e o nly article [veins and lymphatics 2017; 6:6533] [page 41] of participants, and informed consent. all subjects underwent magnetic resonance imaging of the brain during which contrast enhanced imaging of the venous cerebro cervical system was also performed in order to assess the condition of the internal jugular veins (ijvs) and vertebral veins (vvs) and evaluated by the same neuroradiologist (cp) who had no knowledge of the clinical diagnosis. magnetic resonance was performed using a 1.5 t scanner with a standardized imaging protocol consisting of axial and coronal fast spinecho t2-weighted imaging and axial and sagittal spin-echo t1-weighted imaging. the intracranial and cervical venous systems were investigated using computerbased magnetic resonance venography (mrv) performed in three standard orientations (transverse, coronal, and sagittal). a maximum-intensity projection algorithm was used to display three-dimensional mrv reconstruction angiograms. the subjects underwent contrast-enhanced mrv in the supine position and the right and left cross-sectional areas (csa) of the ijvs and vvs were compared. asymmetrical venous flow in the ijvs and vvs was functionally investigated using venous duplex (ecd) (randomly carried out by esaote or general electric with similar probes and settings, by well-trained specialists (bpm), that was unaware of the clinical diagnosis. duplex was performed at 0° and 90° according to the ccsvi protocol and was considered confirmatory of mrv findings when at least two of the five ccsvi criteria were satisfied.10,13,14 three pathological conditions have been taken in account: stenosis (st), vvs hyperplasia (vvh) and alterations of the trunk (at). st was so defined when csa was less than 0.5 cm2, or, at ecd evaluation, if csa in supine position was smaller than in upright position vvh was so defined when csa was more than 0.5 cm2. at was based on ecd findings and included structural abnormalities such as flaps, septa or malformed/immobile valves. statistical analysis the statistical analysis was carried out by an independent well-trained audiologist (df) with statistics 6.1 software (stat. soft inc., tulsa, ok, usa). between-group comparisons were made using analysis of variance (anova). frequencies were compared using the chi-squared. a p value of <0.05 was considered to be statistically significant. results mrv-ecd showed ijvs alterations, any level, in 32 (53%) ms, 13 (46%) men and 6 (16%) ovd with significant difference between ms-men and ovd but not between ms and men. j1 was normal in 34 (57%) ms, 24 (88%) men and 38 (95%) ovd. while comparison between ms and men was significant (p<0.001), difference between men and ovd were not. st were detected, respectively, in 30% in ms and 2% in men and ovd; at in 13% of ms, 10% of men and 3% of ovd. therefore, j1 stenosis specifically regards ms rather than men and ovd (p<0.001). j2 was normal in 47 (78%) ms, 17 (64%) men and 38 (95%) ovd. while comparison between ms and men versus ovd was significant (p<0.001) difference between ms and men were not, but at were detected in 10(17%) ms and 7 (26%) men. thus, even if the p-level is low (p<0.05) j2 at is more represented in ms than in men. j3 was normal in 44 (74%) ms, 17(64%) men and 35 (86%) ovd. at this level difference between men and ovd is low (p=0.04). even the difference between ms and men is less stronger than in j1 and j2 (p=0.005). st were detected, respectively, in 7 (11%) ms and 3 (10%) men and 2 (6%) ovd; at were found in 9 (15%) ms, 7 (26%) men and 3 (8%) ovd. even differences are not statistically significant, j3 at seems more represented in men than in the figure 1 distribution of ijvs anatomic alterations in relationship with topographic segments. ijvs alterations are substantially rare in ovd and, above all, how in ms j1 alterations are more represented while j3 is the specific men abnormal segment. figure 2. regional distribution of ijvs alterations. regional distribution is significantly different between ms and men with medial-distal prevalence in ms and medial-proximal prevalence in men. no n c om me rci al us e o nly article [page 42] [veins and lymphatics 2017; 6:6533] other two groups. figure 1 clearly shows the different patterns of topographic segment alterations distribution, into the three groups with prevalence of alterations in j1 in ms and in j3 in men. adopting a “regional” criterion, j1-j2 may be considered as medial-distal ijvs alterations while j2-j3 as medial-proximal alterations. “regional” ijvs abnormalities difference between ms and men (figure 2) with a higher prevalence of j2-j3 alterations in men (10 patients, 37%) than in ms (14 patients, 23%) and a higher prevalence of j1-j2 in ms (19 patients 32%) than in men (6 patients 22%). differences are significant at p<0.05. hyperplasia of the vertebral venous system was observed in 21 (35%) ms, 11 (40%) men and in 6 (15%) ovd. while difference between ms and men versus ovd was significant, difference between ms and men was not. other compensatory collaterals were detected in 15 (25%) ms and only in 2 (5%) men and ovd. discussion and conclusions our results clearly show that ccsvi may be considered as a typical condition both in ms and md but is substantially rare in other kind of audio-vestibular disorders. if ccsvi may be considered a cause per se or the anatomical condition for triggering the effect of other factors may be debated. anyway, our experience points out that ccsvi is not a unique disorder and that the venous abnormalities pattern might be disease specific. ms is a typical demyelinating disease but demyelination of the vestibular nerve has been described in patients affected with md, too.15 although the hydraulic mechanism of eh is substantially worldwide accepted, there are evidence of md patients without eh16 and eh without md symptoms17 and gacek18 proposed a neuropathic viral mechanism in md pathogenesis. may ccsvi, that is considered to be correlated to ms central nervous system demyelination, be connectable to vestibular nerve demyelination in md, too? it is difficult to answer but our experience highlights the fact that in md patients ijvs alterations regard the proximal segment. anyway, ccsvi pattern seems to be substantially different in ms and in md. our results indicate that the ms pattern is characterized by j1 stenosis, j2 alterations trunk, a prevalence of j1-j2 medialdistal alterations, compensatory collaterals besides vertebral venous system. on the other hand, men pattern is characterized by alteration trunks in j3, a prevalence of j3-j2 medial-proximal alterations and vertebral venous hyperplasia without other detectable collaterals. on the other hand the role of the origin of the ijvs, that to say the jugular bulb in ménière disease is known.19 several studies analyzing the temporal bone imaging20 or anatomy in md patients have found consistent alterations in the arrangement of the sigmoid sinus, anteriorly or medially displaced, and jugular bulb abnormalities. according to redfern et al.21 and park et al.22 there is a higher frequency of jugular bulb abnormalities in patients with md than in patients without inner ear symptoms, particularly, the mediolateral and anteroposterior position of the jugular bulb determines encroachment of the surrounding structures. authors postulated that abnormal position contributes to md development and that temporal bones of md patients might be constituted anatomically different, carrying predisposing factors for the development of clinically apparent md. these findings resemble to our findings: ijvs in general and j3 alterations are significantly highest in md than in ovd. the disease-specificity of venous abnormalities was recently reported also by vannini et al.23 that described different morphology of ijvs’ valves in md patients with respect to normals and sudden neurosensorial hearing loss patients. it is interesting to note that burcon24 observed in md patients a frequent involvement of the upper cervical spine dysfunction, particularly c1 and c2, that the author correlated to vertigo, c1, and hearing loss, c2. it is interesting to underline that in ovd vvs hypeplasia is highly represented than j1-j2 alterations but similarly to j3 abnormalities: vvs 15% j3 14%. both vertebral veins and proximal jugular segment are anatomically placed in c1-c2 region and this fact supports the role of upper cervical venous drainage to explain burcon’s paper. furthermore, franz et al.25 postulated a cervicogenic disorder, mainly trigeminal based mechanism, as forerunner of md. also in this case a venous explanation might be coupled to franz’s trigeminal mechanism as happens in migraine patients.26 the key point of the paper of merchant et al.17 conducted on temporal bone cases with a clinical diagnosis of md or a histopathologic eh diagnosis, is that hydrops per se is not the cause of md while there are evidences of cellular and molecular bases of the various md symptoms.11 thus, a specific anatomical abnormality of the temporal bone, regarding the jugular bulb, and/or the highest portion of the cerebro-cervical venous drainage system, as shown in this paper through mrv and ecd, may lead to abnormal clearance of audiovestibular structures inducing citochemical changement similar to those observed in ms ccsvi positive patients. it is interesting to reveal that, although the group of patients with venous alterations is very small, ovd patients show a ccsvi pattern more similar to md than ms pattern, thus it is reasonable to conclude that ccsvi is not an unique entity and that neurological (ms) pattern is distinguishable from the audiologic (md and ovd) pattern. in author’s opinion this explains the fact that no patients affected with ms and md are reported in literature. references 1. lassmann h, bruck w, lucchinetti cf. the immunopathology of multiple sclerosis: an overview. brain pathol 2007;17:210-8. 2. paparella mm. the cause (multifactorial inheritance) and pathogenesis (endolymphatic malabsorption) of meniere’s disease and its symptoms (mechanical and chemical) acta otolaryngol (stockh) 1985;99:445-51. 3. sajjadi h, paparella mm. meniere’s disease. lancet 2008;372:406-14. 4. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:392-9. 5. zamboni p, menegatti e, galeotti r, et al. the value of cerebral doppler venous haemodynamics in the assessment of multiple sclerosis. j neurol sci 2009;282:21-7. 6. zivadinov r, marr k, cutter g, et al. prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in ms. neurology 2011;77:13844. 7. alpini d, bavera pm, hhan a, mattei v. chronic venous cerebrospinal insufficiency (ccsvi) in meniere disease. case or cause? science med 2013;4:9-15. 8. di berardino f, alpini dc, bavera pm, et al. chronic cerebrospinal venous insufficiency in ménière disease. phlebology 2015;30:274-9. 9. filipo r, ciciarello f, attanasio g, et al. chronic cerebrospinal venous insufficiency in patients with ménière’s disease. eur archiv oto-rhino-laryngol 2015;272:77-82. 10. zivadinov r, bastianello s, dake md, no n c om me rci al us e o nly article [veins and lymphatics 2017; 6:6533] [page 43] et al. international society for neurovascular disease. recommendations for multimodal noninvasive and invasive screening for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency: a position statement of the international society for neurovascular disease. j vasc interv radiol 2014;25:178594.e17 11. lopez-escamez ja, carey j, chung wh, et al. diagnostic criteria for ménière disease. j vest res 2015 [epub ahead of print]. 12. baloh rw. dizziness, hearing loss, and tinnitus. new york: oxford; 1988. 13. zamboni p, morovic s, menegatti e, et al. screening for chronic cerebrospinal venous insufficiency (ccsvi) using ultrasound--recommendations for a protocol. int angiol 2011;30:571-97. 14. bavera pm, agus gb, alpini dc, et al. results from 823 consecutive duplex exams for ccsvi in a vascular centre. acta phlebol 2012;13:141-8. 15. spencer rf, simanis a, kilpatrick jk, shaia wt. demyelination of vestibular nerve axons in unilateral ménière disease. ear nose and throat j 2002;81:785-9. 16. rauch sd, merchant sn, thedinger ba. ménière’s syndrome and endolymphatic hydrops: a double-blind temporal bone study. ann otol rhinol laryngol 1989;98:873-83. 17. merchant sn, adams jc, nadol jb jr. pathophysiology of ménière’s syndrome: are symptoms caused by endolymphatic hydrops? otol neurotol 2005;26:74-81. 18. gacek rr. ménière’s disease is a viral neuropathy. orl 2009;71:78-86. 19. baloh r. prosper ménière and his disease. arch neurol 2001;58:1151-6. 20. hornibrok j, coates m, goh t. mri imaging of the inner ear for ménière disease. n z med j 2010;123:59-63. 21. redfern re, brown m, benson ag. high jugular bulb in a cohort of patients with definite ménière’s disease. j laryngol otol 2014;128:75964. 22. park jj, shen a, keil s, et al. jugular bulb abnormalities in patients with meniere’s disease using high-resolution computed tomography. eur arch otorhinolaryngol 2015;272:1879-84. 23. vannini me, menegatti e, tessari m, et al. high resolution m-mode characterization of jugular veins valves in healthy volunteers and in patients with neurological disorders. poster at vith annual isnvd meetiing, new york city (usa), 29th april 2016 24. burcon tm. health outcomes following cervical speciif protocol in 300 patients with meniere’s followed over six years. j upper cervical chiropractic res 2016;2:13-21. 25. franz b, altidis p, altidis b, collisbrown g. cervicogenic otoocular syndrome: a suspected forerunner of ménière's disease. int tinnitus j 1999;5:125-30. 26. koerte ik, schankin cj, immler s, et al. altered cerebrovenous drainage in patients with migraine as assessed by phase-contrast magnetic resonance imaging. invest radiol 2011;46:434-40. no n c om me rci al us e o nly hrev_master 5th annual meeting of the international society for neurovascular disease march 27-29th, 2015 naples, italy abstract book no nco mm er cia l u se on ly veins and lymphatics eissn 2279-7483 editor-in-chief stefano ricci, italy editorial staff paola granata, managing editor cristiana poggi, production editor claudia castellano, production editor tiziano taccini, technical support veins and lymphatics is published by pagepress publications, italy. the journal is completely free online at www.veinsandlymphatics.org publishing costs are offset by a publication fee charged to authors. for more information and manuscript submission: www.veinsandlymphatics.org copyright information all works published in pagepress journals are subject to the terms of the creative commons attribution license (http:⁄⁄creativecommons.org/licenses/by-nc/3.0) unless otherwise noted. copyright is retained by the authors. any non-commercial reuse is permitted if the original author and source are credited. correspondence our publishing offices are located in via giuseppe belli 7, 27100 pavia, italy. our telephone number is +39.0382.1751762 and our fax number is +39.0382.1750481. e-mail: info@pagepress.org all pagepress journals are open access. pagepress articles are freely available online and deposited in a public archive immediately upon publication. editorial board g. agus, italy g. arpaia, italy i. bihari, hungary f.x. breu, germany a. caggiati, italy m. cairols, spain p. coleridge-smith, uk l. corcos, italy m. dake, usa r. damstra, the netherlands a.h. davies, uk s. de franciscis, italy c. franceschi, france f. ferrara, italy a. frullini, italy m. goldman, usa j.j. guex, france m. izzo, italy a. jawien, poland p. kern, switzerland m. kurtoglu, turkey n. labropoulos, usa b.b. lee, usa, o. maleti, italy a. mansilha, portugal f. mariani, italy r. mattassi, italy m. meissner, usa s. michelini, italy k. myers, australia m. neumann, the netherlands g. palareti, italy f. passariello, italy s. pieri, italy p. pittaluga, france m. stücker, germany a. van rij, new zealand p. thibault, australia c. wittens, the netherlands f. zini, italy r. zivadinov, usa co-editors m. de maeseneer, the netherlands g. mosti, italy p. zamboni, italy associate editors m. cappelli, italy a. cavezzi, italy d. creton, france v. gasbarro, italy n. morrison, usa p. mortimer, uk m. perrin, france l. tessari, italy honorary board c. allegra, italy h. partsch, austria e. rabe, germany a. scuderi, brazil no nco mm er cia l u se on ly veins and lymphatics 2015; volume 4:s1 [page ii] [veins and lymphatics 2015; 4:s1] 5th annual meeting of the international society for neurovascular disease march 27-29th, 2015 naples, italy congress center federico ii via partenope 36 naples, italy table of contents keynote . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 invited abstracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 podium abstracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 poster abstracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 index of authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 no nco mm er cia l u se on ly veins and lymphatics 2015; volume 4:s1 [veins and lymphatics 2015; 4:s1] [page iii] 5th annual meeting of the international society for neurovascular disease march 27-29th, 2015 naples, italy board member listing finance committee robert zivadinov, m.d., ph.d. isnvd treasurer, state university of new york at buffalo, department of neurology, buffalo, ny, usa david hubbard, m.d. hubbard foundation for fmri research, san diego, ca, usa nominating committee salvatore sclafani, m.d. state university of new york, downstate medical center, brooklyn, ny, usa paul h. thibault, m.d. ccsvi diagnostic clinic, nsw, australia annual meeting program committee chih-ping chung, m.d., ph.d. taipei veterans general hospital & national yang ming university, department of neurology, taipei, taiwan e. mark haacke, ph.d. wayne state university, department of biomedical engineering, detroit, mi, usa awards committee marian simka, m.d., ph.d. euromedic medical center, department of vascular surgery, katowice, poland alireza minagar, m.d., faan professor of neurology, louisiana state university, shreveport, la, usa publications committee e. mark haacke, ph.d. wayne state university, department of biomedical engineering, detroit, mi, usa clive beggs, ph.d. university of bradford school of engineering, design and technology bradford, west yorkshire, uk education committee karen marr, rvt state university of new york at buffalo, department of neurology, buffalo neuroimaging analysis center, buffalo, new york, usa marcello mancini, m.d. direttore, istituto di biostrutture e bioimmagini, consiglio nazionale delle ricerche, napoli, italy adnan siddiqui, m.d., ph.d. state university of new york at buffalo department of neurosurgery, buffalo, ny, usa governance committee marian simka, m.d., ph.d. euromedic medical center, department of vascular surgery, katowice, poland joseph hewett, m.d. pacific interventionalists, inc., playa del rey, ca, usa section and affiliations committee nikolaos liasis, dds, ph.d. euromedic psychikou, athens, greece safety committee adnan siddiqui, m.d., ph.d. state university of new york at buffalo department of neurosurgery, buffalo, ny, usa bulent arslan, m.d. associate professor of radiology, director, vascular & interventional radiology, rush university medical center, chicago, il, usa public relations committee sandy mcdonald, m.d. barrie vascular imaging, ontario, canada carol schumacher, director annette funicello research fund for neurological diseases, menlo park, ca, usa disclosure policy statement in accordance with the accreditation council for continuing medical education (accme) standards for commercial support, educational programs sponsored by the international society for neurovascular disease must demonstrate balance, independence, objectivity, and scientific rigor. all faculty, authors, editors, and planning committee members participating in an isnvd-sponsored activity are required to disclose any relevant financial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services that are discussed in an educational activity. disclosure of unlabeled use isnvd requires that faculty participating in any cme activity disclose to the audience when discussing any unlabeled or investigational use of any commercial product or device not yet approved for use in the united states or europe. isnvd executive committe ziv haskal president salvatore sclafani, m.d. president-elect jonathan steven alexander, ph.d vice-president elect robert zivadinov, m.d., ph.d. executive director hector ferral, m.d. chairperson michael dake, m.d. immediate past president marcello mancini, m.d. annual meeting chair paolo zamboni, m.d. chairperson president of the convention address marco salvatore, m.d. italy keynote speaker mat daemen the netherlands no nco mm er cia l u se on ly veins and lymphatics 2015; volume 4:s1 [veins and lymphatics 2015; 4:s1] [page 1] the heart-brain axis; an overlooked cause of brain aging m. daemen university of amsterdam, amsterdam, the netherlands while both cardiac dysfunction and progressive loss of cognitive functioning are prominent features of an aging population, surprisingly few studies have addressed the link between heart and brain function. this is probably due to the monodisciplinary approach to these problems by cardiologists, neurologists and geriatricians. recent data indicate that autoregulation of cerebral flow cannot always protect the brain from hypoperfusion when cardiac output is reduced or atherosclerosis is prominent. this suggests a close link between cardiac function and large vessel atherosclerosis on the one hand and brain perfusion and cognitive functioning on the other. in a national basic and clinical research program supported by the dutch heart foundation, we are testing the hypothesis that impaired hemodynamic status of both heart and brain is an important and potentially reversible cause of vascular cognitive impairment (vci) offering promising opportunities for treatment. using a multidisciplinary approach we address the following questions. i) to what extent do hemodynamic changes contribute to vci? ii) what are the mechanisms involved? iii) does improvement of the hemodynamic status lead to improvement of cognitive dysfunction? to this end we have started a clinical multicentre observational study in elderly patients with either clinically manifest vci, carotid occlusive disease or heart failure and evaluate their cardiac and large vascular function, atherosclerotic load and cerebral perfusion with a comprehensive magnetic resonance imaging (mri) protocol and thoroughly test their cognitive function. furthermore epidemiological data from the rotterdam study will be gathered to assess the associations between the cardiovascular system and cognitive function in the aging population, while mechanistic studies are being performed in animal studies. with this approach we have started a national interdisciplinary collaborative network for the study of vci that will lead to a true multidisciplinary and consensus based approach of the clinical management of vci, the availability of a diagnostic protocol to assess the hemodynamic contribution to vci and clarification of the contribution of hemodynamic changes to vci. the data from our studies will help to define subcategories vci patients that may benefit from treatment aimed at improving the hemodynamic status and provide recommendations for future randomized-controlled trials. disclosures: the author has nothing to disclose. 5th annual meeting of the international society for neurovascular disease march 27-29th, 2015 naples, italy keynote no nco mm er cia l u se on ly veins and lymphatics 2015; volume 4:s1 [veins and lymphatics 2015; 4:s1] [page 3] cardiovascular risk factors and neurodegenerative disorders r. zivadinov buffalo neuroimaging analysis center, department of neurology, university at buffalo, state university of new york, buffalo, ny, usa background: the susceptibility and progression of neurodegenerative disorders may be related to cardiovascular (cv) risk factors, including underlying comorbidities. for example, patients with multiple sclerosis (ms) who reported more than one cv risk factors at the time of diagnosis had an increased chance of ambulatory disability, and the risk increased with the number of cv risk factors reported. objectives: to investigate prevalence and association of cv risks with mri outcomes in neurodegenerative disorders patients. cv risk factors like hypertension, hyperlipidemia and heart disease are associated with increased number of brain white matter (wm) signal abnormalities and decreased gray matter (gm) volume in the general population. methods: in a prospective study, 326 relapsing-remitting (rr) and 163 progressive ms (pms) patients, 61 patients with clinically isolated syndrome (cis) and 175 age-, sexand race-matched healthy controls (hcs) were screened for cv risks and scanned on a 3t mri scanner. examined cv risks included hypertension, heart disease, smoking, overweight/obesity and type 1 diabetes. mri measures assessed lesion volumes (lvs) and brain atrophy. results: ms patients showed increased prevalence of smoking (51.7% vs 36.5%, p=0.001) and hypertension (33.9% vs 24.7%, p=0.035) compared to hcs. 49.9% of ms patients and 36% of hcs showed ≥2 cv risks (p=0.003), while the prevalence of ≥3 cv risks was 18.8% in ms and 8.6% in hcs groups (p=0.002). in ms patients, hypertension and heart disease were associated with decreased gm and cortical volumes (p<0.05), while overweight/obesity was associated with increased t1-lv (p<0.39) and smoking with decreased whole brain volume (p=0.049). increased lateral ventricle volume was associated with heart disease (p=0.029) in cis. having ≥2 cv risks was associated with decreased gm and cortical volumes (p<0.05) in ms patients. conclusions: patients with neurodegenerative disorders, like ms who present with one or more cv risks showed increased lesion burden and more advanced brain atrophy. study conflict: none. disclosures: robert zivadinov received personal compensation from teva neuroscience, biogen idec, novartis, genzyme, claretmedical for speaking and consultant fees. dr. zivadinov received financial support for research activities from biogen idec, teva neuroscience, novartis, genzyme and claret-medical. ultrasound contrast imaging of brain hemodynamic and perfusion m. mancini institute of biostructure and bioimaging, national research council, naples, italy studies based on histopathological techniques and on mr imaging demonstrate hypoxia-like brain tissue injury or thrombosis of small veins in patients with multiple sclerosis (ms). applying dynamic susceptibility contrast magnetic resonance imaging, cerebral mean transit time values were found to be significantly prolonged in ms patients. recent newly developed ultrasound techniques extend our ability to study the cerebral hemodynamics in patients with neurological disease beyond the conventional blood flow velocity analysis. different ultrasound methods are currently under investigation that either qualitatively or quantitatively describe brain perfusion. the most widely used technique is bolus kinetics. after applying a ultrasound contrast agent bolus, time intensity curves of the wash-in and wash-out phase of the bolus passage through the brain are registered by imaging at a set frame rate and analyzing the ultrasound intensity in a given region of interest. based on the time intensity curves, different parameters can be extracted such as peak intensity, time to peak, mean transit time, and incremental time. these parameters can be displayed in a tissue region of interest defined by the examiner. we present the application of contrast enhanced ultrasound (ceus) to assess global cerebral circulation time (cct) in patients with multiple sclerosis (ms). the method is based on the assumption that the time required by an ultrasound contrast agent to pass from the cerebral arteries to the veins should be prolonged in patients with vessel disorders. our results suggest that a microvascular or venous outflow impairment could be associated with ms. the ceus measurement of cct may be useful tool to disclose cerebral microcirculatory dysfunction in ms patients (figures 1 and 2). figure 1. the time-intensity curve analysis displays the acoustic intensity (in db) during acquisition time in three different region of interest: the carotid artery, thyroid parenchyma without artery/vein, internal jugular vein. the wash-in curves were analysed and three parameters were measured for the roi: arrival time, time to peak and absolute intensity peak. ultrasound cerebral perfusion imaging is a technique of microvascular imaging that was introduced in the late 1990s. the main clinical focus has been on stroke patients. high mi phase inversion harmonic imaging of the diencephalic plane using the bolus administration of 2.5 ml sonovuetm (bracco imaging) was applied using ultrasound instrument (philips iu22), equipped with a phased-array transducer (2 mhz). after acquisition (36 to 40 frames), the radiofrequency data were transferred to a pc for further offline analysis. off-line evaluation comprised regionwise analysis of time-intensity curves (tic) of predefined rois and calculated time-to-peak intensity parameter images. us examinations were performed unilaterally with the transtemporal approach. standard sonographic brain imaging starts in the axial plane with the probe positioned in the orbitomeatal line. 5th annual meeting of the international society for neurovascular disease march 27-29th, 2015 naples, italy invited abstracts no nco mm er cia l u se on ly invited abstracts [page 4] [veins and lymphatics 2015; 4:s1] figure 2. the cct in a ms patient (bottom) and in a control subject (top). the difference was evident (cctl in control subject was 3.3 s, in ms patient was 6.9s. the red lined curve depicts the arterial signal, the green lined curve represents tissue signal and yellow lined curve represents the venous signal. the butterfly-shaped hypoechogenic mesencephalic brainstem appears in the center of the image and serves as an orientation structure. most brain structures exhibit a low echogenicity. the hypoechogenic mesencephalic brainstem is surrounded by the hyperechogenic basal cisterns. the hyperechogenic aqueduct in the tectum is easily identified. a hyperechogenic midline represents the brainstem raphe. by tilting the probe upwards the diencephalic and ventricular plane can be displayed giving view to the third ventricle and the frontal horns of the lateral ventricles as anechogenic zones bordered by hyperechogenic lines where the ultrasound beam meets the ependyma in an orthogonal plane. the basal ganglia are not distinguishable from each other and the white matter because all exhibit a low echogenicity. visualization of the m2 segment of the middle cerebral artery (mca) after echo contrast agent injection ensured the correct position in the diencephalic plane. the field of view was set to an imaging depth of 10 cm; the sector angle was 90°. all examinations were performed with the left-sided temporal approach and were digitally recorded and evaluated offline. regional cerebral echo contrast enhancement was quantified using tic. peak intensities (pi), and time to peak intensities (tpi)s, and bolus arrival time (at), were calculated from a model function that was fitted to the measured curve in at least mean square sense. quantitative data were calculated for the following manually placed rois: in the ipsilateral hemisphere, posterior parts of the thalamus, anterior parts of the thalamus, lentiform nucleus, white matter, and mca (m2 segment) (figure 3). axial b-mode image of the diencephalic scanning plane. visualization of mca and parenchimal regions of interest in the ipsilateral hemisphere (posterior parts of the thalamus, lentiform nucleus, white matter). in the lower part of the figure example of the 4 time-intensity curves of the analyzed rois. the vertical axis represents the intensity in decibels. the intensity peak is higher in the middle cerebral artery, lentiform nucleus territory and white matter than in the thalamus. disclosures: the author has nothing to disclose. traumatic brain injury and hemodynamic changes in the brain j.r. stone university of virginia at charlottesville, usa one of the most serious health issues facing individuals under the age of 35 is traumatic brain injury (tbi). in the united states alone, it is estimated that 3.5 million individuals sustain a tbi each year, with 275,000 hospital admissions and 52,000 deaths as a result of this disease process. cerebrovascular pathology is known to play a key role in the morbidity and mortality associated with tbi. post-mortem evaluations of patients with tbi routinely demonstrate evidence of ischemia. although the precise nature of tbi-induced ischemia is not entirely known, cerebral vasospasm, hyperemia, global edema, and uncoupling of cerebral blood flow and metabolism have all been observed in patients with this disease process. also observed is disruption of the blood brain barrier, with concomitant loss of cerebral immune privilege, infiltration of peripheral leukocytes, expression of pro-inflammatory cytokines, and increased production of reactive oxygen species (ros). the current presentation will review the hemodynamic changes and cerebrovascular pathology that are associated with tbi. these topics will be considered both globally and at the cellular and molecular level to provide insight into the range of cerebrovascular pathology seen in tbi, while examining common underlying mechanisms that may play a role in this disease process. also considered will be tbi resulting from explosive devices and emerging evidence suggesting particular vulnerability of the cerebral vasculature to this injury mechanism. disclosures: the author has nothing to disclose. imaging of the microvasculature e.m. haacke wayne state university, usa background: the brain’s vasculature, as well as perfusion and blood flow, can be probed with and without contrast agents using mri. recent evidence shows that vessels as small as 100μ to 250μ can be seen with conventional clinically accessible mr angiographic methods in humans and as small as 40μ in animals. objectives: to assess the current state-of-the-art mr imaging methods with and without contrast agents to study the microvasculature of the brain. methods: to investigate arterial and venous blood vessels without contrast agent, we review conventional mra and susceptibility weighted imaging (swi) methods as well as an interleaved multi-echo version of swi that includes a short echo mra. these time-of-flight (tof) imaging methods have limited snr and so alternate methods must be sought to improve vessel visualization further. to improve the vessel visibility, two types of contrast agent are evaluated: t1 reducing methods and iron particle t2* and susceptibility based methods such as susceptibility weighted imaging and mapping (swim). these are also used to study macromolecular exchange between the venous system and the cerebral spinal fluid (csf). results: with no contrast agents, it is viable to collect 0.5 mm isotropic resolution in a reasonable time period. with a t1 reducing agent, the best resolution to date is 0.25x0.25x0.5 mm allowing vessels as small as 100μ to 250μ to be seen. with a t2* iron based contrast agent, in an animal model, the best resolution to date is 42x42x250μ. using iron tagged dextran it is possible to see the exchange of the dextran macromolecule across the vessel wall into the veins. conclusions: mra and swi offer two powerful means to study the neurovascular system. key words: mr angiography; susceptibility weighted imaging; cerebral spinal fluid. disclosures: dr. haacke has a significant financial relationship with mr innovations, inc. no nco mm er cia l u se on ly invited abstracts [veins and lymphatics 2015; 4:s1] [page 5] imaging of brain microvascular disorders: lessons from the cadasil model h. chabriat department of neurology, gh lariboisiere, aphp, inserm umrs1161, university paris 7 denis diderot, paris, france cadasil (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an archetypal ischemic small vessel disease responsible for stroke, dementia and severe disability. the disease is caused by different mutations of the notch3 gene on chromosome 19. cadasil is considered as a unique model for investigating the classical imaging markers of small vessel disease and for understanding their exact clinical correlates. imaging studies were previously obtained for determining the natural history of subcortical ischemic lesions, evaluating the cortical consequences of incident lesions, measuring the development of cerebral microstructural and morphological changes. imaging markers were also recently identified for prognostication and stratification in this model of small vessel disease. finally, imaging data were found useful for better understanding the pathophysiology of white-matter lesions (so-called leukoaraiosis) parallel to studies obtained in the animal model of the disease. the results strongly support that different types of white-matter lesions are present in cadasil that may be also detected in sporadic small vessel disease. disclosures: the author has nothing to disclose. 2d and 3d analysis of vessels in the retina and the brain b. ter haar romeny eindhoven university of technology, eindhoven, the netherlands; northeastern university, shenyang, china quantitative measurement of geometrical and physiological properties of blood vessels in the retina may indicate early stages of brain and systemic diseases in an efficient and cost-effective way. retinal vasculature is brain vasculature, and can be imaged easily at high resolution with optical fundus or oct cameras. breakdown of the blood-brain barrier, as in diabetes, leads to marked vascular changes, which can be signaled early. this is e.g. exploited in large screening programs for diabetes worldwide. we will discuss how typical quantitative imaging biomarkers are measured automatically, as curvature and tortuosity, width, arteriovenous ratio, bifurcation analysis, micro-bleeds, aneurysms and stenosis, angiogenesis, fractal dimension, etc. for the enhancement, tracking and segmentation of the tiny vessels we exploit highly robust methods learned from modern insight in brain mechanisms of visual perception. optical imaging techniques have revealed multi-scale and multi-orientation columns in the visual cortex, which we model mathematically. the micro-vascular analysis can be done in 2d (retina) and 3d (brain, heart). computer algorithms also enable quantitative analysis and smart interactive 3d visualization of functional imaging, such as 4d blood flow. flow in larger vessels is still poorly understood. modern graphics cards (game cards) enable cheap and massively parallel renderings. we give examples of modern visualization techniques, inspired by brain connectivity visualization, of 3d/4d flow patterns in brain aneurysms, and aortic arch flow turbulence as an indicator for valve functioning. the message of the presentation is that quantitative analysis of micro-vasculature, and interactive 4d visualization of complex flow parameters in larger vessels is now clinically feasible and accessible. disclosures: the author has nothing to disclose. a novel sonographic method for reproducible jugular vein pulse wave assessment p. zamboni, f. sisini, e. menegatti, g. gadda, m. tessari, m. gambaccini vascular diseases center, university of ferrara, ferrara, italy objectives: we investigated in two phases respectively the feasibility to reliably and non invasively derive the jugular venous pulse (jvp) by means of ultrasound (us) equipment, and to preliminarily compare jvp in normal people with patients affected by extracranial venous obstructive diseases, typical of the chronic cerebrospinal venous insufficiency (ccsvi). methods: phase 1. three young healthy subjects underwent bmode us scan of the internal jugular vein (ijv) in order to acquire a sonograms sequence in the transversal plane. on each acquired sonogram we manually traced the ijv contour and measured the cross sectional area (csa) as well as perimeter. the csa dataset represents the us-jvp. the arterial distension wave-form of the subjects were compared with their us jugular diagram. the correlation between the csa with the perimeter was assessed during the cardiac cycle to verify the ijv distension. for each subject a short sonogram sequence of 4.8 seconds has been recorded. we compared 390 manually traced profiles of the ijv cross sectional area with corresponding values automatically calculated by an algorithm made in house. phase 2. we blindly compared ten healthy controls with twenty ccsvi patients by the means of the above reported new diagnostic methodology, synchronized with the ecg trace. results: phase 1. for all subjects the us-jvp showed a periodic behaviour. for the three subjects, the fourier transform showed the pulse duration of the jugular vein. for all the subjects the csa was found correlated with the perimeter (pearson coefficient r >0.9) indicating that the ijv in supine position is distended. for all the subjects the mean sensitivity, specificity and diagnostic accuracy resulted around 90%, by comparing the 390 manual tracing with the algorithm. this indicates that jvp can be reliably measured through a rapid analysis of the recording of a real time 5 seconds of sonograms sequence of the ijv. phase 2. the new methodology to assess the ijv functionality has been compared in a blind pilot study where the jvp was analyzed together the ecg. the analysis clearly shows typical and physiologic curves in the control group respect to abnormalities and high variability assessed in the ccsvi group. conclusions: we have shown that a diagram reflecting the jvp can be obtained by analysing an us b-mode movie. both acquisition and post processing analysis by the means of the developed algorithm require a short time and reduce the operator dependency. moreover, the significance of the jvp in the ccsvi screening seems promising and warrants a large, blinded, multicenter study. disclosures: the authors have nothing to disclose. factors influencing aqueductal cerebrospinal fluid motion in healthy individuals c.b. beggs,1 s.j. shepherd,1 p. cecconi,2 m.m. lagana2 1medical biophysics laboratory, university of bradford, bradford, uk; 2fondazione don carlo gnocchi onlus, irccs s. maria nascente, milan, italy background: increased cerebrospinal fluid (csf) pulsatility in aqueduct of sylvius (aos) has been associated with various neuropathologies. however, the mechanisms driving the aqueductal csf (acsf) pulse are poorly understood. objectives: to gain a deeper understanding the factors that influence acsf motion. methods: twelve healthy young adults (aged 20 to 45 years) with no known neurological disease were investigated using phase contrast mri. acsf flow data, together with arterial, venous and csf flow data at the c2/c3 level, were collected for 32 points throughout the no nco mm er cia l u se on ly invited abstracts [page 6] [veins and lymphatics 2015; 4:s1] cardiac cycle (cc). intracranial fluid volumetric changes were computed from these data to identify the factors that directly influence the acsf pulse. results: the aggregated flow rate signals for all subjects are shown in figure 1. mean cervical csf and acsf stroke volumes were 801.8 (sd=501.2) and 17.6 (sd=19.3) μl/beat, respectively. peak negative acsf flow (towards the fourth ventricle) occurred 14.1% of cc after the arterial peak, while the positive acsf peak flow occurred after 77.9% of cc (figure 1). the intracranial venous volume increased by 626.6 μl over the cc, peaking at 64.0% of cc after the arterial peak, while the corresponding change in acsf volume was 24.0 μl, peaking 71.3% of cc. there was a very strong positive correlation between the intracranial venous blood volume and the acsf volume (r=0.966, p<0.001), as illustrated in figure 2, which shows the change in acsf volume scaled to match the change in intracranial venous volume. figure 1. aggregated fluid flow rates. figure 2. relative intracranial fluid volumes. conclusions: the motion of the csf in the aos appears to be strongly influenced by changes in the intracranial venous volume. as the intracranial csf increases in volume during diastole it causes blood to accumulate in the cortical veins.1,2 as the volume of the cortical veins increases, so the volume of the sub-arachnoid space reduces, with the result that csf is forced up the aos towards the lateral ventricles. only when the stored venous blood is voided from the cranium, does csf flow in the other direction occur in the aos. disclosures: the authors have nothing to disclose. references 1. luce jm, huseby js, kirk w, butler j. a starling resistor regulates cerebral venous outflow in dogs. j appl physiol respir environ exerc physiol 1982;53:1496-503. 2. vignes jr, dagain a, guérin j, liguoro d. a hypothesis of cerebral venous system regulation based on a study of the junction between the cortical bridging veins and the superior sagittal sinus. laboratory investigation. j neurosurg 2007;107:1205-10. update in computational fluid modeling of the brain m. ursino university of bologna, bologna, italy several aspects concur in making the cerebral circulation extremely complex: i) the presence of diffuse anastomotical pathways among cerebral vessels (both in the intracranial arterial and extracranial venous circulations); ii) the presence of sophisticate mechanisms which regulate cerebral blood flow following pressure changes and changes in blood gas content; iii) the occurrence of a portion of this circulation within a closed space (the skull and neuroaxis) with a limited volume storage capacity. a deeper understanding of how these complex factors interact reciprocally, and of their possible role in pathological conditions, may be attained with the use of mathematical models and computer simulation techniques. aim of the presentation is to illustrate the complex mechanisms affecting the cerebral hemodynamics, by making use of computational models developed in past years, and showing some practical examples. the first part of the presentation is focused on the intracranial circulation, laying emphasis on the role of cerebrovascular regulatory mechanisms. a few pathological cases are simulated, to illustrate the complexity of factors operating on brain hemodynamics. an example considers the case of patients with reduced storage capacity and altered csf circulation (a condition, for instance, typically occurring in patients with severe head injury). in these cases, instability of intracranial dynamics may lead to uncontrollable increase in intracranial pressure, with the development of large icp waves.1 a further example simulates hemodynamics in patients with unilateral internal carotid artery stenosis; in this case, local blood flow regulation is progressively lost in the ipsilateral territory with the presence of a steal phenomenon, while the anterior communicating artery plays the major role to redistribute the available blood flow.2 the second part presents a very recent extension of this model, in which a detailed description of the extracranial venous pathways (jugular veins, vertebral-azygos vein complex, collateral anastomoses) are included. the model accounts for the changes in jugular vessels lumen occurring when passing from supine to standing, and simulates how these changes can affect flows and pressures in specific points of the system.3 furthermore, the model provides quantitative predictions on how this redistribution can be altered by stenotic patterns, and how a failure of the extracranial venous drainage may be reflected in the upstream intracranial circulation. we claim these models may have a great perspective value, to help clinicians in reaching a deeper understanding of the multiple mechanisms operating on the brain circulation, and to be acquainted on the complex effects of pathological alterations in brain vessels. disclosures: the author has nothing to disclose. references 1. ursino m, ter minassian a, lodi ca, beydon l. cerebral hemodynamics during arterial and co2 pressure changes; in vivo prediction by a mathematical model. am j physiol heart circ physiol 2000;279: h2439-55. 2. ursino m, giannessi m. a model of cerebrovascular reactivity including the circle of willis and cortical anastomoses. ann biomed eng 2010;38:955-74. 3. gadda g, taibi a, sisini f, et al. a new hemodynamic model for the study of cerebral venous outflow. am j physiol heart circ physiol 2015 [in press]. no nco mm er cia l u se on ly invited abstracts [veins and lymphatics 2015; 4:s1] [page 7] fluid dynamic influences on cerebrovascular endothelial activation responses e.v. stevenson, j.w. yun, s. omura, f. sato, i. tsunoda, a. minagar, f. becker, t. castor, p.-o. couraud, i.a. romero, b. weksler, j.s. alexander lsuhsc-shreveport molecular and cellular physiology, microbiology, virology, neurology, shreveport, la, usa; cochin institute, inserm, paris, france; weill cornell medical college, new york, ny; the open university, walton hall, milton keynes, uk alterations in blood flow and vascular shear stress are known to induce multiple changes in venous and arterial endothelial cells, including modifications in proand anti-inflammatory gene expression, cell differentiation and proliferation, tight junction maintenance, and overall vascular homeostasis. a role for vascular disturbances has also been increasingly apparent in the progression of multiple neurological disorders, such as multiple sclerosis and alzheimer’s disease, particularly in initiation and progression of inflammatory processes and potentially blood-brain barrier disturbances. because changes in vascular shear stress have been implicated in the progression of atherosclerotic disease and in the progression of inflammatory process, we hypothesized that shear stress alterations would lead to inflammatory activation of cerebral endothelial cells. to test this, we exposed human brain endothelial cells (hcmec-d3) to high or low levels of non-linear shear using microcarrier cultured brain endothelial cells to compare the effects on endothelial activation. we found amyloid precursor protein (app) was basally expressed in hcmec-d3 and was released into endothelial microparticles (emps) in response to high fluid shear. similarly, the neurolymphatic marker, lymphatic vascular endothelial hyaluronic acid receptor lyve-1 was increased in both cells and emps in response to high fluid shear. the shear dependent transcription factor kruppel-like factor 4 klf-4 was abundant in hcmec-d3 and appears to increase in response to high and low shear treatment and was transferred into emps under both conditions. the tight junction protein occludin was also increased in hcmec-d3 in response to both levels of fluid shear, with cleaved forms apparent in sheared mps. importantly we found that caveolin-1 was shed into emps in response to shear, consistent with these structures as caveolae discharged by cells following exposure to shear. supported by: aphios corporation alzheimer’s disease therapeutic (5r44ag034760) and the feist cardiovascular institute (lsuhsc-s). venous abnormalities in ménière disease p.m. bavera,1 p. cecconi,1 d. alpini,1 f. di berardino2 1scientific institute s. maria nascente, don c. gnocchi foundation, milan, italy; 2audiology unit, fondazione irccs ca’ granda ospedale maggiore policlinico, milan, italy a brief definition of the ménière disease, with principal symptoms. correlations between these symptoms and those usually present in ccsvi affected patients (mainly multiple sclerosis patients). most evident and frequent results in ménière disease compared with those with over 2000 ccsvi ms duplex exams. anatomic differences and localizations between the two groups of patients at duplex exams. mri imaging of ms patients and ménière disease patients, with comparison and/or differences (anatomical, morphological). conclusions that mainly highlight the characteristics of the venous abnormalities within ménière disease. disclosures: the authors have nothing to disclose. advances in idiopathic intracranial hypertension pathogenesis: a focus on sinus venous stenosis r. de simone, a. ranieri headache centre, department of neurosciences, reproductive sciences and odontostomatology, university federico ii, naples, italy idiopathic intracranial hypertension (iih) is an enigmatic condition characterized by a near daily headache, papilledema, transient visual obscurations, diplopia, vertigo and tinnitus, almost always encountered in overweight women of childbearing age. symptoms arise from an hypertensive intracranial status which is not associated with any detectable cause. iih may run without papilledema (iihwop) in a part of the patients. iihwop may be indistinguishable on clinical basis from primary chronic headache available literature evidences suggest that iihwop could represent a possible, largely underestimated, risk factor for migraine progression.1 to date, the presence of sinus venous stenosis at magnetic resonance venography is considered a reliable radiologic marker of iih.2 sinus stenosis is considered secondary to the raised cerebrospinal fluid (csf) pressure as it may resolve after csf withdrawal. however, in recent years the efficacy of endovascular venous stenting in iih treatment has been consistently reported,3 strongly suggesting that sinus stenosis should be viewed as a causative factor rather than a secondary phenomenon. we propose that in subjects carrying one or more collapsible segments of large cerebral venous collectors, exposed to a number of different promoting factors, sinus venous compression and csf hypertension may influence each other in a circular way, leading to a new relatively stable venous/csf pressures balance state at higher values. the mechanism relay on self-limiting venous collapse (svc) feedback-loop between csf pressure, that compresses the sinus, and the consequent venous pressure rise, that in turn increases csf pressure. the result is the coupled increase of both pressure values, a phenomenon not expected in presence of sufficiently rigid central veins. once the maximum stretch of venous wall is reached the loop stabilize at higher venous/csf pressure values and become self-sustaining, therefore persisting even after the ceasing of the promoting factor. notably, the svc is reversible provided an adequate perturbation is carried to whichever side of the loop such as sinus venous stenting, on one hand, and csf diversion or even a single csf withdrawal by lumbar puncture (lp), on the other. the svc model predicts that any condition leading to an increase of either, cerebral venous or csf pressure may trigger the feedback loop in predisposed individuals. if the svc might be regarded as a crucial iih predisposing mechanism, a primary event triggering the csf and sinus venous higher-pressure balances shift is probably always required. migraine with and without aura, a disease sharing with iih a much higher prevalence among women of childbearing age, is associated with waves of significant brain hyperperfusion. these may lead to the congestion of large cerebral venous collectors and could represent a common svc promoting condition in susceptible individuals and this could account for the high frequency of iihwop observed in headache sufferers. the svc model give reason of the high specificity and sensitivity of sinus stenosis as iih predictor and of the multiplicity of the factors that have been found associated with iih. finally, the svc model fully explain the enigmatic longstanding remissions that can be commonly observed after a single lp with csf subtraction in iih with or without papilledema. disclosures: the authors have nothing to disclose. references 1. de simone r, ranieri a, montella s, et al. intracranial pressure in unresponsive chronic migraine. j neurol 2014;261:1365-73. 2. farb ri, vanek i, scott jn, et al. idiopathic intracranial hypertension: the prevalence and morphology of sinovenous stenosis. neurology 2003;60:1418-24. 3. puffer rc, mustafa w, lanzino g. venous sinus stenting for idiopathic intracranial hypertension: a review of the literature. j neurointerv surg 2013;5:483-6. advances in treatment strategies of extracranial venous disease h. ferral northshore university healthsystem, evanston, il, usa dr. paolo zamboni was the first investigator to report the management of internal jugular vein and azygos vein stenotic lesions to no nco mm er cia l u se on ly invited abstracts [page 8] [veins and lymphatics 2015; 4:s1] improve symptoms in patients with multiple sclerosis.1 his original report describes angioplasty of the stenotic lesions using 8 mm and 10 mm angioplasty balloons.1 dr. zamboni called this entity the chronic cerebrospinal venous insufficiency or ccsvi.1 the endovascular management of ccsvi is controversial. the work of some investigators has supported zamboni’s original contribution,2-6 however, other investigators have not confirmed the encouraging results reported by zamboni7 and for this reason, the concept of ccsvi and its management has been strongly criticized.8,9 endovascular management of jugular vein and azygos vein stenotic lesions has mainly focused on the use of balloon angioplasty2,3,10 and certain modifications to the angioplasty technique, including the use of double balloons and cutting balloons have been employed. measurement of the target vein is imperative; vein measurement using conventional venography with multiple projections2,3 and intravascular ultrasound (ivus) are the most important methods employed for precise vein measurement.4,7,11 endovascular stents have also been used to treat jugular and azygos vein stenoses,6 however, reports of complications with the use of endovascular stents have decreased the enthusiasm for their use in these cases.12 the current presentation will focus on the technical advances in performing endovascular management of ccsvi. vein measurement and therapeutic methods will be discussed along with the potential advantages and disadvantages. disclosures: the author has nothing to disclose. references 1. zamboni p, galeotti r, menegatti e, et al. a prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. j vasc surg 2009;50:1348-58 e1-3. 2. mandato kd, hegener pf, siskin gp, et al. safety of endovascular treatment of chronic cerebrospinal venous insufficiency: a report of 240 patients with multiple sclerosis. j vasc interv radiol 2012;23:55-9. 3. hubbard d, ponec d, gooding j, et al. clinical improvement after extracranial venoplasty in multiple sclerosis. j vasc interv radiol 2012; 23:1302-8. 4. sclafani sj. intravascular ultrasound in the diagnosis and treatment of chronic cerebrospinal venous insufficiency. tech vasc interv radiol 2012;15:131-43. 5. veroux p, giaquinta a, perricone d, et al. internal jugular veins out flow in patients with multiple sclerosis:a catheter venography study. j vasc interv radiol 2013;24:1790-7. 6. ludyga t, kazibudzki m, simka m, et al. endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? phlebology 2010;25:286-95. 7. siddiqui ah, zivadinov r, benedict rh, et al. prospective randomized trial of venous angioplasty in ms (premise). neurology 2014; 83:441-9. 8. reekers ja. ccsvi and ms: a never-ending story. eur j vasc endovasc surg 2012;43:127-8. 9. mayer ca, pfeilschifter w, lorenz mw, et al. the perfect crime? ccsvi not leaving a trace in ms. j neurol neurosurg psychiatry 2011; 82:436-40. 10. ferral h, behrens g, tumer y, riemenschneider m. endovascular diagnosis and management of chronic cerebrospinal venous insufficiency: retrospective analysis of 30-day morbidity and mortality in 95 consecutive patients. ajr am j roentgenol 2013;200:1358-64. 11. karmon y, zivadinov r, weinstock-guttman b, et al. comparison of intravascular ultrasound with conventional venography for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency. j vasc interv radiol 2013;24:1487-98 e1. 12. snyder j, adams k, crooks va, et al. “i knew what was going to happen if i did nothing and so i was going to do something”: faith, hope, and trust in the decisions of canadians with multiple sclerosis to seek unproven interventions abroad. bmc health serv res 2014;14:445. venous dysfunction and neurodegenerative diseases c.-p. chung taipei veterans general hospital, national yang ming university, taipei, taiwan several neurodegenerative diseases such as alzheimer’s disease (ad), parkinson’s disease, normal pressure hydrocephalus, etc. have been reported associated with cerebral or/and extracranial venous abnormalities. the present lecture will focus on the current evidences linking venous abnormalities with ad and cerebral small vessel disease in the elderly, e.g. age-related white matter changes. additionally, the relationship between jugular venous reflux (jvr) and multiple neuropsychological performances in patients of ad, results of our latest study, will be presented. lastly, a discussion about the postulated mechanisms how venous drainage impairment lead to dysfunctions in ad will be provided. disclosures: the author has nothing to disclose. clinical applications of venous treatment m.d. dake thelma and henry doelger professor (iii), department of cardiothoracic surgery, stanford university school of medicine, stanford university, california, usa recent data from the literature suggest a greater role of chronic venous insufficiency in the pathogenesis of a variety of brain disorders. the goal of this talk is to review the contributions made in 2014 to our enhanced understanding of the safety and efficacy of the endovascular or open surgical treatment of chronic venous obstruction in patients with a variety of pathologies including multiple sclerosis, transient global amnesia, alzheimer’s disease, parkinson’s disease, postural orthostatic tachycardia syndrome, transient monocular blindness, headaches, and spontaneous intracranial hypertension. open surgical interventions including, but not limited to operative venous bypass, transposition, venoplasty, and vein interposition have been reported. endovascular procedures detailed in the medical literature include balloon angioplasty, cutting or scoring balloon angioplasty, self-expanding and balloon expandable stent placement, and stent-grafting. in general, all these therapies have been used to treat stenosis and/or occlusions of the jugular and/or azygous veins associated with increased collateral venous drainage. the relationship between anatomic findings and any symptoms related to the range of neurological disorders listed above has not been established and further research is required. disclosures: in the past, dr. dake has been paid consulting fees by abbott vascular, cook medical, metronic and w.l. gore. this is no way influences his research. endothelial dysfunction in neurodegenerative disease j.w. yun, e. stevenson, s. omura, f. sato, i. tsunoda, a. minagar, f. becker, t. castor, a. xiao, j.s. alexander lsuhsc-shreveport molecular and cellular physiology, microbiology, virology, neurology, shreveport, la, usa inflammatory cytokines appear to promote forms of vascular stress in several neurodegenerative diseases and may trigger endothelial disturbances which contribute to blood-brain barrier breakdown and intensification of disease. using bend3 brain endothelial cell model, we found that in response to exposure to tnf-α (20 ng/ml) + interferon-γ (1000 u/ml) (‘t/i’) bend3 endothelial cells released microparticles from both apical and basolateral domains, (amps and bmps respectively.) lymphatic vascular endothelial hyaluronic acid receptor (lyve-1), prospero homeobox 1 (prox-1) and vascular endothelial growth factor receptor (vegfr-3)/flt-4 have been previously described as neurolymphatic biomarkers found in tissue and serum samples in rr multiple sclerosis and sp multiple sclerosis. these biomarkers, as well as amyloid precursor protein (app) were also found to be expressed by bend3 brain endothelial cells, and were transferred into bend3 derived amps following t/i-stimulation. the vascular association of these biomarkers in the cns in distinct clinical forms of ms and experimental neurovascular forms of stress now indicates an endothelial origin for these markers. interestingly, t/i stimulation also potently induced the transfer of caveolin-1, an important caveolar constituent from bend3 brain endothelial cells into amps. similarly, t/i stimulated bend3 cells to also release no nco mm er cia l u se on ly invited abstracts [veins and lymphatics 2015; 4:s1] [page 9] membrane cholesterol, (measured as bodipy-cholesterol fluorescence) another important caveolar component, consistent with endothelial microparticles as fluid phase caveolae liberated by cytokine-activated endothelium. by comparison, endothelial nitric oxide synthase (enos) was detected within endothelial cells and was decreased by t/i treatment; enos also appears to be transferred to amps consistent with these particles potentially representing a shed form of circulating enos. these findings suggest that neurolymphatic markers induction observed in forms of ms and other of neurodegenerative diseases may represent partitioning of these biomarkers within caveloae which may segregate signaling modules related to neurovascular disease. supported by: aphios corporation alzheimer’s disease therapeutic (5r44ag034760) and the feist cardiovascular institute (lsuhsc-s). is there a role for mast cells dependent synthesis of endothelin-1 in neurodegenerative diseases? p. d’orléans-juste,1 l. desbiens,2 d. gris2 1department of pharmacology; 2department pediatrics, université de sherbrooke, sherbrooke, pq, canada background: in the central nervous system mast cells are found in proximity of neurons and blood vessels. during inflammation, activated mastocytes releases several proteases among which chymase is known to generate the potent vasoactive peptide, endothelin-1 (et1). it is of interest that both mast cell density and et-1 levels are significantly increased in neurological disorders such as multiple sclerosis. objectives: to identify the contribution of chymase and et-1 in a murine model of experimental allergic encephalomyelitis (eae). methods: the et-1 producing capacity of a mouse chymase isoform mast cell protease 4 (mmcp-4) will be compared to that of its human isoform using a combined recombinant/triple tof mass spectrometry approach. in addition, the contribution of systemic mmcp4 in radiotelemetry instrumented-conscious mice will be assessed. finally, clinical scores (from 0, normal mouse to 5, moribund state) will be assessed in wt or mmcp-4 ko mice with induced eae. results and conclusions: the present study demonstrates that both mouse and human chymases are involved in the synthesis of et-1. furthermore, preliminary results show reduced morbidity of eaeinduced mice genetically repressed for mmcp-4. we conclude that among several proteases secreted by mast cells in the vicinity of spinal lesions, chymase may play a significant role in the morbid events occurring in the mouse model of multiple sclerosis. disclosures: dr. d’orleans discusses endothelin l, big endothelin-l, endothelin-l (l -31), ty 514 69 which is currently unapproved. endothelin-1 as a potential target for chronic brain hypoperfusion j. de keyser free university of brussels (vub), department of neurology, brussels, belgium in the brain endothelin-1 (et-1) is produced and released by endothelial cells lining the blood vessels and by astrocytes. et-1 exerts its actions through two g-protein coupled receptors subtypes known as eta and etb receptors. in basal conditions, the expression of et-1 in the brain is low, with concentrations of et-1 in the picomolar range and hardly detectable by immunohistochemical techniques. significant expression and release of et-1 by reactive astrocytes occurs in acute cns injuries, such as ischemic stroke and subarachnoid hemorrhage. it also occurs in a number of neurodegenerative disorders, including alzheimer’s disease, multiple sclerosis (ms), and subcortical vascular dementia (binswanger’s disease), which are all associated with chronic brain hypoperfusion. in patients with ms we have been able to show a relationship between chronic brain hypoperfusion and increased et-1 levels. we found that, compared to controls, plasma et-1 levels in ms subjects were significantly elevated in blood drawn from both the internal jugular vein and a peripheral vein. the jugular vein/peripheral vein ratio was 1.4 in ms subjects versus 1.1 in controls, indicating that in ms, et-1 is released from brain to the cerebral circulation. et-1 immunohistochemistry on postmortem white matter brain samples suggested that the likely source of et-1 release were reactive astrocytes in ms plaques. using arterial spin labeling mri to noninvasively measure cbf we assessed the effect of the administration of the et-1a/b receptor antagonist bosentan. cbf was significantly lower in ms subjects than in controls, and increased to control values after bosentan. chronic brain hypoperfusion in animal models induces mitochondrial energy failure and oxidative stress. white matter is more susceptible than gray matter, and shows axonal degeneration, apoptosis of oligodendrocytes, myelin breakdown, inflammatory reactions and gliosis. however, chronic cerebral hypoperfusion in rats is also associated with cognitive impairment, and neuronal loss in the hippocampal ca1 region. axonal degeneration, apoptosis of oligodendrocytes, myelin loss and hippocampal atrophy have been observed in ms, subcortical vascular dementia and alzheimer’s disease. our finding that reduced cbf in subjects with ms is reversible with an et-1 antagonist opens the door for exploring new therapeutic approaches for neurodegenerative disorders associated with chronic brain hypoperfusion. et-1 antagonists are available and are a possible strategy. another approach consists in targeting the mechanisms leading to enhanced et-1 expression in reactive astrocytes. in ms there is evidence that et-1 upregulation in reactive astrocytes may be caused by cytokines that are elevated in ms plaques, including tumor necrosis factor-alpha and interleukin-1b. targeting these inflammatory pathways might reduce et-1 expression, restore brain perfusion and slow down disease progression. the underlying mechanisms with regard to alzheimer’s disease and subcortical vascular dementia may be similar, although other mechanisms may be involved. disclosures: the author has nothing to disclose. circulating vasoactive factors in multiple sclerosis l. monti,1 l. bazzani,2 p. piu,3 l. morbidelli2 1unit of neuroimaging and neurointervention, department of neurological and sensorial sciences, santa maria alle scotte general hospital, university of siena; 2department of life sciences, university of siena; 3department of medicine, surgery & neuroscience, university of siena, italy in multiple sclerosis (ms) patients, advanced neuroimaging techniques demonstrate cerebral hemodynamic alterations such as chronic cerebral hypoperfusion, prolonged cerebral circulation time and cerebral venous outflow alterations. it is established that ms patients have an impaired sympathetic responsiveness. however, to date, it is still not clear if other vasoactive mediators (alone or in combination) contribute to disease progression and severity. as an example, increased endothelin-1 (et-1) plasma levels have been demonstrated in ms patients. other reports document an increase in nitric oxide levels in plasma and cerebrospinal fluid of ms patients. the activity of the no synthase isoforms (both constitutive-endothelial and inducible/inflammatory ones) is however finely controlled by the endogenous inhibitor asymmetric dimethyl-arginine (adma), which is considered a marker of endothelial dysfunction in cardiovascular diseases. in our scientific protocol we have studied the modulation of adma before and after the endovascular treatment in ms patients. our data indicates that the levels of vasoactive factors et-1 and adma increase in ms patients respect to control subjects and change in relation to disease severity, cerebral circulation time and endovascular procedures. disclosures: the authors have nothing to disclose. no nco mm er cia l u se on ly veins and lymphatics 2015; volume 4:s1 [veins and lymphatics 2015; 4:s1] [page 11] internal jugular vein cross-sectional area and cerebrospinal fluid pulsatility in the aqueduct of sylvius c.b. beggs,1,2 c. magnano,2,3 p. belov,2 j. krawiecki,2 d.p. ramasamy,2,3 j. hagemeier,2 r. zivadinov2,3 1centre for infection control and biophysics, university of bradford, uk; 2buffalo neuroimaging analysis center, department of neurology, school of medicine and biomedical sciences, university at buffalo, ny, usa; 3mri clinical translational research center, school of medicine and biomedical sciences, university at buffalo, ny, usa background: constricted cerebral venous outflow has been linked with increased aqueductal csf pulsatility in healthy individuals1 and ms patients.2 however, the relationship between the csf pulsatility and internal jugular vein (ijv) cross-sectional area (csa) is unknown. objectives: to characterize links between ijv csa and aqueductal csf pulsatility in ms patients and healthy subjects. methods: 98 relapsing-remitting ms patients (62 males and 36 females; mean age=44.2 years) and 99 healthy controls (48 males and 51 females; mean age=43.9 years) were investigated. csf flow quantification involved cine phase-contrast mri, while ijv csa was calculated using magnetic resonance venography. cardiovascular risk factor data were collected. statistical analysis involved correlation, and partial least squares correlation (plsc), analysis.3 results: for healthy controls, plsc revealed a significant relationship (p=0.001) between csf pulsatility and ijv csa in the lower neck (c5-c7), and a trend for this relationship (p=0.091) at c2-c4. plsc revealed no relationships in ms patients. after controlling for age and cardiovascular risk factors, many significant correlations were identified in the healthy controls between the csf and ijv variables [e.g. net positive csf flow and left ijv csa at: c7-t1 (r=0.416, p=0.002) and c5-c6 (r=0.389, p=0.003); and net negative csf flow and left ijv csa at: c7-t1 (r=–0.352, p=0.008) and c5c6 (r=–0.349, p=0.009)], whereas there were only two significant correlations in ms patients [i.e. net positive csf flow and right ijv csa at: c5-c6 (r=0.311, p=0.035) and c4 (r=0.298, p=0.047)]. conclusions: in healthy adults, higher aqueductal csf pulsatility is correlated with increased ijv csa (particularly in the lower neck) in a relationship independent of age and cardiovascular risk factors. this relationship is largely absent in ms patients. given csf pulsatility and venous drainage are linked in healthy individuals,1 it may be that increased ijv csa is indicative of stasis in venous outflow. disclosures: robert zivadinov received personal compensation from teva pharmaceuticals, biogen idec, emd serono, novartis and sanofi-genzyme for speaking and consultant fees. r. zivadinov received financial support for research activities from biogen idec, teva pharmaceuticals, sanofi-genzyme, emd serono, novartis and sanofi-genzyme. dr. beggs has nothing to disclose. the other authors have nothing to disclose. references 1. beggs cb, magnano c, shepherd sj, et al. aqueductal cerebrospinal fluid pulsatility in healthy individuals is affected by impaired cerebral venous outflow. j magn reson imaging 2014;40:1215-22. 2. zamboni p, menegatti e, weinstock-guttman b, et al. the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis is related to altered cerebrospinal fluid dynamics. funct neurol 2009;24:133-8. 3. mcintosh ar, misic b. multivariate statistical analysis for neuroimaging data. annu rev psychol 2013;64:499-525. blood storage within the intracranial space and its impact on cerebrospinal fluid dynamics c.b. beggs,1 s.j. shepherd,1 p. cecconi,2 m.m. lagana2 1medical biophysics laboratory, university of bradford, uk; 2fondazione don carlo gnocchi onlus, irccs s. maria nascente, milan, italy background: the volumetric changes that occur throughout the cardiac cycle (cc) in the various intracranial vascular compartments are poorly understood. although blood entering/leaving the cranium is pulsatile, flow in the cerebral vascular bed is non-pulsatile,1 implying the transient storage of blood. objective: to characterise the temporal changes in fluid volume that occur within the cranium throughout the cc. methods: neck mri data were acquired from 14 healthy adults (age<35), using a 1.5 tesla scanner. arterial, venous and cerebrospinal fluid (csf) flow rate data acquired at the c2/c3 level were standardized to 32 points over the cc. the relative changes in the intracranial arterial, venous and csf volumes were calculated by: i) integrating the respective flow rate signals to compute the instantaneous volumetric changes (ivc); ii) mean centering the respective ivc signals; and iii) cumulating the mean centered ivc signals to yield the fluid volumetric changes in the cranium throughout the cc. results: the aggregated flow rate signals for all subjects are shown in figure 1, while figure 2 shows the relative changes in the intracranial arterial, venous and csf volumes. a strong inverse relationship exists between the arterial and venous volumetric signals (r=–0.844, p<0.001). as the intracranial arterial blood volume decreases to a minimum during diastole, so blood is stored in the intracranial venous compartments. this coincides with the period when the intracranial csf volume increases. only when the intracranial csf volume peaks and starts to decrease, is the venous blood stored in the cranium allowed to discharge. figure 1. aggregated fluid flow rates. 5th annual meeting of the international society for neurovascular disease march 27-29th, 2015 naples, italy podium abstracts no nco mm er cia l u se on ly podium abstracts [page 12] [veins and lymphatics 2015; 4:s1] figure 2. relative intracranial fluid volumes. conclusions: the behavior of the venous pulse is controlled by volumetric changes within the cranium in a process that is mediated by the csf. this finding supports the hypothesis that csf interacts with the cortical bridging veins to facilitate the storage of venous blood during diastole.2,3 references 1. bateman ga. pulse-wave encephalopathy: a comparative study of the hydrodynamics of leukoaraiosis and normal-pressure hydrocephalus. neuroradiology 2002;44:740-8. 2. luce jm, huseby js, kirk w, butler j. a starling resistor regulates cerebral venous outflow in dogs. j appl physiol respir environ exerc physiol 1982;53:1496-503. 3. vignes jr, dagain a, guérin j, liguoro d. a hypothesis of cerebral venous system regulation based on a study of the junction between the cortical bridging veins and the superior sagittal sinus. laboratory investigation. j neurosurg 2007;107:1205-10. cerebral circulation in patients with multiple sclerosis. a color-doppler study of extracranial arterial and venous vessels a. cervo,1 m.g. caprio,2 m. ragucci,1 m. mancini2 1department of advanced biomedical sciences, university federico ii, naples; 2institute of biostructure and bioimaging, national research council, naples, italy background: recent studies hypothesized multiple sclerosis (ms) to be influenced by alterations of cerebral circulation. objectives: to assess whether there is a relation between ms and cerebral circulation, by quantifying arterial inflow and venous outflow and by measuring carotid wall intima-media thickness (imt). methods: 82 ms patients and 53 healthy controls (hc) underwent to extracranial color-doppler examination in supine and upright for analysis of arterial and venous blood volume flow. internal carotid artery (ica) was determined 1.5 cm away from the carotid bifurcation. vertebral artery (va) was examined in the v2-segment. cerebral blood flow (cbf) was calculated as the sum of flow volumes in both ica and va. mean intima-media thickness (imt) was measured over a segment of the common carotid artery. cross-sectional areas of j1, j2 and j3 tracts of ijvs and venous blood flow in the j3 tract of ijv and in the most caudal tract of vv were measured. results: the ms group showed lower ijv blood flow than hc in supine position (258.1 ml/m vs 327.7 ml/m; p=0.025). no difference was found in the vvs flow. no parameters in the upright position were different. no difference was found in prevalence of ijv stenosis between the two groups. no differences between groups were seen in arterial inflow (cbf ms mean and range: 597.7 ml, 400.2-821 ml, hc 561.7 ml, 242.2-896.7 ml, p=0.055) and imt (ms 0.54 mm, 0.42-0.92 mm, hc 0.49 mm, 0.4-1.09 mm; p=0.033). conclusions: the results indicate an association between abnormal cerebral venous flow and ms. no differences between ms and hc in cbf and carotid imt were detected. key words: multiple sclerosis; internal jugular vein; cerebral blood flow; carotid; imt; echo-color doppler ultrasonography. disclosures: the authors have nothing to disclose. ultrasound-guided surgical procedure for internal and external jugular veins occlusion in mice: preliminary results a. greco,1,2 l. auletta,3 s. albanese,1,4 m. ragucci,1,4 m. salvatore,3 m. mancini2 1department of advanced biomedical sciences, university federico ii, naples; 2institute of biostructure and bioimaging, national research council, naples; 3irccs sdn, naples; 4ceinge, biotecnologie avanzate, scarl, naples, italy background: the relationship between venous abnormalities and neurological diseases are not widely investigated. only few studies explored the venous involvement in such diseases. some studies show that in mice there are multiple connections between intracranial veins and external jugular veins (ejv). therefore the venous circulation of mouse brain, unlike humans, has two different routes runoff formed by the internal jugular vein (ijv) and ejv. aim of our study was to develop a mice model of cerebral outflow occlusion in order to assess the correlations between venous stasis and the development of neurological diseases. at this purpose, we used high frequency ultrasound (hfus) to assess the feasibility of electrocoagulation to obtain neck veins occlusion in mice. methods: fourteen c57/black, female, five weeks old mice were used for this study. 4 mice underwent to bilateral occlusion of the ijv, 4 mice underwent to bilateral occlusion of the ejv, 4 both of the ejv and ijv and 2 mice were used as controls (sham operated mice). all the procedures were performed under general anesthesia with isoflurane (2%) in 100% oxygen at 0.8 l/min. blood venous flow of jvs was evaluated before and after surgical procedure by color doppler hfus (vevo 2100, visualsonics) with a 40 mhz probe. a ventral midline stab incision was performed on the neck to access the ejv. deeper blunt dissection was completed, on each side of the trachea, to expose the ijv. an electro-surgical equipment (diatermo mb 160, gima spa), mounting a small electrode for monopolar coagulation, was used to induce venous occlusion. skin was closed with 6-0 vicryl (johnson&johnson medical spa) in a simple continuous pattern and a triple antibiotic ointment was applied over the incision. sham operated mice were not subjected to electrocoagulation. all procedures where approved by ethical committee and supervised by a veterinary doctor. figure 1. images of doppler high frequency ultrasound of neck vessels in normal mice (a) and in sham operated mice (b). no nco mm er cia l u se on ly podium abstracts [veins and lymphatics 2015; 4:s1] [page 13] results: two of fourteen mice underwent to pulmonary complications during the surgical procedure, therefore the mortality was of 14%. the ijv and ejv were well identified with color doppler hfus prior (figure 1a) and after the surgical procedure (figure 1b). in all cases examined, hfus allowed us to confirm the absence of flow in the obstructed veins after the electrocoagulation procedure. all survivors are under neurological examination to assess the brain damage secondary to neck veins occlusions. conclusions: in our study, we evaluated the feasibility of ultrasound-guided surgical procedure that resulted a procedure with low mortality and efficacy in 100% of survivors. as the neck mouse veins anatomy is not similar to human, in vivo imaging of normal neck vessels is necessary for the evaluation of animal models. further studies are in progress to evaluate brain damage secondary to the occlusion of extracranial veins in mice. see shadow back due to surgical suture (b). supported by: this work was supported by a research grant from the italian ministry for education university and research in the framework of prin (2010xe5l2r_004). multiparametric automated segmentation of brain veins s. monti,1,2 g. palma,3 e. tedeschi,4 p. borrelli,4 s. cocozza,4 m. salvatore,1 m. mancini3 1irccs sdn, naples; 2department of bioengineering, politecnico di milano, milan; 3institute of biostructure and bioimaging, national research council, naples; 4department of advanced biomedical sciences, university federico ii, naples, italy background: manual segmentation of brain vessels in a typical mr dataset is both complex and time-consuming; therefore automated approaches are actively sought for, as they also improve the reproducibility of the results. objectives: to present a multiparametric segmentation method (mps) that, starting from a vessel likeliness function (vesselness) and r2* map of the brain, applies an expectation maximization (em) algorithm to the bivariate distribution of the data to classify each voxel as belonging or not to veins. methods: based on the assumption that a voxel belonging to a vein has high vesselness and r2* values, on the log-scale joint histogram of the maps, the voxels whose vesselness is higher than 0 were assigned to 3 main classes: i) a gaussian distribution with low r2* and vesselness (false positives enhanced by vesselness); ii) a class with r2* value above a given threshold; iii) another gaussian distribution with medium-high value of r2* and high value of vesselness, the last two truly corresponding to veins. through an em algorithm, the parameters of the 3 classes were estimated and the voxels belonging to the 2 vessel classes were identified. the performance of the mps was compared to the vesselness thresholding (vt) by blindly grading on a 0-5 scale the accuracy of vascular tree depiction. results: the semiquantitative analysis clearly showed that mps achieved greater accuracy in vessel display (scores 4-5 in 88% of the test-sample) than vt (scores 2-3 in 74% of the test-sample). in particular, false positives were the main pitfall of vt compared to mps. conclusions: combining the information obtained from vesselness and r2* maps, the mps substantially increased sensitivity and specificity of the monoparametric tresholding based on vesselness images only. key words: brain veins; vessel enhancing diffusion; r2* map; expectation maximization algorithm; multiparametric segmentation. disclosures: the authors have nothing to disclose. disturbed intracranial venous haemodynamics and macromolecule transport across vessel walls: a mathematical model e.f. toro,1 l. facchini,2 a. bellin1 1department of civil, environmental and mechanical engineering, university of trento, trento; 2department of mathematics, university of trento, trento, italy background: the recent association of extracranial venous strictures to multiple sclerosis1 has posed a number of partly unresolved hypothesis, one of them being intracranial disturbed flow and venous hypertension. by means of a global mathematical model for the human circulation2 it has been found that intracranial flow disturbances and venous hypertension are possible. another step in the chain of events leading to ms, involves increased permeability of the bbb due to altered venous haemodynamics and potential transport of colloids from the vessel lumen to the brain tissue. it is desirable to construct a mathematical model that addresses this issue; preliminary results are given in.3 objectives: to describe a simple mathematical model for plasma and molecule transport across blood vessel walls and perform a parametric study to identify biophysical quantities that affect vessel wall permeability and transport. methods: we use a mathematical model to study the consequences of brain venous hypertension regarding macromolecule transport across vessel walls. results: we studied the effect of three parameters: i) glycocalyx degradation; ii) local hydrostatic pressure; and iii) increase in pore number and/or radius. our results show that an increase in each of these three parameters results in increased plasma filtration and/or solute extravasation, as one would have expected. discussion and conclusions: mathematical modelling is helping in elucidating recently proposed medical hypotheses based on the empirical observation of a strong association between ms and extracranial venous strictures. computational quantification supports the plausibility of the proposed chain of events: extracranial venous strictures, disturbed intracranial venous flow, venous hypertension, increased plasma filtration and/or solute extravasation. more research is needed. disclosures: the authors have nothing to disclose. references 1. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:392-9. 2. mueller lo, toro ef. enhanced global mathematical model for studying cerebral venous blood flow. j biomechanics 2014;47:3361-72. 3. facchini l, bellin a, toro ef. a mathematical model for filtration and macromolecule transport across capillary walls. microvasc res 2014;94:52-63.no nco mm er cia l u se on ly veins and lymphatics 2015; volume 4:s1 [veins and lymphatics 2015; 4:s1] [page 15] vitamin k cream reduces cutaneous reactions to interferon β1a including erythema: the multiple sclerosis experience a. carotenuto,1 r. lanzillo,1 b. satelliti,1 m. moccia,1 g. vacca,1 m. massarelli,1 v. panetta,2 v. brescia-morra1 1multiple sclerosis centre, department of neuroscience, reproductive science and odontostomatology, university federico ii, naples; 2consultancy & training, l’altrastatistica srl, rome, italy background: injectable drugs are usually associated with adverse effects leading to poor adherence and incomplete efficacy. interferon beta (ifnβ) is an approved injectable drug for multiple sclerosis but it can cause a variety of local and systemic adverse events (ae), which include injection site pain, burning and erythema together with itching that can persist for several days, probably because of increased local release of histamine. topic vitamin k seems to be useful to prevent, or at least to reduce, the development of burning sensations acting as cofactor for the γ-glutamyl-carboxylase, taking part in a reaction involved in calcium binding and, as a consequence, in the interaction between coagulation factors and phospholipid layers. the mechanism of vitamin k in improving the cutaneous redness is probably local but not yet fully understood.1-4 objectives: to evaluate if a vitamin k cream local application could reduce injection-site reactions in ms patients treated with subcutaneous ifnβ. methods: this is a prospective, crossover interventional study. we enrolled rr ms patients treated with subcutaneous ifnβ 1-a with injection-site reactions. patients were randomly assigned to receive vitamin k cream from baseline or not (with a ratio of 1:1). at week 8 crossover took place. visual analogic scale (vas) for burning and pain and measure of the maximum width of erythema was performed at 0, 4, 8, 12 and 16 week. linear mixed model was assessed to evaluate the variability of continuous parameters (i.e. vas or erythema width) over time in relation to vitamin k cream use considering repeated measures. a p value <0.05 was considered statistically significant. results: we enrolled 123 subjects. at baseline median erythema width was 30 mm, vas median score for burning sensations was 40 and for pain was 47. vitamin k cream led to a significant reduction of 3.4 mm (p<0.001; ci 95% –5.3; –1.6) of the erythema width in vitamin k treatment period with respect to the period without treatment. vitamin k cream led also to a significant reduction of 3.5 points (p=0.014) of burning vas score and 4.3 points (p=0.002) of pain vas score. conclusions: vitamin k cream could be a helpful tool to improve treatment adherence for injectable drugs in ms. it is effective in reducing erythema, burning and pain sensation over the injection site. the mechanism of vitamin k in improving the cutaneous redness is not completely understood but probably it could take part in some reactions involved in calcium binding and, as a consequence, in the interaction between coagulation factors and phospholipid layers. disclosures: the authors have nothing to disclose. references 1. cohen jl, bhatia ac. the role of topical vitamin k oxide gel in the resolution of postprocedural purpura. j drugs dermatol 2009;11:1020-4. 2. lou ww, quintana at, geronemus rg, grossman mc. effects of topical vitamin k and retinol on laser-induced purpura on nonlesional skin. dermatol surg 1999;12:942-4. 3. shah ns, lazarus mc, bugdodel r, et al. the effects of topical vitamin k on bruising after laser treatment. j am acad dermatol 2002;2:241-4. 4. thorp ja, gaston l, caspers dr, pal ml. current concepts and controversies in the use of vitamin k. drugs 1995;3:376-87. extracranial venous anomalies, intracranial hypertension, ms and ipd: a mathematical and mri study f. caforio,1 e.f. toro,1 e.m. haacke,2 l.o. mueller,3 d.t. utriainen,2 s.k. sethi2 1laboratory of applied mathematics, university of trento, italy; 2the mri institute for biomedical research, detroit, mi, usa; 3computer science department, national laboratory for scientific computing, lncc/mcti, petropolis-rj, brazil background: recent evidence has suggested that the venous system plays a role in several neurodegenerative pathologies. the challenges lay with the complexity of the venous network in the brain and the difficulty to measure pressure in the brain veins. objectives: to assess the impact of unilateral stenoses in the internal jugular veins (ijvs) on pressure changes in the brain, by combining patient-specific mri flow data and a mathematical model, focusing on possible correlations with ms and ipd. methods: a global computational hemodynamic model for the human circulation was utilized. 2d tof and 3d contrast-enhanced mr venography of the head and neck of a healthy subject were collected. two sets of simulations for stenotic veins were performed, one for the lijv and one for the rijv for this left dominant individual. the stenosis was induced by reducing the lumen of the respective valve to 0.01%. results: for the lijv stenosis, significant pressure changes occurred in the sss (+1.6 mmhg, +21%), internal cerebral veins and the basal vein of rosenthal (1.5 mmhg, 11%). changes at the c2/c3 level and in the pterygoid plexus also occurred. negligible changes in the arterial system were observed. for the rijv stenosis, changes in the flow in other veins were now less evident, although some modifications were seen in the straight and transverse sinuses. conclusions: significant changes in pressure inside the brain occurred when the lijv was altered, especially in the midbrain and basal ganglia draining veins, where iron build up over time is observed in ms and ipd patients. we also observed pressure changes in veins draining the eyes. these can lead to ophthalmic problems, which have been related to ms. these results agree with the recent correlation found between unilateral venous abnormalities, ms and ipd. key words: intracranial hypertension; ms; ipd; mri; mathematical modeling. disclosures: the authors have nothing to disclose. hemodynamic model for the study of cerebral venous outflow: comparison with experimental results g. gadda,1 a. taibi,1 f. sisini,1 m. gambaccini,1 s.k. sethi,2 d. utriainen,2 e.m. haacke,2,3 p. zamboni,4 m. ursino5 1department of physics and earth sciences, university of ferrara, 5th annual meeting of the international society for neurovascular disease march 27-29th, 2015 naples, italy poster abstracts no nco mm er cia l u se on ly poster abstracts [page 16] [veins and lymphatics 2015; 4:s1] italy; 2the mri institute of biomedical research, detroit, mi, usa; 3department of radiology, wayne state university, detroit, mi, usa; 4vascular diseases center, university of ferrara, ferrara, italy; 5department of electrical, electronic and information engineering, university of bologna, italy background: blood flow redistributions and pressure variations due to posture changes in patients affected by vascular diseases are associated with the onset of venous obstructions. a hemodynamic model for the study of cerebral venous outflow was developed to study the correlations between extracranial blood redistributions and changes in the intracranial environment. objectives: to validate the model outcomes using flow data from a large cohort of stenotic and non-stenotic people obtained with magnetic resonance (mr) techniques. methods: the model results were tested using a mr flow dataset of 690 supine people (stenotic/non-stenotic ratio=372/318, multiple sclerosis/healthy controls ratio=571/119). internal jugular veins (ijvs) showing a cross section area (csa) of less than 25 mm2 at the lower half of the ijv body was considered stenotic, while a csa of less than 12.5 mm2 was considered stenotic for the upper ijv body. phase-contrast mr images at the c2/c3 and c5/c6 spinal cord level were used to quantify blood flow. results: model simulations of the fraction of cerebral blood flow drained by the jugular ducts for supine nonstenotic people are in agreement with mr data (0.93 and 0.82, respectively), as well as the flow in the spinal ducts (0.06 and 0.09), both with a statistically significant p-value. the same simulations agree with measurements of lack of jugular drainage and increase of extrajugular drainage due to different stenotic patterns. moreover, there is agreement with upright blood flow data assessed by echo colour doppler methodology. conclusions: the present model correlates vascular diseases, extracranial blood redistributions and changes in the intracranial environment, taking into account the posture variation and the amunt of blood coming from anastomotic connections and extrajugular drainage pathways. key words: mathematical modeling; cerebral drainage pathways; posture dependence; ultrasound and magnetic resonance flow quantification. disclosures: the authors have nothing to disclose. impact of extracranial venous outflow disturbances on petrosal sinuses pressure in sudden sensorineural hearing loss: a computational pilot study q. zhang,1 m. cristini,1 a. ciorba,2 m. tessari,3 l.o. mueller,1,4 e. menegatti,3 s. pelucchi,2 a. pastore,2 e.f. toro,1 p. zamboni3 1laboratory of applied mathematics, university of trento, italy; 2department of biomedical sciences and specialty surgery, section of otorinolaringology, university of ferrara, italy; 3vascular diseases center-university of ferrara, programma fisiopatologia dell’apparato vascolare e day surgery az. osp. di ferrara, cona (fe), italy; 4laboratório nacional de computação científica, petrópolis, rio de janeiro, brazil background: anedoctical reports of extracranial venous outflow disturbances have recently been linked to sensorineural hearing loss (i.e. ménière disease). to date, direct measurements of venous hypertension in the main intracranial route of drainage of the inner ear through invasive methods are unavailable. as an alternative, the use of a computational model makes possible cerebral haemodynamical quantifications. extracranial venous outflow and post analysis was blindly assessed in healthy control (hc) and in a group of four patients with different outcome of sudden sensorineural hearing loss (ssnhl). objectives: to study the impact of extracranial cerebral venous outflow on bilateral pressure of the superior and inferior petrosal sinuses (sps, ips), posterior auricular, deep facial, mastoid emissary, internal jugular veins. methods: making use of a global, mathematical model for the human circulation (previously validated against in vivo mri data), we performed five sets of simulations for subjects in supine position, by considering different outflow anomalies. simulations were realized after quantifying flow anomalies eventually found by the means of a validated echocolordoppler quantification protocol. finally, results were compared with the clinical outcome. results: the main finding was the significant increased pressure calculated in the right sps and inferior petrosus sinus in patients with blocked outflow and collateralization at the level of the right ijv obstructed valve. this finding seems to be relevant for the outcome of the patients since 2 patients with such haemodynamic pattern did not show any threshold recovery. to the contrary the patient with not significant raising pressure in the petrosus sinuses responded to treatment. conclusions: the mathematical model applied to our validated ecd protocol of outflow quantification seems to provide coherent and unconventional clinical information on the drainage of the inner ear. this innovative approach was proven to be feasible by the present pilot investigation and warrants further studies with an increased sample of patients. key words: cerebral venous haemodynamics; petrosus sinus hypertension; mathematical modeling; quantification of venous outflow; echocolordoppler; sudden sensorineural hearing loss (ssnhl). disclosures: the authors have nothing to disclose. enhanced vesselness mapping to detect small cerebral veins on swi images s. monti,1 g. palma,3 e. tedeschi,4 s. cocozza,4 p. borrelli,4 m. salvatore,1 m. mancini3 1irccs sdn, naples; 2department of bioengineering, politecnico di milano, milan; 3institute of biostructure and bioimaging, national research council, naples; 4department of advanced biomedical sciences, university federico ii, naples, italy background: cerebral veins are visualized by susceptibility weighted imaging (swi), which may highlight vascular abnormalities in different cerebral diseases. assessing the vascular anatomy in a 3d computer model by a vascular extraction algorithm may improve the study of structural and functional abnormalities in vascular diseases. objectives: to implement a modified version of vessel enhancing diffusion (ved) filter and test its application to swi datasets at different flip angles. methods: a multi-scale (0.1 to 1 mm) vessel enhancement filter was applied to several 3d swi datasets acquired by a 3t scanner (fas=[3~20]°, tr=31 ms, te=22.14 ms, voxel size=0.5x0.5x1 mm3). for each scale and voxel the hessian tensor was calculated and a vesselness estimate was computed on the basis of the hessian eigenvalues, to distinguish tubular from non-tubular structures. the voxel-byvoxel maximum of these estimates was evolved according to a scheme of anisotropic diffusion highly restricted when perpendicular to tubular structures (ved). to improve the ved filtering and obtain highsnr continuous 3d model of the veins, the diffusion time was set to 0.2, the sensitivity s to 3 and, at each diffusion step, the vesselness function was thresholded, suppressing all values below 0.02. results: the visual inspection of the vesselness maps obtained varying the swi flip angle suggests that the better compromise between sensitivity to vessels and specificity against csf-filled sulci was reached using flip angles close to the ernst angle of gray matter (~12° for the given tr). conclusions: dynamical thresholding of the vesselness function within the diffusion evolution provides an increased specificity in vessel visualization that, combined with a proper choice of the acquisition flip angle, allows the detection of deep medullary veins barely visible on the original swi. no nco mm er cia l u se on ly poster abstracts [veins and lymphatics 2015; 4:s1] [page 17] key words: susceptibility weighted imaging; cerebral vein; vessel enhancing diffusion; vesselness function. disclosures: the authors have nothing to disclose. venous theory of ms and other neurological disease l. grozdinski, i. petrov clinic of cardiology and angiology, city clinic, sofia, bulgaria background: the aim of this study was to answer the question whether chronic cerebrospinal venous insufficiency (ссsvi) is a specific syndrome only in ms or it is found in other neurological diseases. methods: the research included 1066 patients examined for chronic cerebrospinal venous insufficiency (ссsvi): мs 1000, als 12, parkinson 17, and alzheimer 9, cvst syndrome transitory global amnesia 2, stga cerebral venous sinus thrombosis 2, migraine 24. the ccsvi and neurological diagnoses were established clinically, with echodoppler, phlebography, mri, ct and emg. endovascular therapy of ccsvi dilatation or stenting of the jugular veins was performed. results: ccsvi was established in 94% of patients with neurological diseases. we found ccsvi in 96 % of ms patients and 77% in other neurological diseases. endovascular therapy was performed in all patients with ccsvi: venous dilation and/or stenting of the venous stenosis of jugular and azygos vein. after therapy reported clinical effects: 61% of the patients had positive clinical effects, 65% had increase in qol. conclusions: ccsvi was established not only in patients with ms, but in patient with other neurological diseases. based on these studies, we believe that a vein theory would explain the presence of ccsvi in various neurological diseases. this is the most likely hypothesis. according to venous theory, ccsvi is a key factor in the development of neurodegenerative, autoimmune and other neurological disease. the improved vein drainage after endovascular therapy of ccsvi had very good clinical effect with low number of post-procedure complications. it is necessary to make the randomized trials. key words: ccsvi; ms; als; parkinson; alzheimer; cvst; stgi. disclosures: the authors have nothing to disclose. ccsvi in ménière’s disease: diagnosis and treatment a. bruno,1 l. califano,2 d. mastrangelo,1 r. de vizia,3 f. salafia,2 v. giugliano,3 b. bernardo1 1vascular surgery department, gepos clinic, telese terme (bn); 2ssd audiology and phoniatrics, g. rummo hospital, benevento; 3radiology departement gepos clinic, telese terme (bn), italy objectives: to evaluate by the means of doppler ultrasound and phlebography the relationship between ménière’s disease and chronic cerebrospinal venous insufficiency (ccsvi) and to test whether angioplasty is an effective procedure in improving symptoms. methods: i) phase 1: 150 patients diagnosed with definite ménière’s disease (aao 1995) who had gained no benefit by medical therapy, underwent echo-enhanced color doppler sonography using the zamboni protocol to check for ccsvi. one-hundred (100) healthy subjects matched for age and gender acted as controls. ii) phase 2. in 40 of ecd positive ménière’s cases we performed a venogram and the diagnosis of associated ccsvi was confirmed. these patients were treated by angioplasty of the internal jugular vein, then re-tested respect the baseline scales of ménière’s disease. twenty of them had a 18-month follow-up. results: out of a total of 150 patients with ménière’s disease, an ultrasound diagnosis of ccsvi was made in 135 patients (90%). in the healthy population, was found in only 10% of cases. in fourthy patients venography confirmed the ccsvi diagnosis and percutaneous transluminal angioplasty (pta) proved to be effective in 80% of patients, with significant improvement of several scales of audiological and vestibular function at 18 month follow-up. conclusions: the prevalence of ccsvi in patients with ménière’s disease is higher than in healthy subjects; pta seems useful because of an improvement in symptoms with audiological and vestibular functions better in the majority of patients. disclosures: the authors have nothing to disclose. ultrasound b-mode to assess the jugular venous pulse f. sisini,1 m. tessari,2 g. gadda,1 g. didomenico,1 a. taibi,1 e. menegatti,2 m. gambaccini,1 p. zamboni2 1department of physics and earth sciences, university of ferrara; 2vascular diseases center, university of ferrara, cona (fe), italy objectives: poor functionality of the brain drainage can lead to brain problems such as delaying venous return and as reported by zivadinov and chung, mounting evidence suggests that a number of inammatory and neurodegenerative central nervous system disorders may be related to vascular factors. since internal jugular vein (ijv) is considered to be the main route for the drainage of the brain when the body is in supine position various authors have investigated the possible relationship between abnormal conditions of the jugular vein functionality and neurological disorders. as pointed out by zivadinov, precise assessment of the cerebral venous return and hence of the ijv functionality is needed in order to relate it with such neurological disorders. unfortunately, the proper ultrasound doppler assessment of the ijv blood ow is challenging because the difficult to assess accurately the blood velocity needed for the ow calculation. in fact, ijv csa varies along the vessel cervical course and also change in time because of its pulsation. for this reason we are investigating alternative approaches to assess ijv drainage functionality based on b-mode modality. we believe that jugular venous pulse (jvp) waveform can be used to investigate ijv drainage functionality. in the past, already mackay, used the jvp obtained using a polygraph to assess the change in venous return induced by posture changing. b-mode ultrasound technique allows the cross section of the ijv to be easily displayed, and therefore the area and perimeter variation to be measured along the cardiac cycle. our idea is that it is possible to obtain the jvp using a sequence of sonograms of the ijv obtained in b-mode. the idea is to create a diagram of ijv csa respect the time; in fact when the ijv is distended (not collapsed), its transmural pressure (i.e. internal minus external pressure) and its csa are correlated and therefore the time diagram of the csa reects the jvp. in this preliminary study, we explore the possibility to produce a diagram reecting the jvp csa variations by means of real time b-mode ultrasound sequences. such approach has been already used to dynamically investigate the arterial distension waveform (adw) of 2 the carotid arteries but it has not been used to assess the jvp. methods: three young healthy subjects underwent b-mode us scan of the internal jugular vein (ijv) in order to acquire a sonograms sequence in the transverse plane. on each acquired sonogram the ijv contour was manually traced and both cross sectional area (csa) and perimeter were measured. for every acquired sequence both the measured csa and the acquisition time of the sonogram were also collected. the csa data set represents the usjugular diagram (usjd). the precision of the operator was evaluated. the us jugular diagrams were then produced by an algorithm developed in house. the sensitivity (se), specificity (sp) and accuracy (ac) of the algorithm has been evaluated. discrete fourier transform and auto-correlation function of the jugular diagrams were evaluated to assess their periodicity. the arterial distension waveform of the subjects was compared with its usjd. the correlation between the csa and the perimeter was assessed during the cardiac cycle to verify the ijv distension. this study was in no nco mm er cia l u se on ly poster abstracts [page 18] [veins and lymphatics 2015; 4:s1] accordance with the ethical standards of the committee on human experimentation of the azienda ospedaliera universitaria di ferrara, italy. results and discussion: for each subject a short sonogram sequence of few seconds was recorded and the obtained usjd showed a periodic behavior. the coefficient of variation of the manual us jugular diagram measurement resulted around 0:015. for the three subjects, the fourier transform showed the pulse duration of 3 the jugular vein. we compared 390 manually traced proles of the ijv cross sectional area with corresponding values automatically calculated by an algorithm made in house. for all the subjects the accuracy resulted over 90%. besides, for all subjects the csa was found correlated with the perimeter (pearson coefficient r>0:9) indicating that the ijv in supine position is distended and then the young modulus for the ijv can in principle be obtained by the measurement of the pulse wave velocity. conclusions: we have shown that a diagram reecting the jvp can be obtained by analyzing an us b-mode sonogram sequence of the ijv; such diagram can result in a new methodology to assess the ijv functionality. key words: internal jugular vein; jugular venous pulse; edge detection; venous return; cerebral outflow. disclosures: the authors have nothing to disclose. evaluation of clinical condition after pta of jugular and azygos veins in 815 pts affected by multiple sclerosis g. bellagamba, p. onorati, e. righi, t. lupattelli istituto clinico-cardiologico gvm, roma, italy since the physical disability in ms (multiple sclerosis) disease is of great importance, therefore q of l (quality of life) measurements have been considered increasingly important with regards to evaluating disease progression, treatment and management for care to ms patients. in all our patients we investigated two symptoms: i) fatigue; ii) bladder conditions. we examined 815 consecutive patients after pta (percutaneous transluminal angioplasty) of jugular and azygos veins, starting from october 2010 to july 2014. the evaluation has been done from 2 to 42 months after pta. the sample in our study showed a large variability in edss score (expanded disability status score, ranging from 1.5 to 7.5) and thus represented the physical performance of the ms population to a great extent. the three principal types of ms were enrolled: rr 522 patients 65%; sp 229 patients 28%; pp 54 patients 6.6%. 10 patients were not enrolled because of uncertain classification. age from 18 to 73 average 43 (f 540 m 285; ratio 2-1). the 2 symptoms, fatigue and conditions of the bladder, were present in a very evident way. the meaning of the fatigue is a subjective deep lack of physical and mental energy perceived from the patient even in rest conditions. from the fatigue we used the scale of analogic evaluation (vas), where the patient is able to refer a value from 0 to10 about personal fatigue. bladder: the necessity to empty the bladder in the morning from almost every hour before pta, and roughly 4 to 6 times after pta; at night time, the necessity was from 1-4 time prior to pta, to 0-1 after pta. in the 85% the pts are in hurry with the impossibility to wait; in 15% there was the difficult to empty the bladder. the results about these two items, very important for q of l, has been a complete resolution of the fatigue and normalized bladder in 458 pts (60.4%). we excluded in the investigation patients with moderate improvement of the 2 items. we would like to highlight that, among the three types of ms in the 815 pts, it was more difficult to obtain an evident disappearance of the symptoms in sp (secondary progressive) and pp (primary progressive) ms types. we would like to underline also our diagnostic approach with ms patients: the examination is carried out with echocolordoppler in the haemodynamic ward before, during and at the end of pta procedure. disclosures: the authors have nothing to disclose. circulating profile of endothelial dysfunction and coagulation/inflammation activation in patients with multiple sclerosis after endovascular treatment of chronic cerebro spinal venous insufficiency: a prospective study m. napolitano,1 a. bruno,2 d. mastrangelo,2 m. de vizia,2 b. bernardo,2 b. rosa,3 v. de lucia,4 g. lus,4 d. de lucia4 1hematology unit, thrombosis and hemostasis reference regional center, university of palermo, palermo; 2division of endovascular and vascular surgery, clinic gepos telese terme, benevento; 3faculty of medicine, university of campobasso, campobasso; 4division of neurology, second university of naples (sun), naples, italy background: the blood brain barrier (bbb) is a multi-cellular complex establishing a stable and immunologically privileged environment for neural functions. recently, changes in cytokine, metabolic and growth modulating networks between bbb endothelium and support cells have been thought to contribute to vascular injury in multiple sclerosis (ms). objectives: we performed a monocentric observational prospective study to evaluate coagulation activation, endothelial dysfunction parameters and circulating cytokines in patients with ms undergoing endovascular treatment for cerebro-spinal-venous insufficiency. methods: between february 2011 and july 2012, 144 endovascular procedures in 110 patients with ms and chronical cerebro-spinal venous insufficiency (ccsvi) were performed and they were prospectively analyzed. each patient was included in the study according to previously published criteria, assessed by the investigators before enrollment. results: endothelial dysfunction and coagulation activation parameters were determined before the procedure and during follow-up at 1, 3, 6, 9, 12, 15 and 18 months after treatment, respectively. after the procedure, patients were treated with standard therapies, with the addition of mesoglycan (50 mg twice-day). fifty-five percent patients experienced a favorable outcome of ms within 1 month after treatment, 25% regressed in the following 3 months, 24.9% did not experience any benefit. no major complications were observed. coagulation activation (activated fx and f1+2), endothelial dysfunction parameters (pai-1, t-pa, d-dimers) and cytokines (sicam, svcam, il-1 and il-6) were shown to be reduced at 1 month and stable up to 12-month follow-up, and they were furthermore associated with a good clinical outcome. conclusions: endovascular procedures performed by a qualified staff are well tolerated. correlations between inflammation, coagulation activation and neurodegenerative disorders here demonstrate that hemodynamic correction is able to restore the normal levels of several coagulation/inflammatory/angiogenic factors characterizing ccsvi in ms. key words: ccsvi; coagulation activation; endothelial dysfunction. disclosures: the authors have nothing to disclose. cortical sources of resting state eeg rhythms differ in relapsing-remitting and secondary progressive multiple sclerosis g. noce,1 c. babiloni,2,3 c. del percio,3 p. capotosto,4 f. infarinato,3 c. muratori,5 a. soricelli,1,6 p. onorati,3,5 t. lupattelli5 1irccs sdn foundation, naples; 2department of physiology and pharmacology, la sapienza university, rome; 3irccs san raffaele pisana, rome; 4department of neuroscience and imaging and clinical science, and itab, university g. d’annunzio, chieti; 5icc istituto clinico cardiologico, casalpalocco (rm); 6department of studies of institutions and territorial systems, university parthenope of naples, italy background: multiple sclerosis (ms) is one of the most common causes of neurological disability in adults with an unpredictable clinical course and variable manifestation. there are two major forms of ms, namely relapsing-remitting (rr) and secondary prono nco mm er cia l u se on ly poster abstracts [veins and lymphatics 2015; 4:s1] [page 19] gressive (sp). it was observed that resting state electroencephalographic (eeg) rhythms are abnormal in ms patients, but it is unclear if they can reflect different neurophysiologic abnormalities in rr and sp forms. objectives: here we tested the hypothesis that abnormal cortical sources of resting state eeg rhythms distinguish rr and sp at group level. methods: resting state eyes-closed eeg activity was recorded in 43 rr, 26 sp, and 60 matched healthy subjects. eeg rhythms of interest were δ (2-4 hz), τ (4-8 hz), α 1 (8-10.5 hz), α 2 (10.5-13 hz), β 1 (13-20 hz), and β 2 (20-30 hz). loreta freeware estimated cortical eeg sources for statistical comparison between the two groups. results: compared to the control group, the ms sub-groups showed an amplitude decrease of widespread α 1 cortical sources and an amplitude increase of parietal delta cortical sources. furthermore, frontal and temporal delta sources were higher in amplitude in the rr compared to the sp sub-group. conclusions: the present results suggest that cortical sources of resting state low-frequency eeg rhythms differ in two common phenotypes of ms patients such as rr and sp. these findings motivate the use of the present eeg biomarkers for future investigations on the effect of standard and new interventions (i.e. medications, rehabilitation, cerebrovascular, etc.) in rr and sp patients. key words: multiple sclerosis; relapsing-remitting; secondary progressive; electroencephalography; low-resolution brain electromagnetic tomography. disclosures: the authors have nothing to disclose. percutaneous trasluminal angioplasty of azygous vein in patients with multiple sclerosis and chronic cerebro spinal venous insufficiency. a single center experience t. lupattelli,1 g. bellagamba,1 e. righi,1 c. muratori,1 g. noce,2 p. onorati,1 c. babiloni3 1istituto clinico cardiologico, gvm sanità, casalpalocco (rm); 2irccs sdn foundation, naples; 3department of physiology and pharmacology, la sapienza university, rome, italy background: chronic cerebrospinal venous insufficiency (ccsvi) is a recently discovered syndrome mainly due to stenoses of internal jugular (ijv) and/or azygos veins (az). the aim of the present study is to retrospectively evaluate technical success after pta±stenting in a cohort of patients with multiple sclerosis (ms) and ccsvi. methods: from september 2010 to october 2014 a total of 2435 ms patients (1391 females) underwent selective venography from a left common femoral vein access, followed by balloon angioplasty±stenting at the same session. all the patients had previously been evaluated for ccsvi with color doppler ultrasound at different institutes. left common iliac, ascending lumbar, vertebral and internal giugular veins as well as azygos territory were selectively studied in all cases. interventional treatment was performed whenever achievement of an improved flow through the az was deemed possible. endovascular treatment was carried out as an outpatient procedure in all patients. results: selective venography of the az was performed in 2433 patients. two patients showed no evidence of az vein despite several attempts at finding it. percutaneous trasluminal angioplasty±stenting of the affected az was performed in 2119 (87.1%) patients. balloon angioplasty alone was performed in 2095 cases (98.9%) whereas additional stent placement was required in 24 patients (1.1%). the decision to implant a stent was taken following 3 unsuccesfull attempts at dilating the vein (23 cases) or following a vein rupture occurring at the time of balloon dilatation (1 case). in all 23 patients with unsuccessful az dilatation a severe kinking of the vessel was noted at confirmation angiography. balloon angioplasty alone showed improvement of the venous drainage >30% in 1849 out of 2119 (87.2%) whereas stenting proved to be successful in 21 out 23 patients (91.3%). major complications included one (0.05%) surgical opening of common femoral vein to remove balloon fragments and one (0.05%) az rupture requiring hospitalization. minor complications included, 3 (0.15%) procedure-related technical issues, 5 (0.24%) transient atrial fibrillation requiring a further 12-hour hospital stay, 15 (0.7%) slight bleeding or haematomas in the groin (3 requiring further hospital care the day after intervention and 5 prolonged hospital stay). conclusions: endovascular treatment of azygous vein in ccsvi patients appeared feasible and safe with a high rate of technical success. disclosures: the authors have nothing to disclose. poroelastic model of glymphatic flow driven by vasculature pulsation e. lanaro,1 c.s. drapaca,2 b.j. gluckman,2 f. costanzo,2 e.f. toro3 1department of mathematics, university of trento, italy; 2department of engineering science and mechanics, pennsylvania state university, university park, pa, usa; 3laboratory of applied mathematics, dicam, university of trento, italy recent experimental observations have shown the existence of a self-cleaning pathway within the central nervous system that removes metabolic waste products from the brain tissue. the natural pulsations of cerebral arteries and mechanotransduction of specialized glial cells facilitate the flow of some of the cerebrospinal fluid through the tissue from the penetrating arteries to the draining veins. this particular dynamics of the cerebrospinal fluid (csf) is called glymphatic flow. mathematical models and corresponding computer simulations are now needed to understand the mechanisms that govern the glymphatic flow. while peristaltic transport of newtonian fluids through porous media can explain the flow of cerebrospinal fluid through the perivascular space, no mathematical models have been proposed yet for the glympathic flow deeper in the brain tissue. we propose to investigate the mechanical response of brain tissue to arterial pulsations. we model the brain as a mixture of an elastically deformable solid phase made of brain cells and a newtonian fluid phase made of cerebrospinal fluid. the environment is assumed to be axisymmetric with impermeable walls. analytic expressions for the stream function and corresponding vorticity of the fluid phase are found from the linearized equations using perturbation theory. these results are then compared to numerical simulations. we conclude that there is non-zero vorticity around the arterial wall. further studies are to be carried out coupling this model with the global circulation model of mueller and toro (2014). key words: theory of mixtures; poroelasticity; glymphatic flow. disclosures: the authors have nothing to disclose. subjects with jugular anomalies exhibit increased collateral venous flow in mri s.k. sethi,1 g. gadda,2 d. utriainen,1 e.m. haacke1,3 1the mri institute of biomedical research, detroit, mi, usa; 2university of ferrara, italy; 3department of radiology, wayne state university, detroit mi, usa background: jugular venous structure and flow anomalies have been shown in multiple sclerosis (ms) subjects compared to healthy controls (hc) using magnetic resonance imaging (mri). objectives: a retrospective analysis of extracranial venous structure and function for a large cohort of ms patients and hc subjects. methods: a group of 571 ms subjects and 119 hc subjects were imaged with 3t mri scanners. we assessed blood flow and anatomy of the extracranial vessels with phasecontrast flow quantification and magnetic resonance (mr) venographic imaging. venous structures were classified by cranial drainage into three collateral types: type i: internal jugular veins, type ii: paraspinal veins, and type iii: superficial veins. jugular veins were classified into stenotic (st) and nonstenotic (nst) groups. individual, total vessel flow, as well as venous flow normalized to total arterial flow (ta) were quantified using in-house software. comparisons in stenosis and no nco mm er cia l u se on ly poster abstracts [page 20] [veins and lymphatics 2015; 4:s1] flow properties were made in ms, hc, and between their subcategories of stenosis type, location, and mstype. results: in the ms group, 352 (62%) classified as st while 20 (22%) hc classified as st (x2=59.3, p<0.05). type i and ii normalized venous flow showed differences between the ms and hc groups (p<0.05 for type i and ii), as well as between the nstms vs stms (p<0.05 for type i and ii), and hc vs stms groups (p<0.05 for type i and ii). conclusions: we were able to show with mri that not only stmsexhibit ijv anomalies with reduced ijv flow, but that the flow in this cohort is elevated in the paraspinal venous collaterals (type ii). this property was observed in the sthc, but the prevalence of flow reduction in the hc group was significantly lower than the ms group. key words: mr venography; phasecontrast flow quantification; venous anatomy and flow. disclosures: the authors have nothing to disclose. where are we in understanding the causes of normal pressure hydrocephalus? l.a. prouty genetics department of pediatrics lsu health shreveport, la, usa the objective of this presentation is to describe the evolution of causal explanations for nph and to review the perspective for future efforts. nph, which has idiopathic (inph) and secondary forms, results from disturbances in the interactions between the blood and cerebrospinal fluid (csf) circulatory systems. despite decades of clinical experience and research, there is scant understanding, especially for inph, of the underlying processes that trigger and sustain the disease. what we know today began with the first description of nph, when hakim proposed a hydraulic press theory to explain enlarged ventricles at normal intracranial pressure (icp).1,2 a transient excess of csf, which circulates through the csf system by bulk flow, elevates intracraniai pressure (icp) and enlarges the ventricles, which remain enlarged due to pascal’s law when icp normalizes. subsequently, it was shown that enhanced choroid plexus pulsations, reflecting the cardiac cycle, are sufficient to enlarge ventricles.3,4 over the next three decades, a dynamic view of csf circulation developed. pulsations of the major arteries into the brain are cushioned by cisternal csf, resulting in an oscillatory flow of csf between cranial and spinal subarachnoid spaces, smoothing pulsations into laminar flow at the capillaries (windkessel effect). subventricular capillaries are recognized as being a major site of csf absorption across the ependyma, reducing the importance of drainage through the superior sagittal sinus. a chain of events is now proposed. reduction of compliance of the craniospinal subarachnoid space, as with aging or trauma, elevates the arterial pulse pressure (including that of the choroid plexus), increases icp, which compresses the dural sinuses and bridging veins, raising venous pressure and inhibiting csf absorption via the sss. these changes produce a stiffened, hyperdynamic brain and the energy of arterial pulsations is displaced to the subventricular capillary beds, disrupting them. the ventricles may thus expand without a pressure gradient between the ventricular walls and the subventricular space.5-11 bateman incorporates these principles into his venous hemodynamic theory of nph.12 he describes a positive feedback loop between the craniospinal compliance and cerebral venous pressure which eventually stops apical csf drainage. shunt placement breaks the feedback loop, restoring craniospinal compliance.12 a simpler causal sequence is due to bradley.13,14 he observes that a substantial percentage of inph patients are macrocephalic, likely due to childhood episodes of benign external hydrocephalus. as adults, these patients lose their ability to compensate for the hydrocephalus at a time when subventricular ischemic disease has diminished the absorption of csf via the ependymal route. there are certainly alterations at the cellular and molecular levels which result in failure of critical biomechanical properties of the brain. the regulation of water via the aquaporins merits attention,15,16 likewise gene identification from reverse genetics in the rare familial cases of inph.17 refinements in magnetic resonance elastography (mre) could better characterize brain biomechanical substrates.18,19 prospective studies with presymptomatic patients would presumably simplify causal analysis. insight into the causes and disease processes of nph will lead to improved diagnosis and treatment and even, it is hoped, lead to preventive measures by identifying those at risk. disclosures: the authors have nothing to disclose. references 1. adams rd, fisher cm, hakim s, et al. symptomatic occult hydrocephalus with “normal” cerebrospinal-fluid pressure. a treatable syndrome. n engl j med 1965;273:117-26. 2. hakim ca, hakim r, hakim s. normal-pressure hydrocephalus. neurosurg clin n am 2001;12:761-73, ix. 3. bering ea. circulation of the cerebrospinal fluid. demonstration of the choroid plexuses as the generator of the force for flow and ventricular enlargement. j neurosurg 1962;19:405-13. 4. pettorossi ve, dirocco c, mancinelli r, et al. communicating hydrocephalus induced by mechanically increased amplitude of the intraventricular cerebrospinal fluid pulse pressure: rationale and method. exper neurol 1978;59:30-9. 5. greitz d. the hydrodynamic hypothesis versus the bulk flow hypothesis. neurosurg rev 2004;27:299-300. 6. greitz d. paradigm shift in hydrocephalus research in legacy of dandy’s pioneering work: rationale for a third ventriculostomy in communicating hydrocephalus. childs nerv syst 2007;23:487-9. 7. greitz d. radiological assessment of hydrocephalus: new theories and implications for therapy. neurosurg rev 2004;27:145-65. 8. egnor m, zheng l, rosiello a, et al. a model of pulsations in communicating hydrocephalus. pediatr neurosurg 2002;36:281-303. 9. bergsneider m. hydrocephalus: new theories and new shunts? clin neurosurg 2005;52:120-6. 10. bateman ga. the reversibility of reduced cortical vein compliance in normal-pressure hydrocephalus following shunt insertion. neuradiol 2003;45:65-70. 11. bateman ga. extending the hydrodynamic hypothesis in chronic hydrocephalus. neurosurg rev 2005;28:333-4. 12. bateman ga. the pathophysiology of idiopathic normal pressure hydrocephalus: cerebral ischemia or altered venous hemodynamics? ajnr 2008;29:198-203. 13. bradley wg, jr, bahl, g, alksne jf. idiopathic normal pressure hydrocephalus may be “two hit” disease: benign external hydrocephalus in infancy followed by deep white matter ischemia in late adulthood. j mag res imag 2006;24:747-55. 14. bradley wg, jr. idiopathic normal pressure hydrocephalus: new findings and thoughts on etiology. ajnr 2008;29:1-4. 15. filippidis as, kalani my, rekate hl. hydrocephalus and aquaporins: the role of aquaporin-4 [review]. acta neurochir suppl 2012;113:55-8. 16. kalani my, filippidis as, rekate hl. hydrocephalus and aquaporins: the role of aquaporin-1 [review]. acta neurochir – suppl 2012; 113:51-54 17. zhang j. the genetics of hydrocephalus. in: rigamonti d, ed. adult hydrocephalus. cambridge: cambridge university press; 2014. pp 36-56. 18. streitberger kj, wiener e, hoffman j, et al. in vivo viscoelastic properties of the brain in normal pressure hydrocephalus. nmr in biomed 2011;24:385-92. 19 freimann bf, streitberger kj, klatt d, et al. alteration of brain viscoelasticity after shunt treatment in normal pressure hydrocephalus. neuroradiol 2012;54:189-96. assessing the correlation between iron deposit in the basal ganglia and flow abnormalities in the neck veins with mri: preliminary experience a. canna,1 g. palma,2 e. tedeschi,1 s. cocozza,1 r. lanzillo,3 c. russo,1 p. borrelli,1 e. postiglione,3 r. liuzzi,2 c. criscuolo,3 v. brescia-morra,3 m. mancini,2 m. salvatore1 1department of advanced biomedical sciences, university federico ii, naples; 2institute of biostructure and bioimaging, national research council, naples; 3department of neurosciences, reproductive and odontostomatological sciences, university federico ii, naples, italy background: in multiple sclerosis (ms), increased iron deposition has been demonstrated in the basal ganglia (bg), possibly related to dysfunction of the intracranial/extracranial venous drainage. also, no nco mm er cia l u se on ly poster abstracts [veins and lymphatics 2015; 4:s1] [page 21] ultrasound studies reported blood flow anomalies of the neck veins draining the intracranial compartment. objectives: to correlate bg r2* values, a measure of iron concentration, and the patterns of neck venous blood flow in patients with ms and healthy controls (hc) obtained with a single magnetic resonance (mr) study. methods: in 51 ms patients (age: 38±11 years; females: 67%) and 14 hc (age: 39±14 years; females: 70%) brain r2* maps were derived at 3t from a double-echo 3d spoiled gre (tr=28 ms, te=7 and 22 ms, fa=20°) mr sequence. using the fsl tool first (oxford, uk), mean r2* values were extracted in automatedly-segmented bg. in the same mr session, quantitative measures of the blood flow in the main neck arteries and veins were obtained at c2 and c6 levels, using a 2d phase-contrast sequence with peripheral retrospective triggering. correlations were analyzed through ibm spss software among bg r2* values and internal jugular vein (ijv) flow measures or an index of the activation of venous collaterals between c2 and c6 levels. results: in ms patients and hc, no significant correlations were found between bg iron deposition in any of the brain structures considered (head of caudate nucleus, pallidus, putamen and thalamus) and neither direct measures of ijv flow nor c2/c6 ijv flow mismatch index. conclusions: in this small cohort, the bg iron deposition in ms patients does not seem to be correlated with flow abnormalities in the veins of the neck. further studies, possibly with quantitative assessment of the intracranial/extracranial flow in larger samples, are needed to investigate the cause of different iron accumulation rates in neurodegenerative disorders. key words: multiple sclerosis; iron deposition; r2* map; jugular vein; extracranial venous flow. prevalence of chronic cerebrospinal venous insufficiency in multiple sclerosis. results of large cohort case-control study r. zivadinov,1,2k. marr,1v. valnarov,1 j. hagemeier,1c. kilanowski,1 c. kennedy,1 t. guttuso,2 d. lichter,2 n. silvestri,2 l.e. fugoso,2 e.a. yeh,2m. ramanathan,2,3r.h.b. benedict,2e. carl,1d. hojnacki,2 b. weinstock-guttman2 1buffalo neuroimaging analysis center, state university of new york, buffalo, ny, usa; 2jacobs ms center, department of neurology, university at buffalo, state university of new york, buffalo, ny, usa; 3department of pharmaceutical sciences, state university of new york, buffalo, ny, usa background: in phase 1 of chronic cerebrospinal venous insufficiency (ccsvi) prevalence study in multiple sclerosis (ms), we enrolled 499 subjects.1 the ccsvi prevalence figures were 56.1% in ms, 42.3% in other neurologic diseases (ond), 38.1% in clinically isolated syndrome (cis) and 22.7% in healthy controls (hc) (p<0.001). ccsvi prevalence was higher in progressive than in non-progressive ms patients (p=0.004). objectives: to cross-validate prevalence of ccsvi in phase 2 study of large cohort of patients with ms, cis and ond and hcs, using specific proposed transcranial and extracranial echo-color doppler (ecd) criteria. methods: in phase 1, ecd exams were carried by a single ecd technologist blinded to the subject disease status. in phase 2, ecd exams were carried out by two ecd technologists blinded to the subject disease status. in addition, in phase 2, subjects were positioned and covered with a blanket on the ecd chair by the unblinded study coordinator. a subject was considered ccsvi positive if ≥2 venous hemodynamic criteria were fulfilled. results: in total the ccsvi prevalence study included a total of 1014 subjects. among those were 569 patients with ms, 78 with ond, 67 with cis, 294 ageand sex-matched hcs and 6 subjects with radiologically isolated syndrome (ris). in phase 2, 515 subjects consisting of 280 patients with ms, 52 with ond, 46 with cis, 131 hcs and 6 subjects with ris, were included. the ccsvi prevalence figures for phase 2 study were: 63.2% in ms, 61.5% in ond, 56.5% in cis, 34.4% in hc and 66.7% in ris (p<0.001). the ccsvi prevalence figures for phase 1 and 2 studies were: 59.6% in ms, 55.1% in ond, 50.7% in cis, 27.9% in hc and 66.7% in ris (p<0.001). in phase 2, ccsvi prevalence was higher in progressive than in non-progressive ms patients (p=0.004). conclusions: our findings of phases 1 and 2 of ccsvi prevalence study are consistent with an increased prevalence of ccsvi in ms, cis and ond patients compared to ageand sex-matched hcs, and in progressive ms patients compared to non-progressive ones. phases 1 and 2 showed similar prevalence of ccsvi in the study groups. study conflict: this study was funded by internal resources of the buffalo neuroimaging analysis center and jacobs ms center, university of buffalo. in addition, we received support from the direct ms foundation, the jacquemin family foundation and from smaller donors. disclosures: karen marr, vesela valnarov, colleen kilanowski, cheryl kennedy, ellen carl e. ann yeh nicholas silvestri, leonardo fugoso have nothing to disclose. robert zivadinov received personal compensation from teva neuroscience, biogen idec, novartis, genzyme, claret-medical for speaking and consultant fees. dr. zivadinov received financial support for research activities from biogen idec, teva neuroscience, novartis, genzyme and claretmedical. thomas guttuso received personal compensation from teva neuroscience. david lichter received personal consultation for consulting, speaking and serving on a scientific advisory board for teva neuroscience. murali ramanathan served as an editor for the american association of pharmaceutical scientists journal, receives royalties for publishing the pharmacy calculations workbook [pinnacle, summit and zenith, 2008], and received research support from emd serono, novartis, pfizer, the national multiple sclerosis society, and the national science foundation. ralph hb benedict serves on advisory boards for biogen idec, bayer, actelion, and novartis, and receives research support from shire, accorda, and biogen. david hojnacki has received speaker honoraria and consultant fees from biogen idec, teva pharmaceutical industries ltd. and emd serono, pfizer inc. bianca weinstock-guttman received personal compensation for consulting, speaking and serving on a scientific advisory board for biogen idec, teva neuroscience and emd serono. dr. weinstock-guttman also received financial support for research activities from nmss, nih, itn, teva neuroscience, biogen idec, emd serono, and aspreva. reference 1. zivadinov r, marr k, cutter g, et al. prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in ms. neurology 2011;77:138-44. an interim analysis on susceptibility to vascular alterations in ms and als e. postiglione,1 c. criscuolo,1 a. cianflone,1 r. lanzillo,1 m. mancini,2 e. tedeschi,3 r. liuzzi,2 g. vacca,1 m. vastola,1 m. capasso,4 t. mancino,4 r. mormile,4 a. passannanti,4 g. palma,2 m. caprio,2 m. incoronato,5 m. salvatore,3 v. brescia-morra1 1neurosciences, reproductive and odontostomatological sciences, university federico ii, naples; 2institute of biostructure and bioimaging, national research council, naples; 3advanced biomedical sciences, university federico ii, naples; 4haemostasis and thrombosis laboratory, dai of laboratory medicine, university federico ii, naples; 5ircss sdn foundation, naples, italy background: among the factors contributing to brain damage in multiple sclerosis (ms), scientific evidences indicate ischemic changes, venous outflow abnormalities and accumulation of proinflammatory and neurotoxic substances. no nco mm er cia l u se on ly poster abstracts [page 22] [veins and lymphatics 2015; 4:s1] objectives: to study the association among ms, amyotrophic lateral sclerosis (als), and vascular changes at molecular, genetic, anatomic and functional level. methods: 300 ms patients, 50 als patients, and 300 healthy subjects (hs) will be recruited over 3 years. to assess the endothelial dysfunction development risk and/or a genetic susceptibility, serum levels and single nucleotide polymorphisms (snp) of homocysteine, vegf-a, endothelin 1 (et-1) and hif1a will be analyzed and correlated to micro and macro vascular abnormalities detected by magnetic resonance (mr) and ultrasound (us) imaging. results: homocysteine levels (hl) were performed in 156 ms, 15 als patients and 145 hs, vegf-a in 50 patients vs 25 hs. median hl were 13.4 μmol/l in ms, 12.82 μmol/l in als patients and 12.6 μmol/l in hs. at kruskal-wallis test median hl values were significantly different in the three groups (p=0.002). in particular, median hl were significantly higher in ms and als patients vs hs (p<0.05). in ms women median hl were significantly higher compared to hs (12 vs 9.94 μmol/l, p<0.00001), furthermore hl correlated to age in ms females. median vegf-a values tended to be higher in ms patients vs hs (9.68 vs 0, p=0.196). 101 patients (78 rr, 2 pp, 11 sp and 10 als) underwent contrast-enhanced brain mr, and 68 patients (54 rr, 1 pp, 10 sp and 3 als) underwent us evaluation. conclusions: combining different molecular analysis and imaging modalities may provide new insights into the vascular aspects of ms pathogenesis. these preliminary results support an altered vascular profile in ms, especially in females, and als patients. definitive results will be available at project termination in 2016. key words: multiple sclerosis; endothelial factors; brain perfusion; intracranial circulation. supported by: research and university ministery. the framingham cardiovascular risk score in multiple sclerosis m. moccia,1 r. lanzillo,1 r. palladino,2,3 g.t. maniscalco,1,4 a. de rosa,1 c. russo,1 m. massarelli,1 a. carotenuto,1 e. postiglione,1 o. caporale,2 m. triassi,2 v. brescia-morra1 1multiple sclerosis centre, department of neuroscience, reproductive science and odontostomatology, university federico ii, naples, italy; 2department of public health, university federico ii, naples, italy; 3department of primary care and public health, imperial college, london, uk; 4clinic of neurology, aorn antonio cardarelli, naples, italy background: different cardiovascular risk factors have been related to the risk of developing multiple sclerosis (ms), and to ms disability and course. however, it is possible that such factors interact variably, thus determining a global risk in ms subjects. objectives: we aim to compare the global cardiovascular risk of ms subjects with controls, and to evaluate its importance on ms-related disability, progression and treatment. methods: in our cross-sectional study design, age, gender, smoking status, body mass index, systolic blood pressure, diabetes, and use of antihypertensive medications have been recorded in ms subjects and controls to calculate the simplified 10-year framingham general cardiovascular disease risk score (fr), an individualized percentage risk score estimating the 10-year likelihood of cardiovascular events. results: we recruited 265 ms subjects and matched 530 controls by propensity score. t-test showed similar fr between ms subjects and controls (p=0.212). linear regression analysis showed a direct relationship between fr and expanded disability status scale (p<0.001) and ms severity scale (p<0.001). analysis of variance showed a trend in reduced fr in natalizumab when compared to interferon, fingolimod or no current disease modifying treatment (p=0.057). ttest showed significantly higher fr in secondary progressive ms when compared to relapsing remitting ms (p<0.001). conclusions: the fr, evaluating the global cardiovascular health by the interaction among different risk factors, seems to be related to ms disability and progression. modifiable cardiovascular risk factors should be carefully investigated and corrected with a possible effect on ms-related outcomes. key words: multiple sclerosis; cardiovascular; framingham; comorbities. disclosures: rl has received honoraria from bayer shering, biogen, merck-serono, teva and novartis for lectures or scientific boards. vbm has received honoraria from bayer shering, biogen, merckserono, teva, genzyme and novartis for lectures or scientific boards. mmoccia, rl, rp, adr, cr, mmassarelli, ac, ep, oc, mt and vbm are currently working at the university federico ii of naples, italy. gtm is currently working at aorn antonio cardarelli, naples, italy. increased endothelin-1 serum levels in patients with multiple sclerosis a. cianflone,1 c. criscuolo,1 r. lanzillo,1 r. liuzzi,2 m. mancini,2 e. tedeschi,3 e. postiglione,1 g. vacca,1 v. vacchiano,1 m. moccia,1 m. vastola,1 g. puorro,1 a. marsili,1 m. incoronato,4 m. salvatore,3 v. brescia-morra1 1neurosciences, reproductive and odontostomatological sciences, university federico ii, naples; 2institute of biostructure and bioimaging, national research council, naples; 3advanced biomedical sciences, university federico ii, naples; 4ircss sdn foundation, naples, italy background: clinical and experimental evidence suggests that endothelin-1 (et-1) plays a role in cardiac and vascular disease. patients with multiple sclerosis (ms) show global cerebral hypoperfusion. the widespread decrease in perfusion in normal-appearing white matter and grey matter in ms seems to be secondary to increased blood concentrations of et-1. objectives: to evaluate et-1 in ms patients vs healthy subjects (hs) in the context of a larger study on the association among ms, amyotrophic lateral sclerosis (als), and vascular changes at molecular, genetic, anatomic and functional level. methods: et-1 will be measured in 300 ms patients, 50 als patients, and 300 healthy subjects (hs) recruited over 3 years. serum et-1 levels were coded and assayed with a commercially available elisa kit in blinded fashion by a laboratory assistant (detection range 0.39-25 pg/ml; r&d systems). results: after two years we recruited 300 ms patients, 46 als patients and 178 hs. et-1 levels were performed in 120 ms patients (79 females, 41 males) and in 125 hs (68 females, 57 males). et-1 median were significantly higher in ms compared to hs (1.59 vs 1.50 pg/ml, p=0.03) at mann-whitney test. when stratified for gender, median et-1 levels were significantly higher in females ms vs hs (1.58 vs 1.44 pg/ml, p=0.03). et-1 levels positively correlated with age in female ms vs hs (p<0.05) but not in males. et-1 median were significantly higher in 23 sp vs 97 rr ms subtype (2.10 vs 1.57 pg/ml, p=0.003). conclusions: we confirm that serum et-1 levels are significantly increased in ms patients, especially in women. this finding could help to explain the higher incidence of ms in females and the sexassociated differences in susceptibility to cardiovascular diseases. correlation of et-1 levels with sp subtype of disease opens new insights in ms pathogenesis. key words: multiple sclerosis; endothelial factors; et-1. supported by: research and university ministery. no nco mm er cia l u se on ly index of authors [veins and lymphatics 2015; 4:s1] [page 23] index of authors a albanese, s. 12 alexander, j.s. 7,8 alpini, d. 7 auletta, l. 12 b babiloni, c. 18,19 bavera, p.m. 7 bazzani, l. 9 becker, f. 7,8 beggs, c.b. 5,11 bellagamba, g. 18,19 bellin, a. 13 belov, p. 11 benedict, r.h.b. 21 bernardo, b. 17,18 borrelli, p. 13,16,20 brescia-morra, v. 15,20,21,22 bruno, a. 17,18 c caforio, f. 15 califano, l. 17 canna, a. 20 capasso, m. 21 caporale, o. 22 capotosto, p. 18 caprio, m. 21 caprio, m.g. 12 carl, e. 21 carotenuto, a. 15,22 castor, t. 7,8 cecconi, p. 5,7,11 cervo, a. 12 chabriat, h. 5 chung, c.-p. 8 cianflone, a. 21,22 ciorba, a. 16 cocozza, s. 13,16,20 costanzo, f. 19 couraud, p.-o. 7 criscuolo, c. 20,21,22 cristini, m. 16 d d’orléans-juste, p. 9 daemen, m. 1 dake, m.d. 8 de keyser, j. 9 de lucia, d. 18 de lucia, v. 18 de rosa, a. 22 de simone, r. 7 de vizia, m. 18 de vizia, r. 17 del percio, c. 18 desbiens, l. 9 di berardino, f. 7 didomenico, g. 17 drapaca, c.s. 19 f facchini, l. 13 ferral, h. 7 fugoso, l.e. 21 g gadda, g. 5,15,17,19 gambaccini, m. 5,15,17 giugliano, v. 17 gluckman, b.j. 19 greco, a. 12 gris, d. 9 grozdinski, l. 17 guttuso, t. 21 h haacke, e.m. 4,15,19 hagemeier, j. 11,21 hojnacki, d. 21 i incoronato, m. 21,22 infarinato, f. 18 k kennedy, c. 21 kilanowski, c. 21 krawiecki, j. 11 l lagana, m.m. 5,11 lanaro, e. 19 lanzillo, r. 15,20,21,22 lichter, d. 21 liuzzi, r. 20,21,22 lupattelli, t. 18,19 lus, g. 18 m magnano, c. 11 mancini, m. 3,12,13,16,20,21,22 mancino, t. 21 maniscalco, g.t. 22 marr, k. 21 marsili, a. 22 massarelli, m. 15,22 mastrangelo, d. 17,18 menegatti, e. 5,16,17 minagar, a. 7,8 moccia, m. 15,22 monti, l. 9 monti, s. 13,16 morbidelli, l. 9 mormile, r. 21 mueller, l.o. 15,16 muratori, c. 18,19 n napolitano, m. 18 noce, g. 18,19 o omura, s. 7,8 onorati, p. 18,19 no nco mm er cia l u se on ly index of authors [page 24] [veins and lymphatics 2015; 4:s1] p palladino, r. 22 palma, g. 13,16,20,21 passannanti, a. 21 pastore, a. 16 pelucchi, s. 16 petrov, i. 17 piu, p. 9 postiglione, e. 20,21,22 prouty, l.a. 20 puorro, g. 22 r ragucci, m. 12 ramanathan, m. 21 ramasamy, d.p. 11 ranieri, a. 7 righi, e. 18,19 romero, i.a. 7 rosa, b. 18 russo, c. 20,22 s salafia, f. 17 salvatore, m. 12,13,16,20,21,22 satelliti, b. 15 sato, f. 7,8 sethi, s.k. 15,19 shepherd, s.j. 5,11 silvestri, n. 21 sisini, f. 5,15,17 soricelli, a. 18 stevenson, e. 8 stevenson, e.v. 7 stone, j.r. 4 t taibi, a. 15,17 tedeschi, e. 13,16,20,21,22 ter haar romeny, b. 5 tessari, m. 5,16,17 toro, e.f. 13,15,16,19 triassi, m. 22 tsunoda, i. 7,8 u ursino, m. 6,15 utriainen, d. 15,19 utriainen, d.t. 15 v vacca, g. 15,21,22 vacchiano, v. 22 valnarov, v. 21 vastola, m. 21,22 w weinstock-guttman, b. 21 weksler, b. 7 x xiao, a. 8 y yeh, e.a. 21 yun, j.w. 7,8 z zamboni, p. 5,15,16,17 zhang, q. 16 zivadinov, r. 3,11,21 no nco mm er cia l u se on ly acknowledgements of supporters & corporate members we gratefully acknowledge the following companies and organization for providing grant support of quality medical education. this live activity is supported by educational grants from: no nco mm er cia l u se on ly no nco mm er cia l u se on ly hrev_master veins and lymphatics 2016; volume 5:5985 [veins and lymphatics 2014; 3:5985] [page 11] ulcers in congenital anemia enzo fracchia,1 carla cantello,1 amerigo gori,1 hugo partsch,2 gianluca forni3 1department of vascular and endovascular surgery, galliera hospital, genova, italy; 2department of dermatology and angiology, medical university of vienna, vienna, austria; 3department of thalassemia, congenital anemia and iron dysmetabolism, galliera hospital, genova, italy introduction survival rates in patients with chronic forms of anemia such as sickle cell disease and thalassemia have improved, but the management of comorbidities, such as leg ulcers, remains a challenge. recalcitrant leg ulcers are a common complication of such conditions and may occur early in life. the incidence of leg ulcers in adults with sickle cell disease is reported to be approximately 30%; ulcers in these patients can last for very long time.1-3 the pathogenesis of ulcerations in congenital anemia is multifactorial: hypoxia due to anemia, increase of blood viscosity because of bone marrow stimulation, changes in the coagulation and fibrinolytic system, rheological effects, iron overload, venous stasis causing red blood cell diapedesis, followed by extravascular hemoglobin catabolism. the higher intravenous pressure in the upright position acts as a predisposing factor even in the absence of a venous pathology. among other factors, hemolysis-induced inflammation resulting from greater osmotic fragility of erythrocytes seems to act as a trigger for underlying tissue damage.4 usually classic treatment is directed against all these pathological factors, by general and local means, which is still considered the basic management. however, the results are rather poor.5-9 the fact that the localization of the ulcers corresponds exactly to typical venous ulcers suggests an underlying venous pathology. based on this similarity, several authors have postulated venous incompetence as the deciding underlying lesion, although others have not identified venous flow disturbances in a majority of patients. none of our patients had large varicose veins, and venous reflux or venous obstruction was excluded according to duplex ultrasonography in all cases.10 using the most recent version of clinical severity, etiology, anatomy, pathophysiology classification, these cases can be categorized as c6 ec an pn, describing active leg ulcers (c6) based on a congenital etiology (ec) with no anatomical or pathophysiological venous abnormality (an, pn).11 doppler ultrasound screening for thrombophilia was normal in our patients, the ankle brachial pressure index was greater than 1.0. since every type of treatment had been done and these ulcers seemed to be similar in pathology to venous ulcers the author decided to treat these lesions as if they were venous ulcers. we started to treat these patients with inelastic multicomponent bandages. at the beginning the bandage was difficult to apply (rosydal sys®; lohmann and rauscher, regensdorf, germany) but many patients lived far away form the hospital and it was necessary to find a single component bandage which was inelastic, cheap and simple applicable by the patients themselves at home. peha haft® (paul hartmann, österreich, austria) was chosen: when properly applied it is able to exert a strong pressure and a strong massaging effect due to its stiffness. walking exercises were encouraged. non-adherent, absorbent material was used for local dressings. case series ten patients affected by congenital dyserythropoietic anemia, sikle cell anemia and thalassemia intermedia with chronic leg ulcers persisting between 12 and 29 years (mean 16 years) without venous out flow disturbances in the lower extremities. compression therapy was able to heal the ulcers in 5 to 8 months (average 7 months) after several attempts of purely local treatment had failed. once the ulcers had healed, compression stockings were prescribed to prevent recurrences. the common denominator in these ten cases was high venous pressure due to gravity. high intravenous pressure caused by sitting and standing without movement is sufficient to trigger chronic inflammation, leading to skin defects on the legs of patients with additional hematological risk factors associated with several microcirculatory abnormalities, as discussed above. trauma may play an additional role by stimulating the damage of red blood cells. the prolonged average healing time of 7 months in our ten patients points is due to the chronic, recalcitrant nature of the ulcers, which had persisted for several years before compression treatment was initiated. only compression treatment with short-stretch bandages and walking exercises made the ulcers heal. the therapeutic success of good compression therapy in our cases shows that this treatment is able not only to act against venous reflux but also to counteract gravity in cases with normal valve function. compression not only reduces edema, it also releases vasoactive enzymes from the endothelial cells, improving microcirculation, reducing inflammation, and promoting lymph drainage. this is especially true for non-yielding, inelastic bandages, which exert a considerable massage effect during walking.12-17 these mechanisms may also explain the beneficial effects of compression treatment in patients with other non-venous lesions on the leg, such as vasculitis, cellulitis, and lesions after trauma or surgery. in conclusion, compression therapy was successful in the treatment of the reported cases and should be considered as a component of treatment strategies for patients with hematological ulcers. in our cases, this simple, inexpensive approach was the winning strategy for resolving a longstanding problem. references 1.trent jt, kirsner rs. leg ulcers in sickle cell disease. adv skin wound care 2004;17:410-6. 2.josifova d, gatt g, aquilina a, et al. treatment of leg ulcers with plateletderived wound healing factor (pdwhfs) in a patient with beta thalassaemia intermedia. br j haematol 2001;112:527-9. 3.clare a, fitzhenley m, harris j, et al. chronic leg ulceration in homozygous sickle cell disease: the role of venous incompetence. br j haematol 2002;119: 567-71. 4.ackerman z, seidenbaum m, loewenthal e, rubinow a. overload of iron in the skin of patients with varicose ulcers. possible contributing role of iron accumulation in progression of the disease. arch dermatol 1988;124:1376-8. 5.miles mg, murphy rx jr. chronic, nonhealing, lower extremity ulcers responsive to splenectomy in a patient with thalassemia major. plast reconstr surg 2003;112:17345. 6.velez a, garcia-aranda jm, moreno jc. hydroxyurea-induced leg ulcers: ismacroerythrocytosis a pathogenic faccorrespondence: enzo fracchia, department of vascular and endovascular surgery, galliera hospital, via ciro menotti 44-45, 3° piano, sestri ponente (ge), italy. e-mail: fracchiaenzo@gmail.com this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright e. fracchia et al., 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5985 doi:10.4081/vl.2016.5985 no n c om me rci al us e o nly conference presentation [page 12] [veins and lymphatics 2016; 5:5985] tor? j eur acad dermatol venereol 1999;12:243-4. 7.pieters rc, rojer ra, saleh aw, et al. molgramostim to treat ss-sickle cell leg ulcers. lancet 1995;345:528. 8.steed dl. clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity ulcers. plast reconstr surg 2006;117:143s9s. 9.londahl m, katzman p, nilsson a, et al. a prospective study: hyperbaric oxygen therapy in diabetics with chronic foot ulcers. j wound care 2006;15:457-9. 10.billett hh, patel y, rivers sp. venous insufficiency is not the cause of leg ulcers in sickle cell disease. am j hematol 1991;37:133-4. 11.eklof b, rutherford rb, bergan jj, et al. revision of the ceap classification for chronic venous disorders: consensus statement. j vasc surg 2004;40:1248-52. 12.partsch h. compression therapy: clinical and experimental evidence. annvasc dis 2012;5:416-22. 13.mosti g, iabichella ml, partsch h. compression therapy in mixed ulcers increase venous output and arterial perfusion. j vasc surg 2012;55:122-8. 14.flour m1, clark m, partsch h, et al. dogmas and controversies in compression therapy: report of an international compression club (icc) meeting, brussels, may 2011. int wound j 2013;10:516-26. 15.mosti g, mattaliano v, partsch h. inelastic compression increase venous ejection fraction more than elastic bandages in patients with superficial venous reflux. phlebology 2008;23;287-94. 16.partsch h. improving the venous pumping function in chronic venous insufficiency by compression as dependent on pressure and material. vasa 1984;13:58-64. 17.partsch h, menzinger g, mostbeck a. inelastic leg compression is more effective to reduce deep venous refluxes than elastic bandages. dermatol surg 1999;25:695700. no n c om me rci al us e o nly hrev_master veins and lymphatics 2013; volume 2:e2 [veins and lymphatics 2013; 2:e2] [page 3] sub-bandage dynamics: stiffness unravelled jan schuren,1 jens bichel2 1retired employee of; 23m deutschland gmbh, neuss, germany abstract the static stiffness index (ssi) is mathematical equation that results in a simple number when the sub-bandage pressure in the supine position is subtracted from the subbandage pressure in the standing weight-bearing position. when ssi data are reported, often a wide range of values is observed for similar materials. the aim of this study was to explore the strength and weakness of the ssi and its measurement. pressure was recorded with bandaging materials with different resting pressures and properties. measurements in the upright position were performed under weight and non-weight bearing conditions for up to 12 min of motionless stance. the measurements reveal that the ssi reveals more about the muscle forces of the person included in the system, rather than providing accurate information on the applied system or how well this system is applied. in addition, venous filling has a major effect on the final ssi. when performed under similar conditions, the ssi is able to differentiate between elastic and inelastic materials. the ssi gives us a rough estimate of the effectiveness of an applied system but interpretation is influenced by the muscle forces of the person being bandaged as well as the measured effects of venous filling and, because of that, the timing of the measurements. future guidelines on measuring the ssi should include that the final standing pressure value should be taken when a stable recording over a certain period is observed. introduction there is a variety of methods to describe the properties of bandaging materials. recently a consensus document was published, in which was stated that sub-bandage pressures and material stiffness characterize the elastic properties of the used materials and are the deciding parameters determining the dosage of compression treatment.1 therefore, it was recommended to measure and report these characteristics in future clinical trials. proposals were made concerning methods for measuring the interface pressure and for assessing the stiffness of a compression device in an individual patient. however, stiffness is more than just a mathematical equation that results in a simple number. this article explores the strength and weakness of the static stiffness index (ssi). the b1-position in the european committee for standardization (cen) prestandard document,2 an overview is provided on the anatomical locations to position pressure sensors on a leg. one of these locations is called cb1, the area at which the achilles tendon changes into the calf muscles, approximately 10-15 cm proximal to the medial malleolus. stolk et al.3 performed static measurements and showed that the largest differences in the circumference between the maximal dorsiflexion and maximal plantar flexion positions of the foot occur at the level of the transition from the gastro cnemius muscle into its aponeurosis (the cb1 level or simplified: b1; figure 1). the international compression club (icc) consensus document proposes that location b1 should always be included in future pressure measurements, with the exact location of the sensor situated at the segment that shows the most extensive enlargement of the leg circumference during dorsiflexion or by standing up from the supine position.1 although b1 should always be included as a measurement location, other sites could be included in any measurement of pressures.1 figure 1 shows a screenshot of measurements with the picopress device (microlab elettronica sas, ponte s. nicolò, italy) and the sensor positioned at the b1 position. the measured pressure values are marked a, b, c. resting pressure, standing pressure, amplitudes the resting pressure gives an indication of how much pressure is provided by a compression system when the subject is in a relaxed supine position with a slightly flexed knee and the foot resting on a flat surface. it is important that the calf muscles are not resting on a surface, as the result may be a too high resting pressure.4 in figure 1, the resting pressure (a) is around 40 mmhg. the standing pressure gives an indication of the pressure when the subject is asked to stand up and put weight on the compressed leg.5,6 in figure 1, the standing pressure (b) is around 70 mmhg. resting and standing pressure are both values recorded in static situations. if a measuring device (like e.g. picopress) allows dynamic recording, it is advisable to measure also the amplitudes of a specified movement. possible movements include the following:1 i) dorsal and plantar flexion of the ankle joint; ii) walking, for example on a treadmill; iii) adopting a tip-toe stance, or flexing of the knees; iv) passive ankle movement. in figure 1, the amplitudes are presented in the column exercise. the range of pressure values (c) is between 45 and 90 mmhg. the difference between these two pressure values results in a working pressure amplitude (wpa) the recording during the exercise in figure 1 gives a wpa of 45. the static stiffness index the cen european prestandard document for medical compression hosiery defines stiffness as the increase in pressure per 1 cm increase of leg circumference.2 for compression bandages, the extensibility of materials is often used to determine their characteristics. partsch5 identified the need for a simple tool to assess both pressure and stiffness on the individual leg. he describes the method to measure the pressure at a defined position of the lower leg at rest (b1), when its circumference is minimal, and to repeat the measurement on the same spot, when the circumference has maximally increased by the muscles actively engaged to stand in the upright position. for measuring stiffness, the pressure in the supine position is subtracted from the pressure in stance. the resulting index indicates the effectiveness of the applied system.1 this index is referred to as ssi and, although it correspondence: jan schuren, grotestraat 34, 6067 br linne, the netherlands. e-mail: jan.schuren@gmail.com key words: compression therapy, static stiffness index, working amplitudes, venous filling. conference presentation: part of this paper was presented at the international compression club (icc) meeting on stiffness of compression devices, 2012 may 25, vienna, austria (http://www.icc-compressionclub.com/). contributions: js, manuscript writing; the authors contributed equally to: conception and design; data acquisition, analysis and interpretation; final approval of the version to be published. conflict of interests: js is a retired 3m employee and invented and co-developed the 3m coban 2 layer compression systems; jb is employed by 3m. received for publication: 20 october 2012. revision received: 22 november 2012. accepted for publication: 29 november 2012. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright j. schuren and j. bichel, 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e2 doi:10.4081/vl.2013.e2 no nco mm er cia l u se on ly conference presentation [page 4] [veins and lymphatics 2013; 2:e2] might be influenced by many variables, provides an indication of how well an applied compression system manages to keep forces produced by the muscle activity to stay in the upright position, inside the compressed area. in the measurement presented in figure 1, a typical picopress recording is presented of the pressure under a 3m™ coban™ 2 layer application (3m™ healthcare, st. paul, mn, usa), with the sensor positioned at the b1 location. the resting pressure is presented in the column supine and is around 40 mmhg (a). the standing pressure can be taken from the column stance and is around 70 mmhg (b). this means that the ssi in this measurement is 30 (70-40). results and discussion muscle forces it is easy to imagine that both ssi and wpa are not only determined by the stiffness of the applied compression system but more by the muscle forces that are produced inside the bandaged area. provided that the measurements are not performed on a leg with major disfigurations due to severe obesity or lymph oedema, the subject inside the system heavily confounds each measurement. as a consequence of measuring the muscle forces inside the compression system, both ssi and wpa tell more about the muscle forces of the person included in the system, rather than providing accurate information on the applied system or how well this system is applied. this can be easily demonstrated with the measurements presented in figure 2. with the same system applied in the same way by the same experienced bandager on different subjects, the amplitudes are 23 on the left (c: 55-32) and 64 on the right pressure profile (c: 102-38). these measurements are from a study on healthy volunteers, recorded with a gaeltec strain gauge temperature-compensated (1540°c) force transducer (gaeltec devices ltd, dunvegan, isle of skye, uk). the transducer was positioned at the b1 position and connected to a computer from which the data was recorded. the only difference in the two recordings is the volunteer. in both readings, a similar resting pressure was achieved. the ssi’s (14 versus 46) as well as the wpa’s during walking on a treadmill (23 versus 61) of the used system show big differences. this phenomenon can also be observed in studies in which actual ssi measurements are presented. a few studies present data on measurements on short-stretch bandages. partsch (derm surg 2005) presents data of measurements on 12 volunteers. the reported ssi values vary between 10 and >40 for both unna’s boot and multilayer short-stretch bandages. similar differences in reported ssi’s are observed in publications by mosti et al.7,8 and partsch et al.9 in some of these measurements, there is even an overlap of individual values from the systems with the highest and lowest mean stiffness (e.g. 7). the static stiffness index and venous filling another factor that might influence the accuracy of the ssi is the timing of the measurements. there are no clear guidelines on when recording of the standing pressure figure 1. a typical picopress recording of a bandaged leg with the sensor positioned at the b1 location shown on the left. the measurements show the pressure in the supine position (a), in the standing position (b) and during functional activities (c). figure 2. sub-bandage pressure recordings from two different volunteers with the same compression system applied by the same experienced bandager. figure 3. recording of sub-bandage pressure of a normal limb in a coban 2 lite compression system, including the change from the supine to a weight bearing standing position. no nco mm er cia l u se on ly conference presentation [veins and lymphatics 2013; 2:e2] [page 5] should be performed. similar to a normal unwrapped leg, the venous filling of a bandaged leg takes a certain period. nicolaides et al.10 recorded intravenous pressure of a normal limb in a vein on the dorsum of the foot. after ten tip-toe movements, it takes more than 30 s before the venous pressure returns to the pressure before the exercise. a similar refilling time can be observed after the application of a compression system, when the subject changes from a supine to an upright posture. figure 3 provides an example of a healthy subject, compressed with coban 2 lite (3m™ healthcare). recording was performed immediately after the application. during the measurements in the upright position, the volunteer holds on to a frame to avoid balancing muscle activities in the leg. if the instructions of the used device (picopress) are followed, the pressure is taken from some of the values in the period located between the first two pink vertical lines. at the second line, the device gives a signal that the standing period is completed. immediately after the position change, the standing pressure is 43 mmhg (b); the pressure at the end of this period is 46 mmhg (c). looking at the resting pressure of 29, a reported ssi could be between 14 and 17. venous filling of the lower limb however, takes much longer than the advised period. after the position change, it takes almost a minute before a stable pressure level of 56 mmhg (d) can be observed. if that recording would be used for the calculation, the ssi would be 27. the consequence of the above observations is that, depending on the time of measurement; the ssi can vary between 14 and 27. figure 4 shows another recording of the same leg in the same bandage. the resting pressure is 30 mmhg (a). now the position change takes place without weight bearing. the volunteer steps on an elevation, bearing full weight on the contralateral leg. the bandaged leg is hanging free with a relaxed achilles tendon. the initial pressure after this position change is 23 mmhg (b) and 28 mmhg after the signal (c) of the device. as in the previous recording, it takes a minute before a final stable pressure is established. this final pressure is 48 mmhg (d). during the change from the supine to the standing position, venous filling in isolation creates a pressure increase of 18 mmhg. in patients with chronic venous insufficiency, veins refill quickly and a stable recording can be observed much faster than in the provided example with a healthy volunteer.11 in addition, it might be assumed, that in patients with significant venous dilatation, pressure increase due to venous refilling is more pronounced than in healthy volunteers. this could be explained by higher volume increase of dilated veins in the upright position, until an increasing venous wall tension prevents further venous filling. this means that in patients with chronic venous insufficiency the right time of standing pressure measurement is even more important. pannier et al.12 measured the increase in leg volume increase after changing from a lying to a standing position and demonstrated that the position change initially leads to a rapid increase in volume. the main change is observed in the 1st min, followed by a further slower increase in the next 9 min. the authors state that the volume increase follows a biexponential function fitting to a rapid filling compartment (venous pooling) and a slow filling compartment-reflecting extravasation. figure 4. recording of sub-bandage pressure of a normal limb under a coban 2 lite application including the change from a supine to a non-weight bearing standing position. figure 5. recording of sub-bandage pressure of a normal limb compressed with coban 2 lite, including the change from the supine to non weight bearing standing position, which was maintained motionless during the entire recording time. figure 6. recording of sub-bandage pressure of a normal limb compressed with a longstretch bandage, including the change from the supine to non weight bearing standing position, which was maintained motionless during the entire recording time. no nco mm er cia l u se on ly conference presentation [page 6] [veins and lymphatics 2013; 2:e2] stick et al.13 used strain gauge plethysmography at calf and ankle level to document the volume changes, which occurred when a subject was tilted from the supine to the upright position. in both ankle and calf, the highest volume increase was observed in the first 2 min, after which the volume further increased at a less steep slope. the authors state that after the subject has been brought into the upright posture, an increased hydrostatic pressure in the arteries makes the blood flow via the arteriolar resistance vessels and via the capillaries into the venous capacitance vessels. next, a further volume increase is observed in the following 10 min, which is due to an increased transcapillary filtration of fluid into the interstitial space. mosti et al.14 demonstrated that there is a significant correlation between the degree of improvement in venous hemodynamics of the ejection fraction (ef) examined by strain gauge plethysmography and both the ssi and the amplitudes of sub-bandage pressure during walking. the authors report that when elastic bandages are applied at high pressure and high stretch, only small pressure differences (ssi and wpa) occur by standing and walking resulting in low ef values. to evaluate the fluid shift into the interstitial space, we measured the effects of the position change on sub-bandage pressures during 12 min of standing with the leg under investigation in the non-weight bearing position. the subject is wearing the inelastic coban 2 lite compression system. as can be seen in figure 5, the initial resting pressure is 29 mmhg (a). next, the volunteer performed ten active maximal dorsal and plantar flexions. after the exercises, the pressure returned to 27 mmhg (b), a little lower that the initial resting pressure. similar to what was observed in figure 4; venous filling brings the pressure to 50 mmhg after 2.5 min (c). during the next 10 min of motionless stance, no change in pressure is observed (d: 50). this means that the bandage, which was applied at full stretch, manages to keep the forces that are generated by the dorsal and plantar flexions, inside the system, as well as the forces generated by the venous refilling. however, because the forces needed for the interstitial fluid shift into the lower leg (edema) are much lower than the gravitational forces responsible for venous refilling, it can be hypothesized that compression applied at full stretch also provides a sufficient counterforce for the forces responsible for the interstitial fluid shift, as they are not high enough to generate an additional increase of sub-bandage pressure (c=d). this procedure was repeated after the application of the long-stretch compression bandage biflex 16+ (thuasne sa, levallois perret, france) with tension indicators for accuracy of application; the tension is correct when the printed markers are square-shaped. the bandage was applied in a spica manner according the included manufacturers instructions for use. the recording of this application is presented in figure 6. the application provides a resting pressure of around 40 mmhg (a). after the exercises, the pressure is 41 mmhg (b). venous filling brings the pressure to 45 mmhg after 2 min (c), a value that is still observed after 10 min of motionless stance (d). these observations, combined with the low amplitudes that are observed, demonstrate that the stretchability of the applied long stretch bandage absorbs a certain amount of the gravitational venous filling forces that are related to the position change and allows volume changes of the included leg. however, these measurements also reveal that the applied force is high enough to counteract the forces responsible for the fluid shift into the interstitial tissue. this means that also extensible materials can play a role in the prevention of edema.15 conclusions it can be concluded that the ssi gives us a rough estimate of the effectiveness of an applied system but interpretation is influenced by the muscle forces of the person being bandaged as well as the measured effects of venous filling and, because of that, the timing of the measurements. however, the well-established ssi in general is able to differentiate between elastic and inelastic materials16 and the suggested cut-off point of 10 by the icc,17 represents a very simple quotient that may be taken as a rule of thumb and is measurable in patients without major disfigurations of the legs due to severe obesity or lymphoedema. future guidelines on measuring the ssi should include that the final standing pressure value should be taken when a stable recording over a certain period is observed. references 1. partsch h, clark m, bassez s, et al. measurement of lower leg compression in vivo: recommendations for the performance of measurements of interface pressure and stiffness: a consensus statement. dermatol surg 2006;32:229-38. 2. european committee for standardization (cen). non-active medical devices. working group 2 env 12718: european pre-standard medical compression hosie ry. cen tc 205. brussels: cen 2001. 3. stolk r, wegen van der-franken cpm, neumann ham. a method for measuring the dynamic behavior of medical compression hosiery during walking. dermatol surg 2004;30:729-36. 4. schuren j. compression unravelled. essen (germany): margreff druck gmbh: 2011. p 134. 5. partsch h. the static stiffness index: a simple method to assess the elastic property of compression material in vivo. dermatol surg 2005;31:625-30. 6. veraart jcjm, neumann ham. interface pressure measurements underneath elastic and non-elastic bandages. phlebology 1996;1:s2-5. 7. mosti g, mattaliano v. simultaneous changes of leg circumference and interface pressure under different compression bandages. eur j vasc endovasc surg 2007; 33:476-82. 8. mosti g, mattaliano v, partsch h. influence of different materials in multi-component bandages on pressure and stiffness of the final bandage. dermatol surg 2008;34:6319. 9. partsch h, clark m, mosti g, et al. classification of compression bandages: practical aspects. dermatol surg 2008;34: 600-9. 10. nicolaides an, zukowski aj. the value of dynamic venous pressure measurements. world j surg 1986;10:919-24. 11. eberhardt rt, raffetto jd. chronic venous insufficiency. circulation 2005;111;2398409. 12. pannier f, rabe e. optoelectric volume measurements to demonstrate volume changes in the lower extremities during orthostasis. int angiol 2010;29:395-400. 13. stick c, hiedl u, witzleb e. volume changes in the lower leg during quite standing and cycling exercise at different ambient temperatures. eur j appl physiol 1993;66:427-33. 14. mosti g, mattaliano v, partsch h. inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous reflux. phlebology 2008;23:287-94. 15. stranden e. edema in venous insufficiency. phlebolymphol 2011;18:3-14. 16. veraart jcjm, daamen e, neumann ham. short stretch versus elastic bandages: effect of time and walking. phlebologie 1997;26:19-24. 17. partsch h. the use of pressure change on standing as a surrogate measure of the stiffness of a compression bandage. eur j vasc endovasc surg 2005;30:415-21. no nco mm er cia l u se on ly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: significant endothelin release in patients treated with foam sclerotherapy by frullini a, barsotti mc, santoni t, duranti e, burchielli s, di stefano r. dermatol surg 2012;38:741–7. francesco ferrara napoli monaldi hospital cardiovascular surgery, italy e-mail: frferr@tiscali.it abstract a greater incidence of cough, transient visual and neurological disturbances have been reported with foam rather than with liquid sclerosant. these complications have often been associated with migraine and patent foramen ovale (pfo), a common condition affecting approximately 25% of the whole adult population. foam bubbles may pass through a pfo to the left heart chambers, with consequent paradoxical systemic embolization. visual and neurological disturbances have often been reported also with liquid sclerosants which conflicts with the bubble theory. in a recent study, the same authors1 demonstrated that pol foam is capable of significantly elevating endothelin 1 (et-1) in an animal model. it is feasible that the release of et-1 is a source of neurological and visual disturbances after sclerotherapy. in the first part of this study, the authors tested et-1 release in 11 rats treated with sts 1% (fibro-vein). five were treated with liquid sts and 6 with sts foam. a significant difference was found between et level at 1 min and at 5 min with foam sts (p comment by francesco ferrara recent studies have shown that the visual and neurological disturbances that can be observed after liquid or foam sclerotherapy are due to the release of two different chemical mediators: histamine and endothelin 1. the increase in both the mediators has the same source: damage to the edothelium membrane. these two theories can live side by side. but a preventive therapy with vasoprotectors cannot be proposed as this treatment contrasts with the action of the sclerosing agents. however, a preventive antihistaminic therapy can be used selectively only versus the mediator of the neurological disturbance. reply by the author (frullini) i thank francesco ferrara for her comments but have to disagree. pharmacological antagonism can be exerted in very different ways and this includes endothelin synthesis inhibition, competitive links with receptors or binding with circulating endothelin. none of these is related to vasoprotection. only inhibition of et-1 release from vacuoles could be considered a protective action but i still think that such an approach could be helpful. in fact, when injecting a sclerosant, by definition its action cannot be limited to the target vessel. it could be interesting to develop the concept of how to protect the veins that we do not want to sclerose. references 1. frullini a, felice f, burchielli s, di stefano r. high production of endothelin after foam sclerotherapy: a new pathogenetic hypothesis for neurological and visual disturbances after sclerotherapy. phlebology 2011;26:203-8.[crossref][pubmed] [top] hrev_master veins and lymphatics 2012; volume 1:e9 [veins and lymphatics 2012; 1:e9] [page 37] terminal valve of sapheno-femoral junction: a comparative assessment between pre-operative color-duplex ultrasound and intra-operative evaluation attilio cavezzi,1,2,3 valerio carigi,2 fausto campana,4 gianni sigismondi,2 concettina elio,2 sonia di paolo,1 simone ugo urso1,2,3 1vascular unit, clinic “stella maris” san benedetto del tronto (ap); 2montefeltro salute hospital, sassocorvaro (pu); 3vascular unit, poliambulatorio hippocrates, san benedetto del tronto (ap); 4vascular medicine unit, bufalini hospital, cesena, italy abstract according to literature data, up to 59% of incompetent great saphenous veins (gsv) have no reflux at the terminal valve (tv) of the saphenofemoral junction (sfj). the aim was to compare color duplex ultrasound (cdu) investigation and direct intra-operative assessment of competence of the tv at sfj. a prospective comparative study was performed on 28 patients, who consecutively presented for surgical intervention for their primary varicose veins of the lower limbs with gsv incompetence. cdu assessment was performed pre-operatively to define gsv and sfj terminal valve morphology and hemodynamics. under local anesthesia these patients underwent sfj disconnection (crossectomy) and segmental inverted saphenous stripping of the incompetent gsv tract + phlebectomy of the varicose tributaries. sfj disconnection was performed in four stages in an ascending fashion: i) division of gsv below the lower sfj tributaries, ii) disconnection of lower sfj tributaries, iii) disconnection of upper tributaries, iv) flush to cfv ligature of gsv stump. after the completion of stage i, the sfj stump was opened and kept open when needed throughout the subsequent stages, in order to highlight any possible blood leak through the sfj stump. to highlight intraoperative blood leak from sfj stump visual observation was carried out both during respiration and when performing valsalva maneuver and manual compression of homolateral iliac fossa. as to pre-operative cdu all limbs showed gsv reflux and they were divided in two groups according to tv competence (group a) or incompetence (group b). group a comprised 18 patients (6 m and 12 f), mean age 50.6 years. group b included 10 patients (4 m and 6 f), mean age 54.8 years. mean calibre of gsv at proximal/mid thigh was 6.4 mm in group a and 7.8 in group b. concerning the intra-operative findings: in the group a, 5 patients had blood leak in the sfj stump after stage i, 4 patients showed blood leak after stage ii. after completion of stage iii, only one severely obese patient had persistent reflux, whereas 17 patients had no reflux. conversely the 10 patients from group b had reflux within gsv stump throughout the 3 stages. cdu pre-operative assessment matches intra-operative findings with regards to gsv tv competence/incompetence, with a good overall accuracy (27/28-94%). different sfj retrograde flow patterns should be elicited through cdu investigation. obese patients need a more thorough cdu examination to avoid false negatives. introduction varicose vein disease may be related to great saphenous vein (gsv) incompetence in many cases. in the past years sapheno-femoral junction (sfj) was considered the key-point of the disease in the vast majority of the cases. in fact color-duplex ultrasound (cdu)-based literature repeatedly showed that several hemodynamic patterns can be highlighted in presence of gsv retrograde flow. there is growing evidence in literature data about the extremely frequent combination of gsv incompetence without any reflux through its terminal valve (tv) of sfj.1-5 cdu investigation permits to map accurately all the incompetent segments of the gsv stem, also elucidating the morphologic and hemodynamic condition of sfj.4,5 sfj is a complex of a few veins, mostly five in number (including gsv, superficial epigastric vein, superficial circumflex iliac vein, pudendal vein/s, anterior accessory saphenous vein. two valves are usually present in the uppermost part of gsv stem: the tv at the confluence between gsv and common femoral vein (cfv) and the pre-terminal valve (ptv), which is usually located below all the sfj tributaries, above giacomini vein entrance, just at the point where gsv crosses superficial fascia (figure 1). ptv may be absent in up to 30% of the subjects, whereas tv is much more constant.6,7 the complexity of the possible morphologic and hemodynamic patterns at sfj has been elucidated through cdu investigation and tv competence/incompetence represents a finding of paramount importance when treating varices related to gsv disease.8 the purpose of this observational comparative clinical and instrumental study has been to assess reliability of cdu investigation of tv of sfj, in presence of gsv incompetence, through the comparison between cdu findings and the intraoperative findings of the same patients during sfj surgical disconnection (crossectomy). materials and methods a prospective comparative study was conducted in two clinics, where varicose vein patients were referred for surgical treatment. a cohort of 28 previously investigated (history taking, clinical assessment and cdu evaluation) patients consecutively presented with primary varicose veins of the lower limbs and gsv incompetence, to be treated by means of stripping and phlebectomy. on the day of the surgical intervention the patients underwent cdu mapping, in order to define pre-operatively the morphological and hemodynamic condition of the varicose lower limb. mean calibre of gsv trunk was measured through transverse scan at proximal and mid thigh, avoiding measurements where saccular dilations existed. through a standardised procedure,5 patients were investigated in standing position, by means of compression/release and valsalva maneuvers and testing each vein segment both with pulsed wave doppler and with colorflow imaging, with transverse and longitudinal scanning. to elicit competence/incompetence of the gsv segments and of tv and ptv, the one-second cut-off was used to detect pathocorrespondence: attilio cavezzi, vascular unit, poliambulatorio hippocrates, via miramare 7, 63074, san benedetto del tronto (ap), italy. e-mail: info@cavezzi.it key words: terminal valve, duplex ultrasound, intra-operative assessment, great saphenous vein. acknowledgments: we sincerely thank massimo cappelli, claude franceschi, sandro pieri and paolo zamboni who significantly contributed to improve our knowledge on vein hemodynamics and indirectly stimulated our research. conflict of interests: the authors declare no potential conflict of interests. received for publication: 17 september 2012. revision received: 19 december 2012. accepted for publication: 7 january 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright a. cavezzi et al., 2012 licensee pagepress, italy veins and lymphatics 2012; 1:e9 doi:10.4081/vl.2012.e9 no nco mm er cia l u se on ly article [page 38] [veins and lymphatics 2012; 1:e9] logical reflux in the investigated venous tracts. using a 10 mhz linear probe, a color/doppler flow setting of 8 cm/s. minimum speed was pre-fixed, in order to detect adequately also slow antegrade/retrograde flows.5 tv incompetence was diagnosed when reflux was highlighted within the cfv, through the tv and within the uppermost segment of gsv immediately below tv (figure 2). gsv incompetence combined with tv competence was characterized by the absence of any reflux in the cfv and the presence of retrograde flow within the gsv segment immediately below the tv (figures 3-5). ptv incompetence was characterized by retrograde flow in the gsv trunk above and below this valve. through the cdu investigation as to above, the 28 patients were pre-operatively divided in two groups: i) group a which comprised patients with an incompetent gsv and a competent tv; ii) group b which included patients with an incompetent gsv and an incompetent tv. all patients were operated in local anesthesia (buffered mepivacaine 0.25% and tumescence infiltration), according to our previously described procedure.9 sapheno-femoral crossectomy (flush ligation of gsv trunk at cfv level and disconnection of all sfj tributaries) was combined with segmental inverted stripping of the refluxing tract of gsv. varicose tributaries were avulsed by means of hook phlebectomy and mini-incisions. in order to assess intra-operatively sfj hemodynamics, and more specifically tv competence/incompetence, crossectomy was performed in four sequential stages in an ascending fashion. the first stage comprised the division of gsv trunk 3-4 cm below sfj, with clamping of the distal gsv tract; the second stage included the disconnection of the lower sfj tributaries (e.g. anterior accessory saphenous vein), and at the third stage the disconnection of upper tributaries (e.g. epigastric vein) of sfj was performed. once all tributaries were ligated and disconnected, the fourth stage included the final flush ligation of gsv at its confluence with cfv. during the whole procedure, after stage i completion, the proximal gsv stump was opened and kept open (by means of a traumatic clamps and trying to avoid any stretching or compression on the gsv stump) when needed for tv testing. throughout all stages, firstly a visual observation of any possible blood leak during normal respiration was performed, whereas subsequently valsalva maneuver was performed by the patient (who was in semirecumbent position), in order to elicit blood reflux in the sfj stump. an external physician repeatedly performed the compression of the homolateral iliac fossa during each of the first three stages, in order to check for blood reflux from cfv towards the sfj open stump as well. once completed crossectomy, inversion stripping of the refluxing gsv tract + hook phlebectomy was performed, as to above. results cdu investigation screened the 28 patients in the two groups according to gsv tv hemodynamics. more in detail group a (tv competence) comprised 18 patients (6 males and 12 females), mean age 50.6 years, and the c variable repartition within ceap classification was the following: 11 limbs c2, 4 limbs c3, 2 limbs c4, and one limb c5. group b (tv incompetence) included 10 patients (4 males 6 females), mean age 54.8 years; ceap subdivision of the varicose limbs as to c variable was as follows: 5 in c2, 2 in c3, 2 in figure 1. ultrasound visualization of terminal valve and pre-terminal valve of great saphenous vein. figure 2. color-duplex ultrasound of terminal valve incompetence at sapheno-femoral junction. no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e9] [page 39] c4 and one in c5. overall mean calibre of gsv trunk at proximal and mid thigh level was 6.4 mm (s.d. +/1.2) in limbs of group a and 7.8 mm (s.d. +/1.6) in limbs of group b. the intra-operative assessment of sfj stump during the four stages was performed and all findings were recorded subsequently. the findings differed significantly between the two groups and a summary of the main results of intraoperative assessment of sfj stump is reported in table 1. basically in group a (competence of tv at cdu pre-operative investigation), 13 patients showed no reflux in sfj stump throughout the first three stages, while a spontaneous blood leak from sfj stump was seen in five patients after the first stage, hence it disappeared in one of them after stage ii completion. finally after performing stage iii, 17/18 patients in total showed no reflux from the open sfj. one severely obese patient showed persistent reflux after completion of stage iii. once completed crossectomy (stage iv), no blood leak was visible in any patient. the 10 patients in group b (tv incompetence), conversely, had blood leak/reflux within the open sfj stump throughout the first 3 stages, both during respiration and performing valsalva manoeuvre or iliac fossa compression. after completion of crossectomy (stage iv) no blood reflux was visualized in any case. discussion sfj represents a complex site both from the anatomy and from the hemodynamics point of view. tv is a fundamental part of sfj and it is designed to prevent reflux from cfv into the superficial venous system. ptv is located just below the entrance of the 4-5 main sfj tributaries, which contribute to constitute the ending part of gsv, also called saphenous cross or saphenous arch. cdu study of this area may require different scanning approaches and maneuvers in order to understand its anatomy and hemodynamics properly. due to the great importance of tv assessment before indicating a proper gsv treatment,8,10 an adequate diagnostic approach is needed to screen tv competence/incompetence. a proper setting of color-flow and doppler module is helpful to pick up slow flows, as well as adequate and reproducible manoeuvres are to be used.5 placing the doppler and color flow sample within cfv and through the tv, allows to reduce false positive diagnoses of valve incompetence, which are possible if sampling only gsv trunk just below tv. on one side cdu literature data show 2859% incidence of tv competence in limbs with primary varicose veins and gsv incompetence,1-5, 8 on the other side tv seems to be affected by reflux at a later stage of the evolution of the varicose disease.11 hence patients with gsv reflux and tv incompetence should be usually older than patients with tv competence. more importantly, limbs with gsv reflux have a smaller saphenous diameter (usually equal or below 5 mm at mid thigh) when tv is competent, whereas gsv diameter is larger (above 6 mm in more than 70% of the cases) when tv is incompetent.10 in our series gsv calibres were slightly higher, probably due to the fact that we calculated the mean value between proximal thigh and mid thigh gsv size. interestingly the 60% (17/28) incidence of tv competence, in our 28 unselected consecutive patients, is slightly higher than the incidence reported in literature,1-5,8 which may depend upon the age of the investigated patients. figure 3. color-duplex ultrasound of terminal valve competence at sapheno-femoral junction (and pelvic tributary retrograde flow during calf-release). figure 4. duplex ultrasound (transverse scanning) of terminal valve competence: no reflux at valsalva maneuver within common femoral vein. no nco mm er cia l u se on ly article [page 40] [veins and lymphatics 2012; 1:e9] in our cdu explorations reflux was elicited both with manual calf muscle compression and valsalva maneuver. the first gravitational gradient (squeezing) maneuver permits to highlight any retrograde flow with or without an escape point, whereas valsalva maneuver (which is based on hyperpressure gradient) shows reflux only in presence of escape points.10,12 with reference to the intra-operative findings, in group a (tv competence at pre-operative cdu) limited blood leak occurred in a few patients after stage i and ii during respiration, and not during valsalva; this leak is probably the expression of the normal/physiologic drainage of the abdominal wall/pelvic tributaries within sfj. conversely two of the three patients who exhibited reflux from the open sfj stump during hyperpressure maneuvers (valsalva and iliaca fossa compression) after stage i and after stage ii, were likely affected by pelvic vein insufficiency (figures 4-6). after stage iii only one patient of group a clearly showed reflux at hyperpressure maneuvers, which obviously relates to persistent tv incompetence (the false negative patient at pre-operative cdu exploration). in group b (tv incompetence at pre-operative cdu) all patients exhibited reflux during respiration and during valsalva and iliac fossa compression, and refluxes resulted qualitatively much more evident (in comparison to group a) at the visual control during the operations. during the in vivo intra-operative assessment possible external interferences may have occurred, such as: patient position, variable geometry of the open sfj stump, non-physiologic venous wall tension and cusp movements. similarly the open sfj stump compliance was obviously much higher than the physiologic one, which may have represented another difference with normal vein pathophysiology. anyway a great attention was given to maintain the normal sfj anatomy and physiology during the intra-operative assessment, in order to minimize all those factors, which could potentially bias the final outcomes. the good correspondence between cdu and intraoperative findings (27 out of 28 cases, which corresponds to 94% accuracy, with 6% false negative rate), somehow show that the in vivo demonstration of tv competence/incompetence (figure 7 and video 1) has represented a reliable method to confirm adequacy of cdu investigation to diagnose this specific morphohemodynamic condition. one single patient in group a showed intraoperative tv incompetence, after being diagnosed pre-operatively with tv competence with cdu. the objective over-complexity of investigating severely obese patients with cdu may be responsible for false/positives/negative findings at sfj, as well as in other vein districts. the limited sample size has not permitted any statistical analysis on our data; notwithstanding the intra-operative results match the cdu ones as overall. this prospective study was performed in 2003 and it included a limited number of patients; in fact the patients’ recruitment was interrupted after few weeks, due to the complexity of the protocol and due to fact that the authors changed their strategy in patients with terminal valve competence, where crossectomy has been considered unnecessary. having achieved adequate outcomes after the first 28 patients, as to the aim of the study, it was decided to limit the comparative study to the data, which were obtained until that time. figure 5. same case of figure 4: reflux during valsalva maneuver within great saphenous vein just below terminal valve (pelvic vein insufficiency). table 1. intra-operative assessment of the terminal valve of great saphenous vein (stage i-iv). group a group b (18 patients with tv competence at cdu) (10 patients with tv incompetence at cdu) respiration valsalva man respiration valsalva man and iliac fossa and iliac fossa compression compression blood no blood reflux no reflux blood reflux leak leak leak after stage i 5 13 3 15 10 10 after stage ii 4 14 3 15 10 10 after stage iii 1 17 1 17 10 10 after stage iv 0 18 0 18 0 0 tv, terminal valve; cdu, color duplex ultrasound. no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e9] [page 41] pre-treatment cdu investigation of gsv tv in varicose vein disease may address towards different therapeutic options. in case of tv competence, simple treatment of the refluxing varicose tributaries (e.g. with selective surgery or foam sclerotherapy) without any ablation of gsv trunk, would provide good outcomes at mid-term8,13 and generally speaking no sfj treatments should be advisable. in fact first step of chiva 2 (which consists of disconnection of the uppermost refluxing tributary from gsv trunk and hook phlebectomy of the proximal segment of the varicose tributaries), or single phlebectomy h, achieve in the vast majority of the cases, after one-to-six months, the abolition of gsv trunk reflux and the gsv calibre reduction.14 similarly asval approach resulted in good clinical and cdu results at 4 years follow-up.13 these transient morphologic and hemodynamic changes15,16 are due to the abolition of the re-entry veins and thus to the reduction of compliance and of the retrograde volume in presence of tv competence a more favorable follow-up could be expected8 in these patients. of importance, any endovenous chemical or thermail ablation leaves the sfj open, which may implicate that in cases of pre-treatment tv competence, mid-long term follow-up may be positively influenced, as the residual sfj stump may have no reflux thanks to tv normal function.17 sound data on this issue are still lacking, but ethiopathogenesis of recurrent varicose veins may somehow relate to the pre/post-treatment morpho-hemodynamic status of tv.17 in 2006 cappelli18 also demonstrated the fundamental role of the iliac-femoral valve, which is located in the deep veins above sfj, as to gsv diameter and with reference to sfj hemodynamics. in fact an absent or incompetent iliacfemoral valve (in combination with tv incompetence) is associated with mid-thigh gsv diameter over 7 mm in more than 50% of the cases. at the time of our study, in fact we did not included iliac-femoral valve assessment in our pre-operative cdu investigation. in this observational comparative study, preoperative cdu investigation of tv at sfj has resulted in coherent results, when compared to in vivo intraoperative tv assessment (figure 7). as tv role in gsv disease has been proved to be of importance, scrupulous pre-treatment cdu investigation of tv could lead to more tailored therapies. a more conservative (less expensive), or, conversely, a more radical treatment could be planned according to the resulting cdu findings. anyway it is auspicable that pre-therapy tv assessment should be an integral part of any scientific study aimed at producing proper evidence on gsv treatments, especially when midlong term data are provided. a few final considerations could be drawn from this study: i) cdu investigation of sfj and tv has proved to be accurate in the vast majority of the cases; ii) tv cdu assessment may lead to a saphenous junction (/trunk?) sparing therapy, as 40-50% of the varicose limbs with gsv reflux have a competent tv; iii) tv competence (hence gsv calibre below 6-7 mm in the vast majority of the cases) may explain the quite good short/mid term outcomes of the published literature on endovenous treatments,19-21 where the treated gsvs have a ≤6 mm diameter in the vast majority of the treated patients. unfortunately no or little data are published on tv competence/incompetence in gsv treatfigure 6. intra-operative assessment of one patient with terminal valve competence: reflux till stage ii completion and abolition of reflux after stage iii. figure 7. comparative pictures of two different patients during intra-operative assessment. no nco mm er cia l u se on ly article [page 42] [veins and lymphatics 2012; 1:e9] ment clinical trials, hence future prospective studies should systematically include more comprehensive morphology and hemodynamics information, if a more advanced diagnosis/therapy of primary and recurrent varicose veins has to be finalized.22 references 1. somjen gm, donlan j, hurse j, et al. venous reflux at the sapheno-femoral junction. phlebology 1995;10:132-5. 2. pieri a, vannuzzi a, duranti a, et al. role central de la valvule pre-ostiale de la veine sapheene interne dans la genese des varices tronculaires des membres inferieurs. phlebologie 1995;48:227-9. 3. abu-own a, scurr jh, coleridge smith pd. saphenous vein reflux without incompetence at the saphenofemoral junction. br j surg 1994;81:1452-4. 4. cavezzi a, labropoulos n, partsch h, et al. a. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs uip consensus document. part ii. anatomy. eur j vasc endovasc surg 2006;31:288-99. 5. coleridge-smith p, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs uip consensus document. part i. basic principles. eur j vasc endovasc surg 2006;31:83-92. 6. caggiati a, rippa bonati m, pieri a, riva a. 1603-2003:four centuries of valves. eur j vasc endovasc surg 2004;28:439-41. 7. mühlberger d, morandini l, brenner e. an anatomical studt of femoral vein valves near the saphenofemoral junction. j vasc surg 2008;48:994-9. 8. zamboni p, gianesini s, menegatti e, et al. great saphenous varicose vein surgery without saphenofemoral junction disconnection. br j surg 2010;97:820-5. 9. cavezzi a, carigi v, collura m. colour-flow duplex scanning as a pre-operative guide for mapping and for local anesthesia in varicose vein surgery. phlebology 2000;15:24-9. 10. cappelli m, molino lova r, ermini s, zamboni p. hemodynamics of the sapheno-femoral junction. patterns of reflux and their clinical implications. int angiol 2004;23:25-8. 11. bernardini e, de rango p, piccioli r, et al. development of primary superficial venous insufficiency: the ascending theory. observational and hemodynamic data from a 9-year experience. ann vasc surg 2010;24:709-20. 12. franceschi c, zamboni p. principles of venous haemodynamics. new york: nova science publisher; 2009. 13. pittaluga p, chastanet s, rea b, barbe r. midterm results of the surgical treatment of varices by phlebectomy with conservation of a refluxing saphenous vein. j vasc surg 2009;50:107-18. 14. zamboni p, cisno c, marchetti f, et al. reflux elimination without any ablation or disconnection of the saphenous vein. a haemodynamic model for venous surgery. eur j vasc endovasc surg 2001;21:361-9. 15. escribano jm, juan j, bofill r, et al. durability of reflux-elimination by a minimally invasive chiva procedure on patients with varicose veins. a 3-year prospective case study. eur j vasc endovasc surg 2003;25:159-63 16. pichot o, sessa c, bosson jl. duplex imaging analysis of the long saphenous vein reflux: basis for strategy of endovenous obliteration treatment. int angiol 2002;21:333-6. 17. de maeseneer m, cavezzi a. etiology and pathophysiology of varicose vein recurrence at the saphenofemoral or saphenopopliteal junction: an update. veins and lymphatics 2012;1:e4. 18. cappelli m, molino lova r, ermini s, et al. hemodynamics of the sapheno-femoral complex: an operational diagnosis of proximal femoral valve function. int angiol 2006;25:356-60. 19. lurie f, creton d, eklof b, et al. prospective randomized study of endovenous radiofrequency obliteration (closure procedure) versus ligation and stripping in a selected patient population (evolves study). j vasc surg 2003;38:207-14. 20. proebstle tm, alm j, göckeritz o, et al. three-year european follow-up of endovenous radiofrequency-powered segmental thermal ablation of the great saphenous vein with or without treatment of calf varicosities. j vasc surg. 2011;54:146-52. 21. darke sg, baker sja. ultrasound-guided foam sclerotherapy for the treatment of varicose veins. br j surg 2006;93:969-74. 22. de maeseneer m, pichot o, cavezzi a, et al. duplex ultrasound investigation of the veins of the lower limbs after treatment for varicose veins uip consensus document. eur j vasc endovasc surg. 2011;42:89-102. no nco mm er cia l u se on ly stefano ricci comment to: the effect of single phlebectomies of a large varicose tributary on great saphenous vein reflux by biemans aam, van den bos rr, hollestein lm, maessen-visch mb, vergouwe y, neumann ham, de maeseneer mgr, nijsten t. j vasc surg 2014;2:179-87. stefano ricci abstract the objective of the present prospective multicenter study was to analyze short-term outcomes after single phlebectomies of a large incompetent tributary joining the gsv at thigh level in patients who also have gsv incompetence and to determine predictors for restoration of great saphenous vein (gsv) competence. recruitment of 100 patients started in april 2010 and ended in march 2012. consecutive adult patients with symptomatic primary gsv incompetence and a clinically visible incompetent tributary of the gsv at the medial thigh (with or without extension below the knee) were eligible to participate. the saphenofemoral junction (sfj), the gsv in the thigh above and below the junction of the tributary, the tributary itself, and the gsv below the knee were studied in particular. valvular function was studied by manual calf compression; the valsalva maneuver was performed to assess reflux at the terminal valve of the sfj. two diameter measurements were performed, respectively, 2 cm above and below the junction of the refluxing tributary. the reflux elimination test was performed by digital compression of the refluxing tributary in the thigh to test whether this could modify gsv reflux. phlebectomy was performed by use of local anesthesia with lidocaine 1%. patients were invited for follow-up 3 months after the procedure: if patients presented with persisting symptomatic gsv incompetence, additional treatment was proposed by either endovenous thermal ablation or ultrasound-guided foam sclerotherapy. patients without gsv incompetence or without symptoms were scheduled for a follow-up visit 12 months after the initial procedure. the primary outcome was absence of reflux in the entire gsv, measured by dus evaluation after 1 year. secondary outcome measures were c class of the clinical, etiologic, anatomic, and pathologic (ceap) classification, vcss (range, 1-10), and avvq score (range, 1-100). multivariable logistic regression including all clinically relevant variables following a backward variable elimination process was used to determine predictors for success. in total, 94 patients were analyzed, 65 women and 29 men; 55.3% patients were classified as c2, 35.1% as c3, and 9.6% as c4. the mean gsv diameter was 0.55 cm (sd, 0.15; range, 0.28-0.95 cm) above the tributary and 0.36 cm (sd, 0.16) below the tributary. half of the patients had terminal valve reflux at the sfj. in approximately half of the patients, reflux was present only in the most proximal segment; the rest also had reflux more distally. a significant relation between reflux at the terminal valve and gsv diameter was found. in patients without terminal valve reflux, gsv diameter was more often <5 mm; a lower c class and diameter <5 mm were significantly related to success. in 47 patients (50%), reflux disappeared completely after 12 months. in 15 patients (16%), phlebectomy resulted in complete relief of complaints despite persisting gsv reflux; these patients did not undergo additional treatment. the remaining 32 patients had persisting symptoms and underwent additional gsv ablation. the mean diameter of the gsv above the tributary decreased significantly after 3 and 12 months from 0.55 cm to 0.36 cm and 0.39 cm. the c class decreased significantly after treatment while vcss and avvq score improved in all patients (independent of hemodynamic effect) after treatment. reflux was more often abolished when the following parameters at baseline were present: c2; short (<10 cm) refluxing segment; reflux in only one gsv segment; smaller diameters of gsv and tributary; positive result of the reflux elimination test; and low vcss and avvq score. patients with a positive reflux elimination test result have a more than 65% chance of success. even if saphenous reflux persists, phlebectomies probably reduce the total refluxing volume, explaining the clinical and hemodynamic improvements. consequently, treatment of varicose vein patients should be individualized because every patient is different in anatomy, hemodynamic, clinical presentation, and impact of varicose veins on quality of life and symptoms. the predictors for success found in the present study may orient the physician toward a less invasive approach, which may consist of single phlebectomies in properly selected patients. even in the presence of saphenous reflux, phlebectomies may be the first-line treatment, avoiding needless saphenous ablation. comment by stefano ricci this interesting paper underlines concepts that were introduced more than 20 years ago by conservative venous treatments fans, like franceschi, cappelli, zamboni, escribano, and other more, correctly cited in the reference section, but not underlined in the discussion. even muller’s philosophy could be recalled: the sentence even in the presence of saphenous reflux, phlebectomies may be the first-line treatment, avoiding needless saphenous ablation could have been one of his own. the study is accurate, complete and well organized, however some aspects deserve a more detailed analysis: i) the reflux elimination test (ret), correctly introduced as a possible predictor test, was described by zamboni as a method for differentiating shunts (shunt i + ii = negative test; shunt iii positive test). in fact when the ret is positive, the reflux on the gsv stops when the tributary connected to the re-entry perforator is compressed, not allowing the flow to re-enter in the deep vessels. if, at the opposite, a re-entry perforator is centered also on the gsv more distally (or in a more distal tributary), the ret will be negative, as the higher tributary compression do not impede the re-entry flow. as a consequence, every phlebectomy performed when the test is positive will make the reflux disappear; with a negative test, the reflux will continue through the untouched circuit although the reflux will decrease (with clinical improvement). in these patients the gsv incompetence involves the vein distally to the tributary showing a larger caliber. this said, the reflux disappearance in ret positive subject is not due to a competence achievement (valves restoration), but to the interruption of the hydraulic circuit (blockage of re-entry) so that doppler cannot trace any retrograde flow, the gsv remaining virtually incompetent; as soon as a new vein begin to develop (recur) where the tributary was interrupted, the reflux appears again, as a flow now is possible again. curiously, ret+ patients were 61 while no-reflux + reflux-without-symptoms were 62 confirming what said. this explanation, that gives a meaning to the paper’s results, should have been analyzed and suggested to the lecturer. ii) another point of interest is related to terminal valve competence –52%/incompetence 48%. authors report that gsv caliber in competence cases was more often (?) 5 mm in incompetent junctions, and they add that success was related to smaller calibers. however, because of statistical non significance, reflux at the terminal valve was removed from the model, apparently a contradiction. this decision is not clear and could be explained. at the opposite, correlation between terminal valve competence, ret +, and reflux disappearance would have been of great interest. iii) finally, it is not reported how tributaries phlebectomy was managed: only thigh varices were avulsed? what about other limb varices? when the reflux re-entered the gsv stem, was the case still included? [top] hrev_master veins and lymphatics 2016; volume 5:5988 compression after trauma rolf jelnes wound clinic, medical center, sygehus sønderjylland, sønderborg, denmark traumatic ulcers are a large entity in wound care. in our clinic, data from the database1 show that the number of patients is comparable to venous leg ulcers, diabetic foot ulcers and pressure ulcers (table 1). in spite of this, not very much is written about the entity in the literature. the traumatic wounds are typically located on the anterior and lateral aspect of the lower limb. the causes are different from low energy trauma (as stumbling up the stairs or a trolley in the supermarket (figures 1 and 2) to accidents with a sharp trauma. after low energy trauma, the patients are able to continue their daily work until a lesion appears on the skin. when it increases in size the patient seeks the general practitioner who typically prescribes an antibiotic treatment. if nothing else is done, apart from moist wound healing, the time to heal can be as long as more than 6 months with the well known consequences for the patient and the society in terms of personal and social costs. studies on deep tissue injury have shown that cell deformity, within minutes, causes cell damage leading to cell death.2 the subcutaneous tissue is the tissue with lowest blood perfusion, thus making it more susceptible to ischemia. a possible mechanism for the development of the traumatic ulcer could be: i) subcutaneous adipose tissue cells die, due to the blunt trauma; ii) within the cell the osmotically active proteins are let loose themselves in the interstitium, drawing water to the area; iii) edema is created in the ageing skin the amount of collagen and elastin is reduced3 especially in women after menopause, leading to reduced forces to counteract the edema (intrinsic compression). as an edema has developed, the rationale for compression, with either bandages or stockings with high stiffness, seems obvious. the impressive healing rate of 25% per week (table 1) supports this view. references 1. hafner j, nobbe s, partsch h, et al. martorell hypertensive ischemic leg ulcer: a model of ischemic subcutaneous arteriolosclerosis. arch dermatol 2010;146:9618. 2. senet p, beneton n, debure c, et al. hypertensive leg ulcers: epidemiological characteristics and prognostic factors for healing in a prospective cohort. ann dermatol venereol 2012;139:346-9. 3. senet p, vicaut e, beneton n, et al. topical treatment of hypertensive leg ulcers with platelet-derived growth factor-bb: a randomized controlled trial. arch dermatol 2011;147:926-30. 4. vuerstaek jd, reeder sw, henquet cj, neumann ha. arteriolosclerotic ulcer of martorell. j eur acad dermatol venereol 2010;24:867-74. correspondence: rolf jelnes, wound clinic, medical center, sygehus sønderjylland, sydvang 1,�6400 sønderborg, denmark. e-mail: rolf.jelnes@stofanet.dk this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright r.jelnes, 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5988 doi:10.4081/vl.2016.5988 table 1. distribution of wounds according to underlying diagnosis. number healing of wounds rate per week traumatic ulcers 558 25% pressure ulcers 503 venous leg ulcers 450 18% neuropathic foot 444 ulceres neuroischemic 283 foot ulcers figure 1. large traumatic ulcer on the postero-lateral aspect of the calf. figure 2. traumatic ulcer on the anterior aspect of the calf. [page 16] [veins and lymphatics 2016; 5:5988] no n c om me rci al us e o nly hrev_master veins and lymphatics 2016; volume 5:5982 [veins and lymphatics 2014; 3:5982] [page 5] compression in dermatolymphangio-adenits alberto macciò lympholab onlus, genova, italy the term dermato-lymphangio-adenits (dla) has been proposed by olszewski1 describing clinical symptoms, which are frequently called erysipelas or cellulitis and which are characterized by local tenderness and erythema of the skin, sometimes red streaks along the distribution of the superficial lymphatics and enlarged inguinal lymph nodes. systemic symptoms include malaise, fever and chills. this entity occurs mainly in patients with disturbed lymph drainage, which is often unrecognized, most commonly on the extremities, which show increased swelling (figure 1). unlike in other ordinary infections of the soft tissues, it is extremely important that the disturbed lymph flow is treated in association with the usual antibiotic therapy (figure 2). recent epidemiologic studies conducted by our team proved that approximately 1% of admissions to emergency departments in italy are due to acute disease of the lymphatic system.2,3 we found that approximately 80% of patients were admitted because of acute or sub-acute dla of different origins as complications of existing lymphatic obstructions, whether primary or secondary. compared with the dozens of millions of admissions to italian emergency departments every year, the figures processed by our team strikingly show a high risk of misdiagnosis and medical malpractice, which delay the proper management and specific treatment of such severe conditions. the acute inflammatory symptoms, that are specifically associated with an impaired lymphatic system, are often confused with the symptoms of thrombophlebitis and these patients are therefore wrongly treated with low-molecular-weight heparins only. to get a more accurate diagnosis, we have to come up with a specific diagnostic score (lymphangitis score), consisting of 8 simple anamnestic-semiology points, in the attempt to help doctors to reduce false negatives in their differential diagnoses (table 1). preliminary unpublished data about the medical application of this score have shown it to be a highly sensitive tool (>99%), which reduces false positives (<4%, if supported by blood and laboratory tests). in patients where there is a clinical suspect of dla, maybe supported by such score, the obstruction in the lymphatic system that is involved as a primary cause of the inflammation must therefore be treated. in such cases a multi-component bandage is necessary to improve lymphatic drainage in addition to the usual broad-spectrum antibiotics and to the complex physical therapy of lymphedema. this specifically means a strictly shortstretch inelastic functional bandage (<40% stretch), even better if associated with a zinc oxide or alginate dressing underneath. figure 3 demonstrates clearly that the inflammation of the skin of the lower leg completely disappeared under the bandage while it is still visible in the proximal parts of the limb. usually, patients perfectly tolerate a functional bandage and failures are often due to wrong bandaging techniques or to the use of unsuitable materials. based on the medical experience gained in emergency and urgent surgery areas, poor compliance must lead us to look for underlying comorbidities, or to change the initial antibiotic treatment provided, if we are sure the limb has been properly bandaged. recently, for instance in wound care, new materials are being produced, such as medicated bandages, where the classic zinc oxide is replaced by a calcium alginate mixture (excellent for treating the exudate) and manuka honey still maintaining their inelastic properties. correspondence: alberto macciò, p.zza santa cecilia 4/2, 17100 savona, italy. e-mail: alberto.maccio@gmail.com this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright a. macciò, 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5982 doi:10.4081/vl.2016.5982 table 1. simple scoring system to diagnose dermato-lymphangio-adenits. diagnosis can be made if 3 or more criteria are present (not applicable after trauma). 1. fever up to 41°c 2. rubor: redness, cutaneous hyperaemia (with normal us-duplex) 3. calor: local heat (with normal us-duplex) 4. dolor: local pain (with normal us-duplex) 5. tumor: swelling or increase of edema (with normal us-duplex) 6. anamnestic data for lymphatic and/or venous insufficiency 7. palpable swelling of local lymph nodes 8. recent primary infected lesion on the affected limb us, ultrasound. figure 1. erysipelas in a leg showing the lymphoscintigraphic pattern of dermal backflow. no n c om me rci al us e o nly conference presentation [page 6] [veins and lymphatics 2014; 3:5982] actually, while the topical use of antibiotics seems to be effective only to a limited extent. preliminary data support the use of manuka honey, occasionally associated with other watery substances, because of its excellent antibacterial activity. unless a synergic effect is created between the systemic pharmacological treatment and the overall local therapy (designed to improve lymphatic drainage), the inflammation will relapse in most cases, sometimes even very quickly. in daily practice, the combined treatment of the lymphedema using compression dramatically reduces frequent infectious complications in chronic patients. erysipelas of the extremities is an excellent indication for compression therapy. we prefer short stretch material (zinc paste) for the acute stage, combined with walking exercises as soon the patient is without fever. references 1. olszewski wl. episodic dermatolymphangioadenitis (dla) in patients with lymphedema of the lower extremities before and after administration of benzathine penicillin: a preliminary study. lymphology 1996;29:126-31. 2. macciò a, boccardo f, eretta c, et al. acute lymphangitis: “lymphological emergency”. lymphology 2007;40:165. 3. boccardo f, eretta c, la ganga v, et al. lymphatic damage in venous surgery. eur j lymphol 2008;18:7-10. figure 3. a bandage applied to the lower leg with erysipelas is able to reverse the clinical sign of redness, which starts proximally where no bandage was applied. figure 2. management of dermato-lymphangio-adenits: in addition to antibiotics compression therapy is recommended to treat the underlying lymphatic pathology. no n c om me rci al us e o nly hrev_master veins and lymphatics 2012; volume 1:e4 [page 10] [veins and lymphatics 2012; 1:e4] etiology and pathophysiology of varicose vein recurrence at the saphenofemoral or saphenopopliteal junction: an update marianne de maeseneer,1,2 attilio cavezzi3 1phlebology, department of dermatology, erasmus medical centre, rotterdam, the netherlands; 2faculty of medicine and health sciences, university of antwerp, antwerp, belgium; 3vascular unit, clinica stella maris and poliambulatorio hippocrates, san benedetto del tronto, italy abstract recurrent varicose veins remain a common problem after varicose vein treatment. with the widespread use of duplex ultrasound and increasing experience in the field of ultrasound-guided procedures, the impact of both tactical and technical failure is likely to diminish. progression of the disease and neovascularization, in particular after surgery at the level of the saphenofemoral junction (sfj) or saphenopopliteal junction (spj), both have their impact on recurrence, and both factors may be interacting. after high ligation, with or without stripping, neovascularization has been attributed to local angiogenesis, transnodal lymphovenous connections, dilation of vasa vasorum, or disturbed venous drainage of the ligated tributaries of the sfj. another typical source of recurrence after surgery is a persistent refluxing residual stump at the sfj or spj. after endovenous thermal ablation new or persistent reflux may be detected sonographically at the sfj or spj residual stump as well. one of the veins often involved in recurrence after great saphenous vein ablation is the anterior accessory saphenous vein. future studies are needed, including adequate preoperative duplex ultrasound investigation and long-term follow-up, to understand the impact of residual or recurrent reflux at the sfj or spj on the incidence of clinical recurrence after different forms of varicose vein treatment. introduction recurrent varicose veins, re-appearing in the shortor long-term after previous treatment, are a common problem (figures 1 and 2). after surgery, according to prospective studies with 5 years follow-up, the incidence of clinical recurrence is estimated to be between 25% and 50%.1,2 after endovenous thermal ablation (evta) the majority of studies report about a shorter follow-up time. often only surrogate outcomes (obliteration of the truncal vein or not, according to duplex ultrasound) have been used without mentioning the incidence of clinical varicose vein recurrence. long-term clinical follow-up data after evta are scarce up to now. after treatment of the great saphenous vein (gsv) with the old radiofrequency system closure plus®, merchant et al.3 reported an incidence of 27% of varicose vein recurrence after 5 years. pröbstle et al.4 noticed the presence of varicose veins after 3 years in 33% of limbs, treated with radiofrequency powered segmental ablation (closure fast®, covidien plc, dublin ireland). recently, the 5-years results of a randomized controlled trial (rct), comparing endovenous laser ablation with and without additional high ligation at the saphenofemoral junction (sfj) in patients with bilateral symptomatic gsv incompetence, have been reported by disselhof et al.5 they did not perform additional phlebectomies but ultrasound guided foam sclerotherapy for residual varicose veins at 6 weeks. after five years, recurrent varicose veins were present in 31% of limbs treated with endovenous laser ablation without sfj ligation and in 49% of those treated with additional high ligation. in a rct comparing endovenous laser treatment with surgery, with additional phlebectomies in both groups, rasmussen et al.6 found an incidence of recurrent varicose veins in respectively 26% and 37% of patients after two years. at the charing cross meeting of 2012, gough reported 33% clinical recurrence in 63 patients at 6.5 years of follow-up after endovenous laser ablation.7 the above cited midand long-term follow-up data illustrate that not only after high ligation and stripping but also after endovenous treatment of the refluxing trunk the clinical reappearance of varicose veins definitely remains a problem. etiology of varicose vein recurrence some causes of recurrence of varicose veins after treatment are obvious: insufficient understanding of venous anatomy and haemodynamics, inadequate preoperative assessment (both leading to tactical failure), and incorrect or insufficient surgical/endovenous intervention (which means technical failure). with the widespread use of duplex ultrasound for evaluation of patients with varicose veins and increasing experience of surgeons and other physicians treating varicose veins, fortunately the impact of both tactical and technical failure is likely to diminish nowadays. there are two other main causes for varicose vein recurrence left, namely progression of the disease and neovascularization. progression of the disease, with new varicose veins appearing over time is somehow part of the game, as superficial venous disease is a chronic condition in which hereditary and constitutional risk factors play a role. over time, new superficial veins may become incompetent, segmental truncal reflux may extend, new incompetence of perforating veins may develop and also pelvic vein insufficiency may play its role in progression of the disease. the term neovascularization describes a phenomenon of formation of new, usually tortuous, venous channels between the saphenous stump on the common femoral vein (cfv) and a residual gsv, anterior accessory saphenous vein (aasv) or superficial tributaries (figure 3).8 although it has mainly been studied at the level of the sfj (figure 4a and 4b) the same phenomenon may occur at the level of the saphenopopliteal junction (spj) after small saphenous vein (ssv) surgery, or after ligation of incompetent perforating veins or even after phlebectomies. the vein term transatlantic interdisciplinary faculty recently accepted the term neovascularization defined as the presence of multiple small tortuous veins in anatomic proximity to a previous intervention.9 the duplex appearance of neovascularization at the junction has also been clearly described in the union internationale de phlébologie (uip) consensus document on duplex ultrasound reporting after varicose veins intervencorrespondence: marianne de maeseneer, department of dermatology, erasmus medical centre, pb 2040, 3000 ca rotterdam, the netherlands. e-mail: marianne.demaeseneer@ua.ac.be m.demaeseneer@erasmusmc.nl key words: varicose vein, phenofemoral junction, saphenopopliteal junction. acknowledgments: the authors would like to thank dr olivier pichot, grenoble, france for providing illustrative duplex ultrasound images for figures 3, 5 and 6. received for publication: 18 june 2012. revision received: 20 june 2012. accepted for publication: 21 june 2012. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright m. de maeseneer and a. cavezzi, 2012 licensee pagepress, italy veins and lymphatics 2012; 1:e4 doi:10.4081/vl.2012.e4 no nco mm er cia l u se on ly review [veins and lymphatics 2012; 1:e4] [page 11] tions, published in 2011.10 according to this document an alternative, more purely sonographic descriptive term may equally be used instead of neovascularization namely groin varicose network at the sfj or popliteal fossa varicose network at the spj. pathophysiology of varicose vein recurrence tactical and technical failure the pathophysiology of varicose vein recurrence due to tactical and technical failure is rather obvious. if the wrong vein has been treated, incompetence may persist in the untreated vein and this may explain why varicose veins recur. insufficient or incorrect surgery, e.g. too low ligation at the junction may result in an obvious cause of recurrence, if a long refluxing sfj stump has been left.11 often a residual aasv forms the typical pathway of reflux from the incompetent sfj to the thigh and leg. the same may occur after endovenous ablation, if the tip of the laser fiber or the radiofrequency catheter has not been positioned correctly, leaving too long a distance between the highest point of saphenous ablation and the refluxing sfj or spj. also in these cases the pathophysiology of recurrence is quite obvious. in some cases duplex ultrasound of the aasv reveals a particular anatomic situation, characterized by merging of the aasv with the gsv exactly at the sfj (figure 5). after any endovenous treatment of the gsv in such case, the aasv will be invariably included in the open stump. neovascularization and disease progression: interacting mechanisms the past two decades, most of the research on recurrence after varicose vein treatment has focused on the potential pathophysiological mechanisms of neovascularization, which – together with progression of the disease – is considered to play an important role in recurrence, in particular after a classic surgical intervention.8,12 after evta, neovascularization at the sfj or spj does not seem to play an important role in recurrence, as it is a very exceptional finding, with an incidence between 0-1%.5,13 the research on neovascularization has mainly focused on the sfj. after surgery, in particular after a so called correct flush sfj ligation, various mechanisms may be involved inducing neovascularization: angiogenic stimulation in the stump endothelium, transnodal lymphovenous connections, dilation of small adventitial vessels, the vasa vasorum of the femoral vein, or disturbed venous drainage of the ligated tributaries of the sfj, in particular in case of pelvic vein insufficiency. all of these occur on a background of the normal woundhealing process, in which angiogenesis is an important component. however the surgical procedure itself cannot be the unique trigger for neovascularization, as this phenomenon does not occur after harvesting of the gsv in the groin in people without varicose veins. it has recently been postulated that venous pressure differences are an important triggering factor for the development of neovascularization and this certainly plays a role after an intervention on the junction and/or on the main saphenous trunk.14 angiogenic stimulation in the free endothelium of the saphenous stump this has been claimed to be one of the most important triggers for the onset of the neovascularization process after surgical ligation and transection of the gsv in patients with varicose figure 1. recurrent varicose veins after high ligation and stripping of the above knee great saphenous vein. figure 3. longitudinal color duplex ultrasound image of the groin: saphenofemoral junction (sfj) with neovascularization several years after high ligation and stripping. figure 4. a) color duplex image of the right groin: superficial tortuous varicose veins in connection with the saphenofemoral junction (not shown) are entering the saphenous compartment (arrow). b) ultrasound shows tortuous veins, typically with multiple lumina, within the saphenous compartment. a) b) figure 2. extensive recurrent varicose veins 12 years after high ligation and stripping of the great saphenous vein; the anterior accessory saphenous vein is typically involved. no nco mm er cia l u se on ly review [page 12] [veins and lymphatics 2012; 1:e4] veins. this might originate from hypoxiainduced activation of endothelial cells distal to the stump ligature, which could be mediated by different growth factors. immunohistochemical staining of the intima with antibodies against vascular endothelial growth factor (vegf) and its receptor (vegf-r) showed both vegf and vegf-r were present in a higher percentage and had a higher expression in tissue samples of recurrent varicose veins with macroscopic neovascularization, compared to those of primary varicose veins and control veins.15 another cause of stump-related neovascularization may be inflammation related to (absorbable) ligature or to the results of surgical dissection in the area around the sfj or spj. transnodal lymphovenous connection lemasle et al.16 have focused on the important role of the lymph nodes close to the ligated gsv stump. their hypothesis is that neovascularization is essentially the development of pre-existing venous vessels in these inguinal lymph nodes. this physiological lymph node vein network (lnvn) is normally thin and drains into the gsv and/or in the pelvic veins. due to mechanical obstruction after crossectomy, or due to the action of angiogenic factors and when pelvic vein insufficiency subsides, lnvn could become larger and incompetent. this could correspond with the tiny refluxing veins passing through the surrounding lymph nodes, often seen at postoperative duplex ultrasound of the groin (figure 6a and 6b).10 further study of the lymph nodes by means of high definition ultrasound before and after surgery at the sfj may help to clarify the role of lymph nodes and lymphovenous connections in varicose vein recurrence. dilation of the vasa vasorum dilation of the vasa vasorum in the adventitia of the femoral vein could theoretically be responsible for new connections between the deep and superficial venous system. it is known that the very tiny veins of the vein wall are draining their blood directly into the lumen of the vein. it has been postulated that these tiny veins might enlarge, and become the source of reflux to the superficial veins. unfortunately this issue has not been extensively studied. disturbed venous drainage of ligated tributaries disturbed venous drainage of tributaries of the sfj that have been ligated has also been cited as a potential pathophysiological mechanism to explain recurrence in the groin. this can be even more frequent when the most cranial tributaries are refluxing preoperatively, due to pelvic vein insufficiency, and when these tributaries are draining into the gsv trunk, in the presence of a competent terminal valve. chandler et al.17 have suggested that neovascularization might also be driven by localized venous hypertension, or frustrated venous drainage secondary to ligation of tributaries as, for instance, the superficial epigastric vein (figure 7) or pudendal veins. the latter might disturb normal venous drainage of the superficial tissues of the lower abdomen and pudendum. the idea that localized venous hypertension might be a trigger for neovascularization is supported by the finding that after endovenous treatment neovascularization seems to be very exceptional.5,13 indeed, as evta usually starts 0.5-1 cm distally from the ostium of the superficial epigastric vein, normal drainage of this vein into the proximal gsv towards the common femoral vein can go on without any problem after endovenous treatment. comparable findings were reported in a retrospective study by pittaluga et al.18 two years after limited surgery in the groin in addition to stripping of the refluxing trunks. ligation of the gsv at a distance from the sfj, preserving the proximal (non-refluxing) tributaries of the gsv resulted in a very low rate of postoperative neovascularization (only 1.8%), far lower than after classic sfj ligation. further prospective studies will be needed to elucidate this pathophysiologic issue. a joint venture? probably neovascularization at the sfj as such cannot be the unique cause for the development of recurrent varicose veins after sfj surgery including flush ligation. something has to occur in the periphery as well, where a refluxing vein will try to make a joint venture with the neovascular veins at the sfj and vice versa, by sending out some – not yet clearly understood – chemotactic signs, which will finally result in reconnection between peripheral veins and neovascular veins at the junction. in addition, differences in venous pressure may play a role in establishing these reconnections.14 in this way recurrence can appear early after the operation (sometimes already within the first or second year) if residual varicose veins or a refluxing gsv or aasv trunk have been left in place: prompt reconnection between these pathologic veins and neovascular veins could be quite evident in such situation.19 recurrence developing late (several years) after the operation is more often primarily due to progression of the varicose disease. at the previous sfj site neovascularization can play a secondary role in these cases. after a few years little by little new varicose veins develop in the leg and these can connect with neovascular veins in the groin, which at the long term can become larger and refluxing. this leads to the typical clinical picture of thigh or whole leg varicose vein recurrence several years after gsv surgery, being an end stage of this development (figure 2). at the level of the spj the pathophysiology of recurrent reflux has not been studied that extensively as at the level of the sfj. after surgery, in particular when this has been limited to flush ligation at the spj, it is often seen that large tortuous neovascular vessels reconnect the ssv stump with the residual refluxing trunk. this can be typically recognized on duplex ultrasound and, in such case, the refluxing ssv can be easily treated by means of evta up to the level of the neovascular veins in the figure 6. a) transverse image of large lymph node with refluxing vein in a patient with extensive varicose vein recurrence. b) longitudinal image of the same lymph node. a) b) figure 5. typical presentation at the saphenofemoral junction in some cases: the anterior accessory saphenous vein (aasv) merges with the great saphenous vein (gsv). transverse image of the left groin. cfv, common femoral vein; cfa, common femoral artery. no nco mm er cia l u se on ly review [veins and lymphatics 2012; 1:e4] [page 13] popliteal fossa or by means of ultrasound guided foam sclerotherapy. after ligation at the spj and stripping of the ssv to mid-calf level, neovascularization at the spj may result in formation of new tortuous veins running from the popliteal fossa to the calf (figure 8). in case of clinical recurrence after ssv surgery or evta, another typical feature in the popliteal fossa is the presence of a popliteal fossa perforating vein, which may be related to progression of the disease (figure 9). on duplex ultrasound it can be recognized from its typical location in front of the lateral condyle of the femur.10 also, the preoperative presence of reflux during calf compression (systolic), or compression and release (systolic-diastolic) at the spj (found in 6% of cases of spj reflux in primary varicose veins)20 has been advocated to play a role in the early recurrence at the popliteal fossa. such systolic reflux is typically associated with obstructed outflow of the deep vein after previous deep vein thrombosis (dvt). interestingly, a spj systolic reflux has been found in limbs without any sign of dvt. it is usually associated with a diverted flow from the popliteal vein towards a giacomini vein or towards a thigh extension of the ssv. this hemodynamic abnormality is more likely due to an outflow problem in the popliteal-femoral axis or due to other specific conditions of venous anatomy. any treatment of the spj (crossectomy, sclerotherapy) may have a negative hemodynamic effect and may lead to early recurrence. careful duplex ultrasound investigation of the deep venous system is mandatory before considering any intervention in these cases. the role of the saphenofemoral junction (or saphenopopliteal junction) in recurrence following endovenous thermal ablation it is remarkable to notice that the fate of the sfj is not at all mentioned in the majority of studies looking at outcome after evta of the gsv. this explains why hard data about this issue are missing until now. theivacumar et al.21 specifically studied the fate and clinical significance of persistent sfj tributaries one year after endovenous laser ablation of the gsv. one or more patent tributaries were visible in 60% of legs. all were competent and they did not appear to have an adverse impact on clinical outcome at short-term after successful gsv ablation. however, in some cases reflux may persist or reappear at the level of the sfj after evta, even if the gsv trunk has been completely obliterated. this may particularly be the case when an incompetent aasv is involved.5,6,22 it represents either new incompetence, or failure of the pre-treatment duplex ultrasound to demonstrate reflux into the aasv, which has been left untreated.22 before as well as after evta treatment, the possible role of competence or incompetence of the terminal valve and the preterminal valve of the gsv should be studied more carefully. indeed, it has been shown that the gsv trunk is smaller in presence of a competent terminal valve, and larger when the terminal valve is incompetent.23 also, haemodynamics of the sfj may be different in case of incompetence or absence of the proximal femoral valve (above the sfj) and this may influence outcome after endovenous treatment of the gsv.24 as already mentioned previously, new reflux at the sfj due to neovascularization shortly after evta is very exceptional and may be the result of vein wall perforation and/or hematoma formation in these rare cases.13 up until now, only a few randomized trials, comparing evta with surgery, have investigated the incidence of new reflux at the sfj. just very recently the two year results of the german relacs-study have been published.25 in this study, duplex-detected reflux at the sfj appeared to occur significantly more frequently after endovenous laser ablation (17.8%) than after high ligation and stripping under tumescent anesthesia (1.3%). in the surgical group of this study a particular technique was used to mitigate the effect of neovascularization after high ligation at the sfj, consisting of invagination of the gsv stump with a nonabsorbable suture. this might explain somehow the low incidence of postoperative recurrent reflux at the sfj. moreover, all procedures were performed under local tumescent anesthesia, which facilitates dissection at the sfj and minimizes blood loss. it may be hypothesized that both these factors reduced surgical trauma and haematoma formation, and hence the incidence of neovascularization.25 the importance of reporting not only the findings at the level of the ablated trunk but also figure 7. longitudinal duplex scan of the saphenofemoral junction, clearly showing the superficial epigastric vein. gsv, great saphenous vein; cfv, common femoral vein. figure 8. recurrent varicose veins 10 years after high ligation and stripping of the small saphenous vein – the black line indicates the site of the previous incision in the popliteal fossa. figure 9. incompetent popliteal fossa perforating vein. figure 10. transverse duplex image at mid thigh: recanalization of the great saphenous (gsv) vein 5 years after endovenous laser ablation; reflux is present at the saphenofemoral junction and continues along the thigh in the recanalized gsv. no nco mm er cia l u se on ly review [page 14] [veins and lymphatics 2012; 1:e4] at the sfj or spj after endovenous treatment has been extensively highlighted in the recent uip consensus document on duplex evaluation after treatment.10 persistence or re-appearance of reflux at the sfj or spj and/or at the level of the saphenous stump after evta is always to be considered pathological. during serial follow-up it can be observed how the incompetent most cranial part of the gsv in the groin connects with recurrent thigh varicosities, even if the main trunk is completely obliterated. in case of partial or complete recanalization of the gsv after evta, reflux may of course be transmitted from the sfj directly to the recanalized gsv trunk (figure 10). the same may occur at the level of the spj and ssv. more studies looking at the fate of the sfj (or spj) after different treatment forms are certainly needed to further clarify its role in recurrence at the long-term. constitutional risk factors in addition to all the above-mentioned pathophysiological mechanisms, constitutional risk factors, which could potentially enhance the tendency to recurrence, should also be further examined. the importance of risk factors such as female gender, left sided disease, associated deep vein incompetence, severe chronic venous disease (c4-6 of the ceap classification), obesity, subsequent pregnancies after surgery, which have all been claimed to promote recurrence, should be prospectively studied. conclusions our understanding of the etiology and pathophysiology of varicose vein recurrence has grown considerably during the last decades. continuous education and in particular handson training in duplex ultrasound and duplexguided procedures may further reduce the impact of both tactical and technical failure. however, progression of the disease, with or without associated neovascularization, remains a problem for all physicians involved in varicose vein treatment, as well as for their patients. properly designed prospective studies, with adequate preoperative duplex investigation and long-term follow-up, carefully studying the fate of the sfj and spj after different forms of varicose vein treatment, are still needed. references 1. van rij am, jiang p, solomon c, et al. recurrence after varicose vein surgery: a prospective long-term clinical study with duplex ultrasound scanning and air plethysmography. j vasc surg 2003;38:935-43 2. kostas t, ioannou cv, touloupakis e, et al. recurrent varicose veins after surgery: a new appraisal of a common and complex problem in vascular surgery. eur j vasc endovasc surg 2004;27:275-82. 3. merchant rf, pichot o, closure study group. long-term outcomes of endovenous radiofrequency obliteration of saphenous reflux as a treatment for superficial venous insufficiency. j vasc surg 2005;42: 502-9. 4. proebstle tm, alm j, göckeritz o, et al. three-year european follow-up of endovenous rediofrequency-powered segmental thermal ablation of the great saphenous vein with or without treatment of calf varicosities. j vasc surg 2011;54:146-52. 5. disselhof bc, der kinderen dj, kelder jc, moll fl. five-year results of a randomised clinical trial of endovenous laser ablation of the great saphenous vein with and without ligation of the saphenofemoral junction. eur j vasc endovasc surg 2011;41: 685-90. 6. rasmussen lh, bjoern l, lawaetz m, et al. randomised clinical trial comparing endovenous laser ablation with stripping of the great saphenous vein: clinical outcome and recurrence after 2 years. eur j vasc endovasc surg 2010:39:630-5. 7. gough m. satisfactory results with endovenous laser ablation 6.5 years after treatment. available from: http://www.cxvascular.com/vn-venous -news 8. de maeseneer mgr. the role of postoperative neovascularization in recurrence of varicose veins: from historical background to today’s evidence. acta chir belg 2004; 104:283-9. 9. eklöf b, perrin m, delis kt, et al. updated terminology of chronic venous disorders: the vein-term transatlantic interdisciplinary document. j vasc surg 2009;49: 498-501. 10. de maeseneer m, pichot o, cavezzi a, et al. duplex ultrasound investigation of the veins of the lower limbs after treatment for varicose veins – uip consensus document. eur j vasc endovasc surg 2011;42:89-102. 11. geier b, stücker m, hummel t, et al. residual stumps associated with inguinal varicose recurrences: a multicenter study. eur j vasc endovasc surg 2008;36:207-10. 12. van rij am, jones gt, hill gb, jiang p. neovascularization and recurrent varicose veins: more histologic and ultrasound evidence. j vasc surg 2004;40:296-302. 13. pichot o, kabnick ls, creton d, et al. duplex ultrasound findings two years after great saphenous vein radiofrequency endovenous obliteration. j vasc surg 2004; 39:189-95. 14. recek c. venous pressure gradients in the lower extremity and the hemodynamic consequences. vasa 2010;39:292-7. 15. rewerk s, noppeney t, winkler m, et al. pathogenesis of primary and recurrent varicose veins at the sapheno-femoral junction. the role of vegf and vegf-receptor. phlébologie 2007;36:137-42. [article in german]. 16. lemasle p, lefebvre-vilardebo m, uhl jf, et al. postoperative recurrence of varices: what if inguinal neovascularization was nothing more than the development of a pre-existing network? phlébologie 2009; 62:42-8. [article in french]. 17. chandler jg, pichot o, sessa c, et al. defining the role of extended saphenofemoral junction ligation: a prospective comparative study. j vasc surg 2000;32: 941-53. 18. pittaluga p, chastanet s, guex jj. great saphenous vein stripping with preservation of sapheno-femoral confluence: hemodynamic and clinical results. j vasc surg 2008;47:1300-5. 19. jones l, braithwaite ed, selwyn d, et al. reprinted article “neovascularization is the principal cause of varicose vein recurrence: results of a randomised trial of stripping the long saphenous vein”. eur j vasc endovasc surg 2011;42 suppl 1:s5760. 20. cavezzi a, tarabini c, collura m, et al. hemodynamics of sapheno-popliteal junction: colour-flow duplex investigation. phlébologie 2002;55:309-16. [article in french]. 21. theivacumar ns, dellagrammaticas d, beale rj, et al. fate and clinical significance of saphenofemoral junction tributaries following endovenous laser ablation of great saphenous vein. br j surg 2007; 94:722-5. 22. theivacumar ns, darwood r, gough mj. neovascularization and recurrence 2 years after varicose vein treatment for saphenofemoral and great saphenous vein reflux: a comparison of surgery and endovenous laser ablation. eur j vasc endovasc surg 2009;38:203-7. 23. cappelli m, molino lova r, ermini s, zamboni p. hemodynamics of the sapheno-femoral junction. patterns of reflux and their clinical implications. int angiol 2004;23:25-8. 24. capelli m, molino lova r, ermini s, et al. hemodynamics of the sapheno-femoral complex: an operational diagnosis of proximal femoral valve function. int angiol 2006;25:356-60. 25. rass k, frings n, glowacki p, et al. comparable effectiveness of endovenous laser ablation and high ligation with stripping of the great saphenous vein. two-year results of a randomized clinical trial (relacs study). arch dermatol 2012;148: 49-58. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2015; volume 4:5098 [veins and lymphatics 2015; 4:5098] [page 29] venous anomalies as potentially lethal risk factors during ordinary catheterization savino occhionorelli,1 sergio gianesini,1 lorenzo marinelli,2 marianna daniele,2 sara chierici,2 paolo zamboni1 1vascular disease center, university of ferrara; 2department of forensic medicine, university of ferrara, italy abstract venous malformations are rare but possible findings too, constituting a further risk factor for central venous catheter procedures. herein we describe a case of death because of an innominate vein perforation by a catheter that incidentally was tucked into a sacciform malformation. even if the technology advancement is constantly offering us new investigation tools, up to now diagnostic options are limited in the detection of those malformations that could potentially lead to dramatic complications as the described one. the present work raises the awareness about rare venous anomalies and their potential clinical implications. a proper literature review and diagnostic implementation proposal are reported. introduction nowadays, central venous access (cva) is used on a daily basis worldwide.1 the seldinger technique for the access has demonstrated to be safe and easy.2 nevertheless, rare but possible mechanical severe complications have been reported.3 venous malformations are rare but possible findings too, constituting a further risk factor for cva-induced complications.4 we herein present an unlucky case of death because of a innominate vein perforation by a catheter that incidentally were tucked in a sacciform malformation. related review of the literature is reported. case report a 77-year old female was scheduled for revision of an excessively shunting brachiocephalic dialysis-access. her anamnesis reported atrial fibrillation with warfarin prophylaxis, dilatative and hypertensive right cardiomyopathy, sjögren syndrome, chronic renal failure leading to a dialytic treatment since 7 years before. a neck venous doppler ultrasound (dus) investigation was performed in order to evaluate the feasibility of cva placement. the scanning revealed a right internal jugular vein (ijv) thrombosis and a physiological left venous district. while waiting for the scheduled arteriovenous-fistula revision, after the administration of 500 iu of human prothrombin complex because of a 2.01 international normalized ratio value, an echo-guided quintontm catheter (11 fr; covidien ag, dublin, ireland) placement was performed on the left ijv by means of a standard seldinger technique. the echoguide was kept all along the vein poking and guidewire positioning, in order to verify the procedure correctness. the catheterization was performed by an expert anesthesiologist. after the guide wire placement the catheter was introduced, finding a moderate resistance after just a few centimeters. the catheter was than retracted and easily positioned at the second try. the final correct catheter position was confirmed. some minutes later the patient begun to wag and to pale, suddenly turning pulseless but with a normal cardiac activity, as testified by the constant electrocardiogram monitoring. despite immediate cardio-pulmonary resuscitation (cpr), asystole occurred. atropine and adrenaline were administered, together with red blood cells. initially the patient responded, while an emergent x-ray demonstrated a massive hemothorax. the computed tomography revealed a left subclavian vein leakage on the posterior surface. an emergent angiography was performed, detecting a bleeding from the left innominate vein. a vacs ii balloon catheter (osypka ag, rheinfelden-herten, germany) was positioned in correspondence of the leaking point, so stopping the active bleeding. despite the procedure and the massive cpr (atropine 4 vials, adrenaline 6 vials, saline solution and colloids 6000 cc, red blood cells 8 iu to counteract a hemoglobin lowest level of 4.3 g/dl) the patient was declared dead 2 h after the cva placement, without even the time to undergo an emothorax drainage. the autopsy revealed an innominate vein venous malformation that was located 3.8 cm distally to the cva insertion point, at 1.2 cm from the ijv-innominate vein confluence. the venous anomaly was a circular aneurismal like dilation, presenting a 0.9 cm diameter and a 0.7 cm depth. at its caudal margin a 0.3 cm long linear full-thickness perforation was detected (figure 1). the forensic scientist report analyzed the adverse event that occurred (the innominate vein rupture), pointing out both the unpredictability and inevitability of the fact. no further legal actions were undertaken. discussion and conclusions as testified by their worldwide use, cva options have significantly improved the treatment chance and quality of a significant number of patients.3,4 nevertheless, since it is very beginning, cva use has been linked to rare but potentially severe complications.5 according to the literature, mechanical adverse events include arterial puncture (5%), catheter malposition (4%), catheter unsuccessful placement (4%), subcutaneous hematoma (1%), cardiac arrest (less than 1%), pneumothorax (1%), hemothorax (1%).3,6 aspirating blood from the catheter must be considered as not the only needed sign for correct placement: the catheter tip could be outside the vein, draining a blood collection caused by the vessel injury. for this reason infusion rates and diminished outflow from the catheter are adjunctive signs to be taken in immediate consideration. venous malformations represent an intriguing topic, often underestimated in its epidemiology. according to the literature this condition can be present as structural/morphological and hemodynamic/functional anomalies with an incidence of 1.2.7,8 as initially reported by gadallah in 1995, awareness of venous malformations is a key element prior to whatever catheterization.4 as pointed out by this forensic scientist report, up to now the diagnostic options are unluckily limited in the detection of such increased risk elements, while no specific correlations have been reported among specific anamnesis and the described venous anomaly. correspondence: sergio gianesini, vascular disease center, university of ferrara, via aldo moro 8, 44128 cona (fe), italy. tel.: +39.349.8012304. e-mail: sergiogianesini@hotmail.com key words: venous malformations; cerebral venous return; central venous catheters. received for publication: 8 march 2015. revision received: 24 april 2015. accepted for publication: 27 april 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s. occhionorelli et al., 2015 licensee pagepress, italy veins and lymphatics 2015; 4:5098 doi:10.4081/vl.2015.5098 no n c om me rci al us e o nly case report [page 30] [veins and lymphatics 2015; 4:5098] nevertheless the technology advancement is constantly offering us new investigation tools. in this contest we can postulate that an emerging role of intra-venous ultrasound (ivus) could happen in the near future. this investigation technique is already available in the highly specialized vascular centers, where it demonstrated to be as effective as a traditional dus in the detection of venous wall anomalies.9 the herein described case suggests the need of changing the inevitability and unpredictability of this kind of lethal adverse event in a so common procedure. surely not removing a not performing catheterization before further diagnostic assessments is the first advice to avoid immediate bleeding from an alternatively patent perforation.10 the awareness of the described possible vascular malformations opens a discussion regarding the emergent diagnostic protocols, eventually giving direct access to the angiographic suite once a bleeding is detected. another aspect to be taken into consideration from now on is the opportunity to access the jugular vein while the contralateral is obstructed. further investigations are suggested to evaluate the choice of an adequately soft and flexible tip and an immediate routine x-ray control could be integrated by an accurate sonographic assessment, with or without contrast media, and/or an ivus assessment to avoid a catastrophic scenario. references 1. o’grady, naomi p. guidelines for the prevention of intravascular catheter-related infections, 2011. atlanta, ga: healthcare infection control practices advisory committee; centers for disease control and prevention; 2011. available from: http://stacks.cdc.gov/view/cdc/5916/ accessed: 6 february, 2014. 2. higgs zc, macafee da, braithwaite bd, et al. the seldinger technique: 50 years on. lancet 2005;366:1407-9. 3. eisen la, narasimhan m, berger js, et al. mechanical complications of central venous catheters. j intensive care med 2006;21:40-6. 4. gadallah mf, white r, vickers b, et al. awareness of internal jugular, subclavian, superior vena cava and femoral venous anomalies may reduce morbidity of acute venous catheter procedures. clin nephrol 1995;44:345-8. 5. apps mcp, clark jmf, skeater sj. hydrothorax, a complication of the insertion of central venous cannulae. intens care med 1977;3:41-3. 6. bardosi l, mostafa sm, wilkes rg, et al. contralateral haemothorax: a late complication of subclavian vein cannulation. br j anaesth 1988;60:461-3. 7. tasnadi g. epidemiology and etiology of congenital vascular malformations. semin vasc surg 1993;6:200-3. 8. lee bb, baumgartner i, berlien p, et al. diagnosis and treatment of venous malformations. consensus document of the international union of phlebology (iup): updated 2013. int angiol 2014 [epub ahead of print]. 9. scalise f, farina m, manfredi m, et al. assessment of jugular endovascular malformations in chronic cerebrospinal venous insufficiency: colour-doppler scanning and catheter venography compared with intravascular ultrasound. phlebology 2013;28:409-17. 10. gibson f, bodenham a. misplaced central venous catheters: applied anatomy and practical management. br j anaesth 2013; 110:333-46. figure 1. innominate vein doppler ultrasound-not detectable saccular malformation where the catheter tip were tucked in, causing the vessel perforation. no n c om me rci al us e o nly hrev_master veins and lymphatics 2016; volume 5:5992 [page 24] [veins and lymphatics 2016; 5:5992] compression and sports jean-patrick benigni french university group for medical compression, saints peres university, paris, france introduction sportsmen are healthy people who theoretically do not suffer from disabling chronic venous disorders. in these subjects, wearing compressions is not helpful. but the search for a better performance pushed the sporting world to look for devices that can improve muscle performance especially at the calf. the use of compression stockings (cs) is widespread. their usefulness should be demonstrated. this is the purpose of this abstract. the expected effects of wearing compression stockings during or after sport are: i) improved performance and recovery; ii) acceleration of blood flow; iii) increase of oxygen supplied to the muscles; iv) elimination of toxins. clinical studies of sports performance evidence from clinical trials is paradoxically poor. only one study showed an improvement of performance after sub maximal running.1 it studied the contribution of cs after a run on a treadmill. jump height has been improved with less fatigue and better feeling of comfort. after short duration sprints from 10 to 60 m, no real improvement on performance could be shown.2-5 in endurance racings, only one study3 showed a discreet effect of cs (18-20 mmhg) after running on the treadmill, the running time and lactate levels. all other studies6-9 did not show a conclusive difference (cycling, running and netball). a compression garment on the upper body10 also did not show improved performance among kayakers. effects on paraclinical parameters during endurance races,11 no significant difference in vo² max, blood lactates and o² consumption was found. concerning the cardio-respiratory function, one study showed a significant effect on oxygen consumption, o2 pulse, and local blood flow. however, these improvements appear trivial to athletes, as they did not correspond to any improvement in endurance running performance. other published studies did not find any particular effects.12-14 concerning temperature, 3 studies2,7,15 showed that wearing cs increased skin temperature but not body temperature. effects on proprioception and muscle oscillations a study16 demonstrated improved proprioception, which can be explained by stimulating cutaneous receptors and decreasing muscle oscillations during vertical jumps. but such findings are questionable among runners. clinical studies during recovery during the recovery phase after a race of endurance there is clearly a positive effect on symptoms (fatigue, swelling, muscle pain) if cs are worn during the race.13,17,18 positive effects of cs, wearing on the post-exercise pain, persist for 48 to 72 h after exercise. wearing cs also improves muscle performances during the recovery phase with positive effects on jump height 24 to 96 h after exercise. effects on lactate in a study,19 the authors compare the kinetics of lactate wearing a cs (18 mmhg at the ankle and 8 mmhg at the calf) versus no cs. under cs, 15 min after exercise, the lactate levels were lower with cs than without cs. but if cs are removed just after the effort, lactate levels were higher in the cs group than in the group without cs. this means that cs retained lactate in the muscle. after a marathon in a case-control study,20 after a marathonrun the authors showed a positive effect of wearing cs for 48 h on muscle fatigue and swelling. a surprising finding a recent study21 demonstrates that wearing cs reduces muscle oscillations and inflammatory lesions assessed by muscle biopsy 48 h after a race of 40 min on a treadmill. these data could explain the beneficial effects of cs observed during recovery. what can we conclude from these studies? published studies are very different and it is difficult to give clear conclusions. it seems obvious that cs wearing has no effect on performance during a sprint. the effects appear marginal during an endurance effort. however, there is sufficient evidence to claim that cs wearing has an effect on pain during recovery up to 48 h after exercise. the exact mechanisms are discussed (reduction of inflammatory lesions, improving venous flow, etc.). new studies are needed among amateur runners to study new generations of cs. partsch and mosti22,23 have shown that in venous patients conventional graduated cs improve the calf muscle pump slightly, but that higher pressure over the calf (progressive cs) is more effective. similarly, stiff bands wrapped over the calf with a pressure of 30-40 mmhg narrow deep veins and lead to an increase of the ejection fraction of the calf pump in healthy sports people. references 1. rugg s, sternlicht e. the effect of graduated compression tights, compared with running shorts, on counter movement jump performance before and after sub maximal running. j strength cond res 2013;27:1 067-73. 2. doan b, kwon y, newton r, et al. evaluation of a lower body compression garment. j sports sci 2003;21:601-10. 3. kraemer w, bush j, newton r, et al. influence of a compression garment on correspondence: jean-patrick benigni, french university group for medical compression, saints peres university, 45 rue des saints pères 75005 paris, france. e-mail: benigni.jp@orange.fr this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright j-p. benigni et al., 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5992 doi:10.4081/vl.2016.5992 no n c om me rci al us e o nly conference presentation [veins and lymphatics 2016; 5:5992] [page 25] repetitive power output production before and after different types of muscle fatigue. sports med training rehabil 1998;8:16384. 4. uffield r, portus m. comparison of three type of full-body compression garments on throwing and repeat-sprint performance in cricket players. br j sports med 2007;41:409-14. 5. faulkner ja, gleadon d, mclaren j, jakeman jr. effect of lower-limb compression clothing on 400-m sprint performance. j strength cond res 2013;27:669-76. 6. sperlich b, haegele m, achtzehn s, et al. different types of compression clothing do not increase sub-maximal and maximal endurance performance in well-trained athletes. j sports sci 2010;28:609-14. 7. higging t, naughton g, burgess d. effects of wearing a compression garment on physiological and performance measures in a simulated game-specific circuit for netball. j sports sci 2009;12:223-6. 8. berry m, mcmurray r. effects of graduated compression stockings on blood lactates following an exhaustive bout of exercise. am j phys med 1987;66:121-32. 9. scalan a, dascombe b, reaburn p, osborne m. the effects of wearing lower body compression garments during endurance cycling. int j sports physiol perform 2008;3:424-38. 10. dascombe b, laursen p, nosaka k, polglaz e. no effect of upper body compression garments in elite-flat-water kayakers. eur j sport sci 2013;13:341-9. 11. born d, sperlich b, holmberg h. bringing light into the dark: effects of compression clothing on performances and recovery. int j sports physiol perform 2013;8:4-18. 12. dascombe b, hoare t, sear j, et al. the effects of wearing undersized lower-body compression garments on endurance running performance. int j sports physiol perform 2011;6:160-73. 13. mac rae ba, cotter jd, laing r. compression garments and exercise, garments considerations, physiology and performance. sports med 2011;41:815-43. 14. sperlich b, haegele m, krüger m, et al. cardio-respiratory and metabolic responses to different levels of compression during sub maximal exercise. phlebology 2011;26:102-6. 15. houghton la, dawson b, maloney sk. effects of wearing compression garments on thermoregulation during simulated team sport activity in temperate environmental conditions. j sci med sport 2009;12:303-9. 16. kraemer w, bush j, newton r, et al. influence of a compression garment on repetitive power output production before and after different type of muscle fatigue. sports med training rehabil 1998;8:16384. 17. ali a, creasy r, edge j. the effect of graduated compression stockings on running performance. j strength cond res 2011;25:1385-92. 18. jakemann j, byrne c, eston r. lower limb compression garment improves recovery from exercise induced muscle damage in young, active females. eur j appl physiol 2010;109:1137-44. 19. berry m, mcmurray r. effects of graduated compression stockings on blood lactates following an exhaustive bout of exercise. am j phys med 1987;66:121-32. 20. allaert fa, gardon-mollard c, benigni jp. effect of compression stockings (18-21 mmhg) on muscular adaptation and recovery of the marathoners. phlébologie 2011;64:57-62. 21. borràs x, balius x, drobnic f, et al. effects of lower body compression garments in muscle oscillation and tissular injury during intense exercise. muscles ligaments tendons j 2014;3:295-302. 22. partsch h, mosti g. the progressive medical cs increase the capacity of the venous pump of the calf than the conventional graduated cs. phlébologie 2012,65:13-8. 23. partsch h, mosti g. sport socks do not enhance calf muscle function but inelastic wraps do. int angiol 2014;33:511-7. no n c om me rci al us e o nly hrev_master veins and lymphatics 2017; volume 6:6624 [veins and lymphatics 2017; 6:6624] [page 5] velcro compression devices joseph a. caprini university of chicago, pritzker school of medicine, chicago, il, usa leg swelling can occur from obstruction of the veins or venous reflux, resulting in increasing the volume of blood in the leg. this increases pressure in the capillaries causing them to dilate and, as this process continues, the endothelium cracks. the combination of slow flow in the capillary due to increased pressure and the endothelial damage causes white cells along with activated hemostatic elements to obstruct the capillary. no longer is there exchange of nutrients and waste products through the capillary membrane, so the area normally supplied by these capillaries becomes ischemic. tissue necrosis may slowly occur resulting in skin ulceration. correction of leg swelling is not easy in many patients when the process is severe and has persisted for a long time. selection of the proper compression modality is critical to achieve a successful result. compression for this purpose includes both elastic and inelastic compression modalities. elastic long-stretch compression is characterized by a high resting pressure, which may be uncomfortable over time. when the patient ambulates, a low ambulatory pressure results since the bandage gives way with walking and edema increases.1 the static stiffness index for elastic compression is less than 10 mmhg and this may be defined as the difference between the under bandage pressure in the lying vs standing position.2 elastic bandages and stockings of various strengths are typical long-stretch products. they may suffice for mild swelling but are inadequate for patients with advanced leg edema. inelastic or short-stretch compression products feature low resting pressure, which is comfortable at rest. as the patient stands and walks the pressure underneath the bandage increases, resulting in a decrease in edema as blood is pumped out of the leg. the rigid nature of the bandage produces this effect and the static stiffness index is greater than 10 for a good short-stretch compression product. typical examples include a paste bandage (unna’s boot), short-stretch bandages and velcro devices. the fourlayer bandage consists of elastic products but when they are wrapped over one another they produce a similar effect to a good short-stretch bandage. a two -layer system is also an option.3 the initial compression treatment of the patient with leg swelling should consist of a good short-stretch product. when the edema is reduced, one of the best methods to maintain this effect and prevent recurrence is a proper velcro device. these devices use short-stretch material which achieves a high working pressure and are quite comfortable at rest. as leg edema is further reduced with these devices the straps can be tightened to maintain a good compression effect. these products are usually worn over a light stocking or hybrid liner with foot compression only. in most cases the static stiffness index will exceed 20 mmhg and may be much higher depending on the tightness of the device.4 indications for these velcro devices include patients having difficulty donning or doffing stockings due to advanced age, decreased hand and arm strength, the presence of arthritis or restricted mobility from obesity or advanced pregnancy. they are also very useful to prevent postoperative swelling after joint replacement as well as to reduce swelling in the preoperative patient. they are ideal for those suffering from lymphedema of the lower extremity. patients with a large abdominal girth have increased venous pressure due to increased intra-abdominal pressure which may exceed 50 mmhg in some patients. the standard 30 to 40 mmhg stockings are unable to reduce swelling, pain and discomfort due to their elastic properties, and are extremely difficult to apply and remove especially in the obese patient. poor compliance in these patients due to the above-mentioned factors results in further increased leg swelling, venous stasis and increased fragility. finally, a point is reached when the stockings no longer even fit due to the increased size of the legs. some patients in addition to using the velcro devices on the calf, will require velcro foot compression for swelling. most patients with slight foot swelling can wear hybrid stockings under the calf velcro device. these hybrid stockings are popular and feature 20 mm foot compression and negligible leg compression. patients are encouraged to wear good, laced shoes to help control the swelling.5 velcro devices are a good alternative to compression bandaging in some patients with leg ulcers. they have shown to be effective for ulcer healing and have several advantages compared to bandages. the patient can remove these devices daily for cleansing of the wound and dressing changes. one manufacturer has a unique system to adjust velcro pressures using a simple measuring system. this device can be fitted in the office and tailored to the individual patient without the need for special fitting at an outside facility. this may represent an economic advantage for the patient as well as the treating physician. follow-up care once the ulcer is healed is simplified as long as the patient is compliant with wearing their velcro devices.6 mixed arterial and venous insufficiency occurs in at least 25% of patients and these individuals have reduced ankle pressures as well as swollen legs. use of elastic products on these legs may be hazardous due to the high resting pressure which may further compromise the leg circulation. velcro compression devices are ideal for this type of patient as they provide a low resting pressure and high working pressure. they are easily adjusted to tighten or loosen depending on the patient’s tolerance and symptoms such as pain, numbness or tingling. they can be used as long as the resting pressure of the velcro device is less than the systolic pressure at the ankle. arterial inflow may actually increase due to the decrease in venous volume and pressure of the leg allowing improved arterial perfusion.7 patients requiring major arterial revascularization such as open femoral popliteal bypass procedures often suffer from reperfusion leg edema. this swelling can result in breakdown of the incisions leading to infection and eventual graft rejection. the use of velcro devices in these situations is an ideal way to control the swelling in a safe manner without compromising the newly re-vascularized limb. patients requiring major leg resection for cancer often suffer from significant swelling including lymphedema after lymph node dissection. velcro devices are a very valuable adjunct for these individuals. another important management problem occurs in patients who have life-threatening leg infection requiring major resection of the tissues. the long-term control of healed wounds and leg swelling is greatly facilitated using velcro devices. in conclusion, we feel it is very important for practitioners to understand the basic principles concerning leg swelling and the characteristics of different compression products. practitioners dealing with these patients should learn when stockings are not correspondence: joseph a. caprini, university of chicago, pritzker school of medicine, chicago, il, usa. e-mail: jcaprini2@aol.com this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright j.a. caprini, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6624 doi:10.4081/vl.2017.6624 no n c om me rci al us e o nly conference presentation [page 6] [veins and lymphatics 2017; 6:6624] appropriate and be familiar with the shortstretch products that may achieve success. velcro compression appliances should be considered in patients who fail standard support stockings. some patients who should not be prescribed stockings include noncompliance due to donning or doffing issues, failure to control swelling, morbid obesity, and patients with arthritis and decreased flexibility which may occur with advanced age. patients with mixed arteriovenous insufficiency are excellent candidates for these devices as are those having joint replacement or major leg surgery for infection or cancer. they may also be effective as an alternative treatment to compression bandages for selected leg wounds. references 1. mosti g, mattaliano v, partsch h. inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous reflux. phlebology 2008;23:287-94. 2. partsch h. the static stiffness indexa simple method to assess the elastic property of compression material in vivo. dermatol surg 2005:625-30. 3. mosti g. comparing 2 bandages in ulcer healing. wounds 2011;23:126-34. 4. mosti g, mattaliano v, partsch h. inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous reflux. phlebology 2008;23:287-94. 5. mosti g, cavezzi a, partsch h, et al. adjustable velcro compression devices are more effective than inelastic bandages in reducing venous edema in the initial treatment phase: a randomized controlled trial. eur j vasc endovasc surg 2015;50:368-74. 6. depalma rg, kowallek d, spence rk. comparison of costs and healing rates of two forms of compression in treating venous ulcers. j vascular surgery 1999;33:683-90. 7. mosti g. compression in mixed ulcers. veins and lymphatics 2016;5:5986. no n c om me rci al us e o nly hocaoglu c. clozapine-induced rabbit syndrome: a case report a history of sclerotherapy francesco ferrara objective just how useful can be a study into the history of sclerotherapy is not dictated by mere curiosity but rather by the need to find a scientific model which can help develop clinical method. this means looking for an overall vision of fundamental principles and assumptions that can explain the technical choices and options offered by sclerotherapy and that can guide their development. that means defining an evolutionary rationale capable of understanding and calculating how sclerotherapeutic methods should be developed. materials and methods the search for a scientific model was made through examination and analysis of historical documents (tables 1 and 2) according to philosophical scientific methods. this type of approach is much pertinent to the field of medicine than, for example, the philosophy of law is part of the expertise of someone who works in the field of legal science. in fact, it allows the physician to evaluate the nature of the scientific model, methods of treatment and their effects and efficacy. this process can be compared to a compass that can help us navigate between different scientific proposals. but the compass needle needs to be drawn in a specific direction and in the field of medical and scientific research it is historiography that provides the necessary magnetism. in fact, historiography is the interpretation of historical events with the aim of identifying valid reference and pertinence to current ethical and behavioral choices. table 1. from the origins to the discovery of the circulation. table 2. the documents: after the discovery of blood circulation. discussion our question is, what type of historiographic investigation, or what method of historical analysis, should be used to validate the construction of the scientific model? among the many available we have chosen the method of the phases of science proposed by thomas samuel kuhn (1922–1996) that has been widely used in the biomedical field. in his analysis of a historical journey/development/narrative of a technique or a scientific discovery kuhn identified 5 phases: i. phase 0 or the pre-paradigmatic phase phase 0 or the pre-paradigmatic phase is that in which artistic inspiration dominates over scientific inspiration due to the obvious lack of a system of technically and scientifically accepted principles. we can call this the period of ancient and medieval sclerotherapy, in line with the related historical eras. ancient sclerotherapy from its origins to the surgery congress in lyons in 1894. the origins of the art of therapeutic veins thrombosis date from the 4th century bc and come from incidental reports. hippocrates reports an ulcer being healed after a thrombosis, perhaps due to iatrogenic infection, in the affected vein. a similar experience was reported on a dog in 1642 by etmüller, and in 1667, on a man by elshortz who had made repeated attempts to use a hollow bone to cannulate a vein in order to introduce pharmacological substances. it was only in the 19th century that hodgson (1788-1869) had the idea of suppressing the blood flow in a vein during a thrombotic event. but it was home who, on 16th september 1825 in chelsea hospital, was the first to carry out a thermal percutaneous thrombosis of an aneurism by introducing a heated needle in the external iliac artery. the method was used for the first time in the field of phlebology by palasciano at the ospedale incurabili in naples in 1851. instead of heat, he used a galvanic current delivered to the upper leg through the large saphenous vein by two crossed needles that pierced the blood vessel. the same year, pravaz (1791-1853) in lyons, using a syringe of his own invention, thrombosed an aneurism by injecting iron perchloride. however, the first venous sclerosing injection was performed in paris in 1853 by chassignac. use of the method soon spread thanks to the efforts of the two groups in lyons and in paris. the principal members of the lyons group were valette, petrequin, soquet, desgranges and guillermand. they proposed the use of iodotanic liquid as sclerosing agent. in italy, the leading figures in this field were porta (1800-1875), who used chloral hydrate, and schiassi, who in 1908 suggested the use of intraoperative sclerotherapy during venous ligation with iodinated solutions (potassium iodide). septic and phlebotic complications were common and the surgery congress in lyons in 1894 banned the use of sclerotherapy. this is a date worth remembering. just as the fall of the roman empire in 476 ad signaled the end of the ancient world, so the surgery congress in lyons signaled the end of the era of ancient sclerotherapy and opened the doors to....... the middle ages of sclerotherapy everyone knows that the first part of the middle ages was dominated by the bigoted fear of imminent universal catastrophe. this is a useful analog for our discussion because it gives the idea of how, at the dawn of the 20th century, the fear of provoking pulmonary embolism and other complications was widespread. in spite of this, delore continued to defend the use of sclerotherapy declaring, with visionary insight, that its mechanism of action was to harden the vein and not thrombose it. but a new age also began for phlebology and it was precisely in 1916 that linser accidentally discovered that an injection of salvarsan hardened the veins without any important thrombotic element. delore’s prophetic innovation, ignored as it was at first, became clinical evidence in those young men who were saved from the agonies of syphilis only to be sacrificed in an absurd war. they called it simply the great war, before they were forced to number it by the wave of fanaticism and murderous fury that swept out of germany and which, only decades later, devastated the whole of europe. the evils that gave it birth fed the melting pot of the 1920s, followed by crisis and a degeneration of ethical values. these years did, however, see a happy return to the use of sclerotherapy thanks to the ingenious activity of sicard (1872-1929) and his school. already in 1920, together with paraf, forestier and gaugier, sicard used sodium carbonate as a sclerosing agent in blood vessels. he went on to perfect the technique using sodium salicylate in 1922 thanks to the assistance of other young students such as delater, july, filderman, humbert and a certain raimond tournay, who had already stepped into the limelight in 1928 for his proposed method of thrombotic evacuation. in 1932, the madrid congress of the international society of surgery officially rehabilitated sclerotherapy. this was an unexpected and important development and it signaled the end of the dark middle ages. ii. phase 1 is known as the acceptance of the paradigm kuhn believed that the pre-paradigmatic phase is followed by that in which the collection of theories and methods that defined an acceptable course of conduct is articulated and called paradigm. continuing our comparison with historical periods, this phase can be said to correspond to the modern age that opens with the renaissance. the ancient and medieval technique of sclerotherapy was, case by case, an improvised technique using subjective intuition. this differed from doctor to doctor who sometimes used contradictory approaches; some performed the injection using a tourniquet, while others banned its use, some who carried out the technique on patients with their legs raised and others with their legs hanging down, some with the patient standing, or starting with the biggest veins or those lowest down or even allowing the patient to choose which veins to intervene on first! finally, there were some doctors who added heparin to the sclerosing agent such as savonuzzi e cavallini. in its renaissance period in the 1940s, three well-defined and codified methods or paradigms (according to kuhn) of sclerotherapy were developed. the key players in their development were tournay in paris (1893-1984), karl sigg in basle (1912-1987) and fegan in dublin (1921-2007). these three methods were accepted and introduced by phlebologists everywhere with the exception of the usa. sclerotherapy had been introduced into the us by dixon in 1928 at the mayo clinic. but after 10 years of disappointing results the technique was abandoned. in fact, sclerotherapy was adopted mostly in france, italy and switzerland. iii. kuhn called phase 2 the phase of normal science this was the period in which most related scientific articles were produced. this led to knowledge of the technique becoming more widespread. it was during this period that most of the sclerosing agents, many still in use today, were first introduced into clinical practice (figure 1). only three paradigms dominate over all the others because they reflect with precision the three fundamental classes of scientific speculation: rational, practical and critical. the rational method is typical of deductive logic as exercised by aristotle and cartesium. it privileges the application of a universal principle to the individual context. this was the method adopted by tournay. in fact, it was he who raised the experience of trendelenburg (the theory of the descending vessels) to a universal principle that proposed to use sclerosis to occlude only the saphenic reflux, thus suppressing venous hypertension and with it most of the varicosis. sigg held a different view. he did not recognize the value of a universal principle in determining varicosis. he, therefore, adopted the inductive logic of bacon and galilei who used practical experience as a basis on which to develop general rules (not to the universal principles of the rationalists). sigg preferred to suppress first of all the veins, the only practical way to guarantee that every reflux would be controlled wherever it was located. sigg developed his assumption through simple rules that today we would call recommendations: injection in the drained vein, with an uplifted limb and immediate elastic compression. everyone knows that the old conflict between rationalists and empiricists was only laid to rest when kant introduced criticism; with his i the legislator he perceived the need to criticize the same empirically perceived faculties of reasoning as he would any piece of evidence. this teaching inspired fegan who continued on both the principles of trendelenburg and the rules of sigg. he did not believe that varicose veins were the result of venous hypertension, nor did he relegate the saphenous-femoral reflux to a mere effect of the veins. he proposed sclerotherapy of the perforators and raised the turbulent flow generated by their reflux to the realms of primum movens in the pathogenesis of varicosis (ascending theory). in paris in 1947, tournay founded the first phlebological society. during the meeting of 28 february 1948, he outlined a new professional figure called the phlebologist. whether he or she was to be considered a specialist or not, the field of interest of this new figure would be venous and circulatory diseases of the extremities. more and more meetings were organized with ever-growing numbers of people taking part. this growing interest led to the launch of the first journal, phlebologie. as the journal became better known, the first international congresses were organized which, in turn, required the support of other societies. the first was founded in italy in 1953 with bassi and comel. this was followed by other societies being formed in belgium in 1957 with van der molen, in germany with olsen, krieg and jaeger, in switzerland in 1961, in canada in 1973, in argentina in 1975, in japan in 1981, in the usa in 1985 and in australia in 1993. this normal science period saw both successes and failures. according to kuhn, these failures are to be considered abnormalities or events that go against the efficacy of the paradigm. figure 1. diffusion and development of sclerosing agents. iv. in phase 3 the researcher comes up against the abnormalities when the failure is particularly stubborn or obvious, the abnormality can throw into doubt techniques and methods that had been consolidated by the paradigm. v. phase 4 is the crisis of the paradigm in this period, different paradigms are created. these are developed not from the results obtained from the previous theory, but only from the abandonment of pre-constituted schemes of the dominant paradigm. this is what happened with the revolutionary introduction of foam, which if we want to look for a historical comparison we can compare to the french revolution, since this also marks the end of the modern age of sclerotherapy in the year 2000 and opens the new era of contemporary sclerotherapy. vi. phase 5 is that of the extraordinary science or the scientific revolution the paradigms that form part of this revolution do not share the rational foundations of the previous convalidated principles and are not, therefore, comparable even among themselves. in such a context, the choice of the new paradigm, according to kuhn, is not supported by solid methodology. it arises rather from social and mediatic foundations that are promoted by class, power and economic interests, and is thus beyond the control of scientific societies or by the scientific community itself. in fact, when this happens, the scientific community soon stops considering themselves part of it. the societies lose their scientific value and become just simple professional corporations or, even worse, become servile fig leaves, destined to cover up the shameful occult market interests. the sequence set out by kuhn demonstrates in synthesis a sharp backward step towards the pre-paradigmatic phase 0. we will not allow all this to happen to our sclerotherapy! the new experiences must, therefore, be developed in consideration of the logical classes of paradigms that have already been convalidated. results verify the efficacy of the scientific model and move among the different new paradigms. on its own, is the well-known greater efficacy of foam enough to convalidate the greater superiority of any technique with scleromousse, with respect to the three ancient, paradigmatic and accepted methods that use liquid? this presumed superiority is thought of as a destabilizing element in the journey undertaken by kuhn. in our experience, we have seen that the efficacy of sclerotherapy is directly proportional to the possibility of compressing the vein. that being said, we have seen the need to use compression support with sclerotherapy of the saphenous trunks, particularly in large limbs. therefore, a sort of compression crossectomy was introduced using a particular compression medication called safeguard. this is applied for 3 days after the sclerosis of the saphenous trunks on the site of the saphenofemoral or popliteal junction. with this innovation, while not running the risk of adventurous physical hypotheses about the mechanism of compression which has not been convalidated by any previous experience, we can draw directly from tournay and recognize the rational principle of not allowing the wash-out of cross reflux to destabilize the sclerosis of the trunk, obtained with our usual technique according to sigg. this strategy (known as hippocampal sclerosis or hcs) has improved results in the use of both sclerosing liquids and foams without showing mousse to have any superior efficacy. while not questioning the undoubted theoretical superiority of foam, the destabilizing effect of its introduction into therapeutic practice has been normalized by the management of the research carried out throughout the evolutionary phases of the scientific model. in fact, this requires the transition from the revolution in phase 5 (extraordinary science) to phase 1 (ordinary science) without falling back into the dark mists of phase 0 (pre-paradigmatic). conclusions we cannot propose a technique (with or without the support of evidence-based medicine or ebm, and with or without striking results) taken out of the context of a logic that can be defined with a scientific model. its use would be desirable in every aspect of the scientific evolution of sclerotherapy, but above all in the sector that has fallen most behind, that of pharmacological research. it is here that the lack of a scientific method has been felt most. it is enough for us to look carefully at the graph presented in figure 1. the introduction on the market of sclerosing agents currently in use dates from the 1940s-1960s. this means that we are still stuck back in the renaissance! references 1. ferrara f. sclérothérapie: ma méthode. angéiologie 2010;62:78-82. 2. ferrara f. histoire de la phlébologie rassegna monografica. phlébologie 2008;61:119-24.[abstract] 3. kuhn ts. the road since structure: philosophical essays, 1970-93. chicago: university of chicago press, 2000. 4. genovese g, tori a, donadi gc. flebologia ieri ed oggi. milano: nuove edizioni; 1994. 5. kuhn,ts. the function of dogma in scientific research. pp. 347-69. in: a.c. crombie (ed.). scientific change (symposium on the history of science, university of oxford, 9–15 july 1961). new york and london: basic books and heineman; 1963. 6. kuhn ts. the structure of scientific revolutions. chicago: university of chicago press; 1962. [top] hrev_master veins and lymphatics 2015; volume 4:5141 [veins and lymphatics 2015; 4:5141] [page 31] sclerofoam assisted laser therapy for saphenous refluxes: an innovative tumescence-free technique francesco zini,1 lorenzo tessari,2 renato torre3 1surgical department, casa di cura città di parma, parma; 2glauco bassi foundation, trieste; 3casa di cura privata, piacenza, italy abstract endovenous laser (el) and radiofrequency devices have continuously increased their appealing in the last decade. even if miniinvasive, such procedure still requires multiple high volume injections of tumescent anesthesia: a medical act that is not totally complications-free. aim of the present investigation is to evaluate the feasibility of a hybrid technique (so called sclerofoam assisted laser therapy, sfalt) combining foam sclerotherapy (fs) and el in a tumescence free approach. fourty primary chronic venous disease patients (8 males, 32 females, c2-4epaspr) presenting a sapheno-femoral reflux both at the valsalva and compression/relaxation maneuver underwent a sfalt procedure. diameters were measured at mid-thigh in supine. it consists in a el fiber introduction into the great saphenous vein (gsv), shrinking it for a single cm at 200 j/cm. after a shrunk plug is created, keeping the fiber stuck in it, 5 cc of foam sclerotherapy [tessari method, 1% polidocanol (pol) or 1% sodium tetradecyl sulfate (sts)] are injected through the same 6 fr el introducer. the consequent spasm allows a following el mediated shrinkage by means of a significantly reduced fluence. clinical and sonographic follow up were performed at one and three weeks. at 3 weeks follow up all the 40 cases presented a shrunk gsv, without recanalization signs. neither major nor minor complications were reported. at the mid-thigh the standing gsv caliber decreased from a preoperative mean value of 0.6±0.2 cm to a post fs injection 0.3±0.1 cm value (p<0.05), showing no statistical difference among sts and pol. sfalt approach is feasible, safe and with potentially interesting outcomes. more investigations are needed in order to define the proper fluence parameters and the chance of eliminating the even mild sedation. this technique offers the chance of a possible tumescence free gsv treatment, even in case of major calibers vessels. introduction endovenous laser (el) and radiofrequency (rf) devices have continuously increased their appealing in the last decade, so much to be recommended with a 1b grade in the most recent guidelines.1 thanks to its ease of use, fast procedural time, safety and effectiveness profiles, endovenous procedures have been progressively substituting in most counties the traditional surgical stripping.2 even if mini-invasive, such a procedure still requires multiple high volume injections of tumescent anesthesia (ta). ta represents a relatively safe act. nevertheless it is not only responsible for quite easily observed painful and not aesthetic hematomas along the saphenous area, but is also not free from potential complications.3-5 at the same time, foam sclerotherapy (fs) has proved to represent an extremely valid alternative therapeutic tool, since the diffusion of a powerful, cost-effective and easily reproducible extemporary production method.6,7 a brand new holmium laser device has been developed and combined with fs in order to avoid ta and being effective even in a large diameter great saphenous vein (gsv), demonstrating preliminary promising outcomes.7 objectives aim of the present investigation is to explore the feasibility of a fs assisted-traditional el use in absence of ta exploiting the spasm effect that is caused by the sclerosing drug. secondary endpoint is the exploration of new el energy deliver settings, eventually significantly reduced thanks to the synergic fs action, thus leading the procedure to a simplified office-based scenario. materials and methods forty chronic venous disease patients with a symptomatic gsv incompetence (8 males; 32 females; c2-4epaspr c2(17), c3(20), c4(3); mean age was 51±8 years old; body mass index 22±4) underwent a standing-up pre-operative ultrasound (us) scanning demonstrating the homogeneity in the reflux pattern (saphenofemoral junction incompetence placing the sample volume at the femoral side of terminal valve detected by both positive valsalva and compression/relaxation maneuver, single or multiple incompetent saphenous tributaries along the lower limb). a normally developed incompetent saphenous trunk (anatomically found always in between the fascia splitting, according to the so called saphenous eye)8 was present all the way from the sapheno-femoral junction to below the knee. no pelvic varicose veins were reported. diameters were measured at mid-thigh in supine to evaluate the foam injection-induced spasm. a second scanning was repeated immediately before the procedure, gsv diameters were recorded below the superficial epigastric vein and at the middle thigh, in supine. after a mild intra-venous sedation with dosages related to the short procedural time and limited pain trigger (midazolam 3+1 cc), the procedure included a percutaneous gsv access without local anesthesia at the distal third of the thigh or below the knee, depending on the incompetent tributary localization, a 0.0035-in guide-wire insertion, placement of a 6 fr introducer, insertion of 1470 nm diode laser radial fiber 600 µm up to 1 cm below the superficial epigastric vein confluence. particular care was used in detecting the anterior accessory saphenous vein confluence with the gsv and its eventual incompetence that potentially could be treated in the same procedural session. all patients were accurately informed about the procedure, according to international rules. the el was then activated (6-8w, 30-50 j/cm), shrinking the gsv by a 200 j fluence for the first cm in order to create a shrunk plug, completely obliterating the vessel in that limited segment. keeping the fiber tip tucked into the shrunk plug, 5 cc of fs 1:4 (drug/air ratio according to the tessari method, using two 5 ml siliconefree syringes), were then injected directly by the 3-way introducer using 1% polidocanol (pol) (30 cases of whom 5 males, 25 females) or 1% sodium tetradecyl sulfate (sts) (10 cases of whom 3 males and 7 females) (figure 1). a finger compression below the introducer insertion point guaranteed the fs upward flow. the injected foam was clearly detected echographically getting up to the shrunk plug and then filling up the minor gsv tributaries (figure 2). correspondence: francesco zini, surgical department, casa di cura città di parma, p.zza a. maestri 5, 43123 parma, italy tel.: +39.0521.284472. e-mail: fzflebo@tin.it key words: tumescense; laser; foam. received for publication: 7 march 2015. revision received: 17 april 2015. accepted for publication: 17 april 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright f. zini et al., 2015 licensee pagepress, italy veins and lymphatics 2015; 4:5141 doi:10.4081/vl.2015.5141 no n c om me rci al us e o nly article [page 32] [veins and lymphatics 2015; 4:5141] a sudden venous spasm is obtained, optimizing the subsequent el shrinkage that was performed all the way down to the knee gsv region with a significant reduction of the usual fluence. varicose veins that were not previously reached by the injected foam can than be treated both by phebectomies or fs itself, as occurred in 3 patients of our study population. an above-knee 20-30 mmhg elastic stocking compression was prescribed to all the patients for one week 24 h a day, then just during the daytime for the following two weeks. all the patients underwent an immediately post-operative us and clinical follow-up, that was repeated by the same assessor at 7 and 21 days. results in supine at the mid-thigh the gsv caliber decreased from a pre-operative mean value of 0.6±0.2 cm to a post fs injection 0.3±0.1 cm value (p<0.05), showing no statistical difference among sts and pol (p=0.7). at the two follow-up visits (7 and 21 days after the procedure) all the patients presented a gsv shrinkage with reflux suppression. neither major nor minor complications were reported. in particular neither ecchymosis nor hematoma were detected at the thigh. no significant pain was reported by the patients, clearly demonstrating the feasibility of the herein presented tumescence-free technique. discussion and conclusions el and rf have progressively gathered a major role in therapeutic international indications for varicose veins treatment.1 nevertheless, the same guidelines point out the need of a smaller than 15 mm caliber gsv for a rf approach, while stating that, even if there are no absolute contraindicated gsv calibers for el,9 an association among larger than 8 mm gsv and femoral thrombus extension was reported.10,11 el is scarless, aesthetically satisfying and considered as a mini-invasive effective therapeutic approach. nevertheless, up to now, el is strictly related to ta. this last one has four main aims: cooling and protecting the perivascular tissue from heating and burns, pain control, guaranteeing at least 1 cm of depth from the skin surface, reducing the gsv caliber in order to remove blood and improving surface contact. on the other side, eve if minimally, ta is an invasive act that can be related to unpleasant consequences such as perivenous ecchymosis and hematoma, up to 52% of patients, all along the treated gsv tract.12,13 this fact is responsible for a temporarily aesthetic impact, involving the patient dissatisfaction. rare but extremely severe ta complications have also been described in the literature.2-4 at the same time the same ta injection technique can present some difficulties leading to complications. in the same way, if the injecting needle remains too far away from the vein the perivenous tissue will remain attached to the vein, so suffering of heat damage.5 nowadays, technological innovations are developing in order to eliminate the ta need. in particular, a holmium laser assisted foam sclerotherapy (lafos) has been introduced with definitely promising outcomes.7 thanks to the low temperature generated by lafos a gsv caliber reduction is made possible even at the lowest energy delivery, so avoiding the need of any kind of ta. a following foam sclerotherapy injection completes the venous shrinkage. the herein reported absence of peri-operative and early post-operative complications points out how our strategic proposal produces preliminary evidences regarding the feasibility of a new el use without the need of both any ta and of any new laser device. the fs introduction in a previously partially shrunk gsv induces a venous spasm around the fiber, creating an endothelial damage, so allowing a lower el energy delivery. moreover, the creation of a shrinkage plug on the cranial saphenous side, limit the diffusion of fs derived cathabolites (like endothelin and histamin), maximizing the same drug local effect, while minimizing the systemic possible even if extremely rare side effects.14 the synergic el 1470 nm and fs effect, thanks to the more available water cromophore (water is specific target of 1470 nm laser frequency), may be that paves the way for a brand new definition of the energy delivery parameters in endovenous techniques, with hypothetical consequent smaller side effects and higher patient satisfaction, providing a ta-free strategy to be performed in the future in an officesetting. further investigations to this feasibility study are ongoing regarding the el energy delivery settings and the spasm effect induced by different concentrations of pol vs sts in a wider and thus more significant patient population, in absence we hope also of any kind of sedation. further investigations are needed for the proposed strategy application both in larger gsv calibers and with the use also of rf devices. this study is a feasibility study. number of patients and, in particular, follow-up time are clearly insufficient to draw conclusions. a more complex and accurate study is in progress. figure 1. foam sclerotherapy preparation and injection through the same laser fiber introducer. laser fiber remains endovenous, blocked by the initially performed shrunk plug. figure 2. a) laser fiber into the great saphenous vein (gsv) after a shrunk plug was created just below the superficial epigastric vein confluence, sparing the remaining gsv trunk. b) foam injection into the gsv with the laser fiber still inside the vein. a consequent significant caliber decrease is detected after the injection. foam easily reaches the gsv tributaries along the thigh thanks to the block caused by the shrunk plug. no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:5141] [page 33] references 1. gloviczki p, comerota aj, dalsing mc, et al. the care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the society for vascular surgery and the american venous forum. j vasc surg 2011;53:2s-48s. 2. khilnani nm, winokur rs. varicose vein treatment with endovenous laser therapy. medscape; apr 10, 2014. available from: http://emedicine.medscape.com/article/18 15850-overview 3. holdstock jm, marsh p, whiteley ms, price ba. it is possible to cause damage to a laser fibre during delivery of tumescent anaesthesia for endovenous laser ablation (evla). eur j vasc endovasc surg 2008;36: 473-6. 4. hubmer mg, koch h, haas fm, et al. necrotizing fasciitis after ambulatory phlebectomy performed with use of tumescent anesthesia j vasc surg 2004;39:263-5. 5. memetoglu me, kurtcan s, kalkan a, özel d. combination technique of tumescent anesthesia during endovenous laser therapy of saphenous vein insufficiency. interact cardiovasc thorac surg 2010;11: 774-8. 6. cavezzi a, tessari l. foam sclerotherapy techniques: different gases and methods of preparation, catheter versus direct injection. phlebology 2009;24:247-51. 7. coleridge smith p. sclerotherapy and foam sclerotherapy for varicose veins. phlebology 2009;24:260-9. 8. caggiati a. fascial relationship of the long saphenous vein. circulation 1999;100: 2547-9. 9. frullini a, fortuna b. laser assisted foam sclerotherapy (lafos): a new approach to the treatment of incompetent saphenous veins. phlébologie 2013;66:51-4. 10. florescu c, curry g, buckenham t. role of endovenous laser therapy in large and very large diameter great saphenous veins. anz j surg 2014 [epub ahead of print]. 11. lawrence pf, chandra a, wu m, et al. classification of proximal endovenous closure levels and treatment algorithm. j vasc surg 2010;52:388-93. 12. chaar ci, hirsch sa, cwenar mt, et al. expanding the role of endovenous laser therapy: results in large diameter saphenous, small saphenous, and anterior accessory veins. ann vasc surg 2011; 25:656-61. 13. vaz c, matos a, sameiro m, et al. iatrogenic complications following laser ablation of varicose veins. in: yamanaochi d, ed. vascular surgery. rijeka: intech; 2012. available from: http://www.intechopen.com/books/vascular-surgery/iatrogenic-complications-following-laser-ablation-of-varicose-veins 14. frullini a, barsotti mc, santoni t, et al. significant endothelin release in patients treated with foam sclerotherapy. dermatol surg 2012;38:741-7. no n c om me rci al us e o nly hrev_master veins and lymphatics 2013; volume 2:e5 [veins and lymphatics 2013; 2:e5] [page 13] where should stiffness be measured in vivo? jean-françois uhl,1 jean-patrick benigni,2 andré cornu-thenard3 1urdia, research unit ea4465 – university paris descartes, paris; 2hia bégin, saint mandé; 3st antoine hospital, paris, france abstract three points in the medial aspect of the leg are routinely used to measure the interface pressure of a compression: the c point, at the largest circumference of the calf; the b point, at the smallest circumference of the leg; the anatomical b1 point, at the apex of the gastrocnemius muscle and the manufacturer’s b1 point, computed in the midline of the line joining the b point to the c point). the anatomical b1 point is the most reliable point from a practical point of view, and is easier to use. the underlying anatomy is the soleus muscle. stiffness at the anatomical b1 point seems adequate sufficient to assess stiffness of a medical device in vivo. introduction in laboratory the stiffness of a medical compression device is defined as the pressure change (in mmhg) that occurs with an increase in circumference of one centimeter (δp/δc). in vivo, this is very difficult to measure. for this reason the static stiffness index (ssi) proposed by partsch et al.1 is used as a rough estimate of stiffness. by definition, ssi is calculated by substracting the interface pressure (in mmhg) in the lying position from the interface pressure (in mmhg) in standing position. compression devices are defined as stiff if ssi is 10 mmhg or more. another stiffness index has also been proposed: the dynamic or dorsiflexion stiffness index (dsi) calculated by substracting the diastolic from the systolic interface pressure (in mmhg) during dorsiflection, while lying down.2 although slightly higher, the values of the dsi are similar to those of the ssi. anatomical review of the venous muscular pumps the muscular pumps of the lower limb represent the peripheral heart of the venous system. they push blood upward against gravity, so that downward reflux can be prevented by normally functioning valves. the main muscular pump of the lower limb is the calf pump. it is divided into two parts: i) the soleus muscle pump which works at the leg level. the soleal veins are divided into two parts, lateral and medial. the lateral veins are bigger and drain, vertically, into the fibular veins. the smaller medial veins drain horizontally into the posterior tibial veins; ii) the gastrocnemius muscle pump which works at the popliteal level. the medial part of the muscle and the medial gastrocnemius veins are very important. these veins originate by the gastrocnemius perforators, connecting end-to end at the apex of the calf. two or three big veins form a network inside the muscle, which join in a unique collector ending in the popliteal vein. the main reference points of the leg four points in the medial aspect of the leg are routinely used to measure the interface pressure of a compression device,3 all situated at the medial aspect of the leg (figure 1). these are: i) the c point (at the largest circumference of the calf); ii) the b point (at the smallest circumference of the leg); iii) the anatomical b1 point (b1a at the apex of the gastrocnemius muscle); iv) lastly, the manufacturer’s b1 point (b1m in the midline of the line joining the b point to the c point). figure 2 shows a realistic 3d anatomical model, reconstructed by a multi-slice computed tomography (msct). this medial view demonstrates that, below the apex of the medial gastrocnemius, the soleus muscle is the main muscle of the underlying anatomy. this muscle represents the deeper part of the triseps suralis (calf pump muscle). figure 3 shows that the anatomical b1 point which is easily found by a simple clinical exam during the muscular contraction of the calf. objectives the aims of this studies were: i) to verify if these reference points are reliable; ii) to assess their variability; iii) to assess the optimal site for calculating stiffness: at the anatomical b1 point, the c point, or both; iv) to compare stiffness with two different short stretch bandages. materials and methods we performed three different studies: a clinical study on 22 healthy subjects to localize reference points, a radiological computed tomography venography (ctv) study with msct was performed on 19 patients to assess the anatomical landmarks of the leg, and a study assessing stiffness by two compression devices applied on ten legs. clinical study to localize reference points: measurements of the legs of 22 healthy subjects (17 women and five men) were done in the standing position. the evaluations included the measure of the distance of the b and c points from the ground, the distances of the anatomical b1 and manufacturer’s b1 points from the ground, and the height of the subject. study by ct venography to assess the anatomical landmarks of the leg:4 msct scanning was performed with a siemens somatom® definition flash 64 slice ct scanner, with contrast injection into a dorsal foot vein. the ct parameters were acquisition from feet to head, 120 kv, and 150 mas. reconstruction parameters: slice width 1 mm, slice increment 0.75, matrix 512¥512, zoom factor 1.7. post processing was performed with the volume rendering technique by osirix 64bit, version 5 (pixmeo company, www.osirix. foundation.com) nineteen patients (thirteen women and six men) were investigated in the lying position before varicose vein surgery. measurements were made using the osirix software on the 3d reconstructed images. localization of the c, b, b1a, and b1m points were made and the distances between the points were computed, as well. the length of the tibia was considered to be equal to the distance from knee joint to the apex of the medial malleolus. clinical study to assess the stiffness of two compression devices: the stiffness of two compression devices was assessed in 23 healthy legs. rosidal k™ (lohmann & rauscher), was applied to eleven legs and coban™2 (3m™) to twelve. rosidal k™ (lohmann & rauscher) is a short stretch bandage (5 m ¥ 10 cm). the bandage was applied in a circular way with full correspondence: jean-françois uhl, urdia, research unit ea4465 – university paris descartes, paris, france. e-mail: jeanfrancois.uhl@gmail.com key words: compression, stiffness index. conference presentation: part of this paper was presented at the international compression club (icc) meeting on stiffness of compression devices, 2012 may 25, vienna, austria (http://www.icc-compressionclub.com/). received for publication: 29 september 2012. revision received: 2 november 2012. accepted for publication: 15 november 2012. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright j.-f. uhl et al., 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e5 doi:10.4081/vl.2013.e5 no nco mm er cia l u se on ly stretch. coban™2 is a two layer bandage consisting in a padding layer (10 cm ¥ 2.7 m) and a short stretch bandage (10 cm ¥ 4.7 m). the two bandages were applied according to the recommendations of the manufacturer. each bandage being overlapped by 65%. bandages were applied so that a target pressure of 40 mmhg at the anatomical b1 and c points could be achieved. the interface pressure was measured with a kikuhime® device (makoto takahashi and sanae, biomedical systems engineering, graduate school of engineering, hokkaido university, japan), using the small probe, in the lying position, at rest and during muscular contraction, and in the standing position (figures 4 and 5). statistical methods we used statview, version 5 (copyright 1998 sas institute inc., usa), to compute the mean and standard deviation (σ) of the samples and to determine the median for interface pressures. results clinical measurement the height from the ground was measured for the c point (at the largest circumference of the calf), the b1a point (at the apex of the gastrocnemius muscle), and the b1m point (in the midline of the line joining the b point to the c point), and distances between these points were all measured on 22 healthy subjects. results are shown in table 1. the mean distance b1a-c was 5.66 cm [standard deviation (sd) 1.76] and the mean distance b1a-m was 3.95 cm (sd 1.87). there was no correlation between the distances observed and the height of the subject. computed tomography venography anatomical measurement the same parameters were measured by ctv on 19 patients before varicose vein surgery. by ctv, the average distance from b1a to conference presentation [page 14] [veins and lymphatics 2013; 2:e5] table 1. values of the heights of b1a, b1m, c points above the ground. distance between b1m, b1a and c points on 22 healthy subjects (in centimeters, single values, means±standard deviation). height from ground distance between points b1m b1a c b1 a-m b1a-c 19 23 30 4 7 22 26 32 4 6 18 22 27 4 5 19 23 30 4 7 19 24 29 5 5 20 22 28 2 6 22 27 32 5 5 22 25.5 30 4 4.5 20 26 29 6 3 21 28 31 7 3 16 19.5 26 4 6.5 20 28 31 8 3 19 22.5 27.5 4 5 21 21 30 0 9 21 24.5 30 4 5.5 19 22 28 3 6 20 23.5 30 4 6.5 24 29 34.5 5 5.5 23 23 33 0 10 25 28 32 3 4 22 27.5 32.5 6 5 22 26 33 4 7 mean sd 20.64±2.06 24.59±2.65 30.25±2.16 3.95±1.87 5.66±1.76 sd, standard deviation. figure 1. the main reference points of the leg commonly used to measure the interface pressure of a compression device. figure 2. study of the anatomical landmarks of the reference points by 3d reconstruction with multi-slice computed tomography. arrow shows the apex of the medial gastrocnemius muscle (b1a). mg, medial gastrocnemius muscle; sol, soleus muscle; b1m, half distance measured between c and b. figure 3. clinical assessment of the b1 point at the apex of the calf. no nco mm er cia l u se on ly conference presentation [veins and lymphatics 2013; 2:e5] [page 15] b1m was 3.6 cm (sd 1.63), average distance from b1a to c was 9.3 cm (sd 1.69). there was a significant correlation with tibial length (r=0.4, table 2). a comparison between the two measurement methods shows: i) there was a significant difference in the distance from the c point to the ground between the two measurement methods. the c point required repeated measurements and so appears to be difficult to locate clinically; ii) the manufacturer’s b1 point is in the middle of the bc line and is not easy to locate; iii) the anatomical b1 point is the easiest to identify in clinical practice because it is located at the apex of the medial gastrocnemius muscle. as a result, it is easy to assess clinically and, if necessary, to verify by ultrasound. it is also the most reproducible; iv) the distance between the anatomical b1 and the manufacturer’s b1 points are closer than the anatomical b1 and c points according to either calculation method. calculation of stiffness calculation of the median stiffness index on 11 legs with a rosidal k™ (lohmann & rauscher, table 3) shows that the ssi and the dsi were very similar at the b1a and c points; this is considered stiff. median ssi was 14 mmhg at b1 vs 19 mmhg at c. median dfsi was 29 mmhg at b1 vs 31 mmhg at c. stiffness index measurement on 12 legs with a coban™2 (3m™) (table 4) also shows that ssi and dsi were very close at the b1a and c points; they are also considered stiff. median ssi was 13.7 mmhg at b1 vs 14.3 mmhg at c. median dsi was 26 mmhg at b1 vs 25.6 mmhg at c. wherever the calculation of the stiffness is performed, the values at the c point and the anatomical b1 points were very close for both compression devices. table 2. distances between the c point and b1a, b and b1m points. distance b1a to b1m and the tibial length measured in centimeters measured on the 3d model of 19 legs prior to varicose vein surgery with osirix software (pixmeo company, www.osirix.foundation.com). tibial length distance between points c-b1a c-b c-b1m b1a-m 33 9 22 11 2 46 13 36 18 5 46 12.8 34.4 17.2 4.4 34 8.3 22.7 11.35 3.05 36 9 23.2 11.6 2.6 39 10.7 24.8 12.4 1.7 38 7.8 21.3 10.65 2.85 37 10.4 23 11.5 1.1 39 9.4 27 13.5 4.1 37 8.5 25.4 12.7 4.2 38 8.5 26 13 4.5 35 7.1 25.7 12.85 5.75 36 10.8 24.4 12.2 1.4 34.6 7.5 20.8 10.4 2.9 43.6 8.3 26 13 4.7 32.8 7.3 19.5 9.75 2.45 39 9 31 15.5 6.5 45.6 8.2 29 14.5 6.3 40 10.2 25.2 12.6 2.4 average 38.4 9.3 25.7 12.8 3.6 sd 4.21 1.69 4.37 2.18 1.63 sd, standard deviation. figure 4. pressures at rest, with dorsiflexions, during standing and stiffness indices under a rosidal k (lohman & rauscher) on 11 legs. ranges of 95% confidence interval. rest, at rest; contr, with dorsiflexion; stand, standing; ssi, static stiffness index; dsi, dorsiflexion stiffness index. figure 5. pressures at rest, with dorsiflexions, during standing and stiffness indices under coban™2 (3m™) on 12 legs. ranges of 95% confidence interval. rest, at rest; contr, with dorsiflexion; stand, standing; ssi, static stiffness index; dsi, dorsiflexion stiffness index. table 3. interface pressure (mmhg) at b1 and c points under a rosidal k (lohman & rauscher) bandage (11 legs). b1 point c point rest contr stand rest contr stand average 41.4 74.5 58.3 36 61.5 51.5 sd 4.4 15 11.4 9.4 24 14.3 median 41 70 55 35 67 54 rest, at rest; contr, with dorsiflexion; stand, standing; sd, standard deviation. no nco mm er cia l u se on ly conference presentation [page 16] [veins and lymphatics 2013; 2:e5] discussion the distance between the c and anatomical b1 points was found to be significantly different by clinical and ct measurement (average 9.3 vs 5.6 cm; p<0.1). the possible explanation for this result could be the different position of the subjects, supine when submitted to ct and standing during the clinical examination. in fact, the c point varies according to positioning due to isometric contraction, lying or standing. conclusions the c point is difficult to locate in practice. the anatomical b1 point is the most reliable point from a practical point of view, and is easier to use. the underlying anatomy is the soleus muscle. stiffness at the anatomical b1 point seems adequate sufficient to assess stiffness of a medical device in vivo. references 1. partsch h, clark m, mosti g, et al. classification of compression bandages: practical aspects. dermatol surg 2008; 34:601-8. 2. partsch h, clark m, bassez s, et al. measurements of lower leg compression in vivo: recommendations for the performance of measurements of interface pressure and stiffness. dermatol surg 2006; 32:224-33. 3. benigni jp, cornu-thenard a, uhl jf, blin e. superimposition of medical compression stockings: interface pressure measurements in normal legs and calculation of the stiffness indices. phlébologie 2009; 62:67-74. 4. uhl jf. 3d modeling of the venous system by direct multi-slice helical ct venography (ctv): technique, indications and results. phlebology 2012;27:270-88. table 4. interface pressure (mmhg) in b1 and c points under a coban™2 bandage (12 legs). b1 point c point rest contr stand rest contr stand average 43.3 70.9 57.6 43.9 68.8 58.4 sd 5.4 13.1 10.2 10.8 21.8 13.8 median 42 68 55.7 45.7 71.3 60 rest, at rest; contr, with dorsiflexion; stand, standing; sd, standard deviation. no nco mm er cia l u se on ly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: an investigation of the influence of glycerin on sclerosant foam stability by peterson jd, goldman mp. phlebology 2011;26:232-4. stefano ricci abstract in a recent article, cavezzi and tessari speculated that the addition of glycerin may prolong half liquid time. the authors studied the stability of sodiumtetradecyl sulphate (sts) after addition to glycerin 72%. the sclerosant combinations investigated were: 1.0 ml 0.5% sts to 0 ml 72% glycerin; 0.9 ml 0.5% sts to 0.1 ml 72% glycerin; and 0.8 ml 0.5% sts to 0.2 ml 72% glycerin. for each trial, 1.0 ml of 0.50% sts sclerosant was charged using new sterile syringes and connectors attached to a w/w adaptor and to a 5 ml syringe with 4 ml of pre-drawn air. using the double-syringe system technique, air is pushed to fill the syringe with the sclerosing agent. this method usually requires ten passages from one syringe to the other. finally, the 5 ml syringe filled with the foam iss placed exactly vertically with the rubber stopcock on the bottom and the timer is started. as the foam degenerates back into its constituents, the sclerosing solution gradually re-forms at the bottom of the syringe. when the solution’s meniscus reaches a volume of 0.5 ml (half of the original sclerosing volume of 1.0 ml), the timer is stopped and data are recorded. table 1 clearly shows that the addition of glycerin to foam prolongs foam stability due to the increased viscosity of glycerin, increasing the sts foam half-life by 35.29%. possibly more efficacious sclerotherapy could be achieved from a prolonged contact time of the foam bubbles with the endothelial cells. however, this same prolonged stability could cause an increase in the incidence of distant side effects. the most effective amount of glycerin into the solution still needs to be studied. table 1. foam half-life stability. comment by stefano ricci foam never ceases to surprise us! the most interesting aspect of this method is its simplicity, with consequent low costs and easy availability for use in research and development. this is in spite of all attempts to change the foam sclerotherapy into a commercial business. tessari’s inventiveness must again be recognized. in the paper in question, as the co2 foam is less stable, although more harmless, adding a stabilizer to this gas-based foam could be of particular interest. much research is still needed into the association of tensioactive (foaming) agents with other traditional sclerosing non-foaming agents, such as glycerin and also iodine. we must not forget also the possible association with other surgical or endovascular treatment methods, an aspect which up till now has been completely neglected. those interested in the subject may read cavezzi and tessari’s paper for themselves: foam sclerotherapy techniques: different gases and methods of preparation, catheter versus direct injection. phlebology 2009;24:247-51. reply by the author (goldman) the story of foam is even more interesting when we consider that the duration and quality of foam is also influenced by the type of syringe used to make it. each syringe manufacturer uses a different type of plastic and silicon to coat the inside barrel of the syringe. this has been studied in lai and goldman’s paper: does the relative silicone content of different syringes affect the stability of foam in sclerotherapy? j drugs dermatol 2008;7:399-400. abstract this study examined the possibility that relative silicone content of different syringes may affect the overall foam stability. a double-syringe system (dss) technique to make sclerosing foam (sts 0.5% and air) was applied. four different brands of syringes were tested. the time required for half of the original volume of sclerosing solution to settle was recorded. the time for the sclerosing solution to settle to half of its initial volume varied with each brand of syringes. the type of syringe used in the dss technique to produce foam for sclerotherapy is a determinant of foam stability. whether this will affect the result of sclerotherapy requires further investigation. [top] hrev_master veins and lymphatics 2016; volume 5:5573 [page 36] [veins and lymphatics 2016; 5:5573] stump evolution after great saphenous vein stripping with high ligation paolo casoni,1,2 marc lefebvre-vilardebo,3 fabio villa,1 piero corona1 1phlebo-lymphologic center piccole figlie hospital, parma, italy; 2department of phlebology, royal marbella hospital, marbella, spain; 3office of surgical and medical phlebology, paris, france abstract the aim of the present observational study is to show the evolution of great saphenous vein (gsv) stump in two different periods of follow up. from 2001 to 2009, 500 legs with gsv insufficiency and terminal valve reflux, operated on with stripping by invagination without crossectomy, were followed. doppler were performed at 1 month (early) and then mid-term (2-year follow-up). the hemodynamic examination of residual stumps showed 4 different types: s1) draining and competent terminal valve; s2) thrombosis and fibrosis; s3) turbulence under valsalva maneuver and normal antegrade flow at rest; s4) turbulence with reflux at rest: refluxing terminal valve. early: the most common finding was s1 (64%), then s2 (18%), s3 (12%) and s4 (6%); s1-s3 patterns were considered as good evolution (94%), whereas s4 were considered recurrence. mid-term phase: the most common finding was again s1 (67%), then s3 (15%), s4 (10%) and s2 (8%). s1 evolution: out of 319 legs in s1 group at early phase, 294 (92%) remained still in s1 at mid-term follow up; 25 (8%) worsen to s3. s2 evolution: out of 92 legs in s2 at early phase, 42 (46%) improved to s1, 40 (43%) did not change pattern across time and 10 legs (11%) worsen to s4. s3 evolution: almost the legs in s3 (51, 86%) remained unchanged at mid-term, whereas 8 (14%) worsen to s4. s4 evolution: all the patients in s4 class at early follow up were still in the same class at mid-term. the evolution of gsv stump can be classified in 4 different patterns, where only s4 should be considered failure. introduction incorrect ligation of saphenofemoral junction (sfj) with a residual stump of great saphenous vein (gsv) left at first vein procedure has been advocated as the main reason for recurrence. the stump can enlarge with time due to persistent retrograde flow from the common femoral vein; in presence of connection to superficial venous system it causes recurrent varicose veins.1,2 however, this concept has been confuted by the results of many studies, reporting high rate of recurrence (up to 60%), even in presence of extremely correct sfj at first surgery.3,4 finally, the advent of either endovascular treatment or surgery with high ligation, sparing sfj junction and leaving gsv stump, with lower rate of late recurrence (from 9.8 to 26%), has definitely demonstrated that the presence of gsv stump in the groin is not necessarily correlated to late recurrence.5-8 in the era of sfj sparing,5-15 one of the most important issue to deal with is the assessment of evolution of gsv stump. disselhoff and colleagues6 evaluated just the abolition of gsv reflux after endovenous laser ablation by its complete obliteration, and duplex ultrasound (dus) recurrent varicose veins were classified in accordance with an old classification.16 pichot and colleagues7 described the evolution of 60 limbs after radiofrequency operation, stratifying in three groups: complete sfj complete occlusion, open sfj with short patent gsv segment (with and without sfj reflux) and open sfj with long patent gsv segment (with and without sfj reflux). the aim of the present observational study is to show the evolution of gsv stump in two different period of follow up (early to midterm). materials and methods population from 2001 to 2009, 500 legs in 481 patients (389 females, 92 males) with gsv insufficiency and terminal valve reflux, operated on with invaginating stripping with high ligation,5 were followed up in order to classify the evolution of residual stump. this was retrospective study of prospectively collected data. the study was approved by the institutional review board (local ethical committee) and given the retrospective observational nature of the research the informed consent was waived. in 19 cases, a bilateral gsv disease was treated. the average age was 46±15 years.17 all the patients showed class ≥2 of the clinicaletiology-anatomy-pathophysiology (ceap) classification. duplex evaluation the anatomic and hemodynamic features were evaluated by means of dus (esaote av4 and mylab 50, esaote group, genova, italy) always performed by the same operator (cp), with the patient in the upright position; the diameter of the gsv was measured preoperatively 10 cm below the junction. surgery surgery was performed under local anesthesia, femoral block and klein tumescence (20 ml of 2% lidocaine, 1 ml adrenaline (1:1000), 5 ml of sodium bicarbonate solution (8.4%) and mixed in 500 mll of lactated ringer’s solution). all the operations were performed by a single expert surgeon (pc). the first step was to hook gsv at leg level, via a very small incision and then a stripper was inserted. the invaginating stripping was limited by echoguided mapping. finally, gsv was hooked at level of the thigh, 2-3 cm below the groin (sfj), so, the gsv ligature was performed roughly close to one tributary vein, to leave a physiological drainage. in all cases associated phlebectomy was performed.5 anterior accessory saphenous vein was treated simultaneously to gsv only in 2 cases. follow-up clinical examination and dus were performed at 1 month (early) and then every year, considering mid-term as 2-year follow-up. the valsalva maneuver was also used to assess the terminal valve competence at groin level. all the patients blow through a small straw to standardize the test. definitions the hemodynamic examination of residual stumps either early or mid-term after gsv surgery without high ligation of the sfj was subdivided into four different types: s1) draining and competent terminal valve (figure 1); s2) correspondence: paolo casoni, department of phlebo-lymphologic center piccole figlie hospital, ippocrate vein clinic, via po 134/a, 43125 parma, italy. tel.: +39.0521.986049 fax: +39.0521.948080. e-mail: casonip@tin.it key words: vein stump; no crossectomy; varicose veins; great saphenous vein reflux. conflict of interest: the authors declare no potential conflict of interest. received for publication: 2 may 2016. revision received: 19 april 2016. accepted for publication: 2 may 2016. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright p. casoni et al., 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5573 doi:10.4081/vl.2016.5573 no n c om me rci al us e o nly article [veins and lymphatics 2016; 5:5573] [page 37] thrombosis and fibrosis: partial or total thrombosis of the stump (figure 2) that might evolve towards fibrosis; s3) draining at rest and turbulence under valsalva maneuver (figure 3); s4) turbulence with reflux at rest: refluxing terminal valve with possible formation of large neovascular vessel (figure 4). good evolution was defined as absence of reflux at the sfj. conversely, recurrence identified legs where there was a recurrent reflux at the sfj. statistics categorical data was reported as count and percentage. wilcoxon’s test was used to compare early and mid-term stump evolution. software used was spss (spss inc, chicago, il, usa). results at preoperative dus evaluation, all terminal valves were incompetent. the average diameter of gsv was 8.1±1.3 mm. early postoperative phase the most common finding was obviously s1 (319.64%), then s2 (92.18%), s3 (59.12%) and s4 (30.6%) (figure 5); s1 to s3 were considered as good evolution (47.9%), whereas s4 was considered recurrence. mid-term phase at 2-year dus control, the most common finding was again s1 (336.67%), then s3 (76.15%), s4 (48.10%) and s2 (40.8%) (figure 5). early-to-midterm evolution the evolution of 4 stumps from early to midterm phase showed that the change over time was statistically significant (p<0.001). s1 evolution: out of 319 legs in s1 group at early phase, 294 (92%) remained still in s1 at mid-term follow up; 25 (8%) worsened to s3. s2 evolution: out of 92 legs in s2 at early figure 1. pattern s1. ise, inferior superficial epigastric; fv, femoral vein; sep, superficial external pudenda; tv, terminal valve. figure 2. pattern s2. ise, inferior superficial epigastric; sep, superficial external pudenda; fv, femoral vein; tv, terminal valve. figure 4. pattern s4. ise, inferior superficial epigastric; sep, superficial external pudenda; i, incompetence; fv, femoral vein; tv, terminal valve; t, turbulence. figure 5. stump evolution from early to mid-term phase. figure 3. pattern s3. ise, inferior superficial epigastric; sep, superficial external pudenda; fv, femoral vein; tv, terminal valve; i, incompetence; t, turbulence. no n c om me rci al us e o nly article [page 38] [veins and lymphatics 2016; 5:5573] phase, 42 (46%) improved to s1, 40 (43%) did not change pattern across time and 10 legs (11%) worsened to s4. s3 evolution: almost the legs in s3 (51.86%) remained unchanged at mid-term, whereas 8 (14%) worsened to s4. s4 evolution: all the patients in s4 class at early follow up were still in the same class at mid-term. discussion this observational study describes the evolution of gsv stump left in site after surgery with high ligation. with the aid of dus, four different patterns of stumps have been identified. most of patients (64%) showed good outcome with a stump draining well along with a competent terminal valve. pichot and colleagues7 reported a similar pattern ranging from 50% to 92.4%, in their experience, according to the length of the stump. in these cases, terminal valve (tv) is open at rest with drainage from some tributaries such as inferior superficial epigastric and superficial external pudenda. however, pichot and colleagues7 did not describe the behavior of tv under valsalva maneuver. in our experience, the tv remains competent even in this case with no reflux from common femoral vein to gsv stump; in these cases, surgery was effective to reduce gsv dilatation at the level of tv, providing a new competence to the valve. this pattern remained stable in most of cases, but in 8% of cases it involved towards s2 with turbulence and no reflux. the explanation of this worsening is not so clear, likely due to abnormal flow through little veins and lymphatic along with an involution of tv, which becomes incompetent even at rest. in 18% of cases (s2), the presence of thrombosis in the stump is per se occlusive and hampers the reflux from common femoral vein to gsv stump. our rate is higher than the one reported by pichot and colleagues7 (8.3%), but even in their study no reflux was recorded. in high rate of cases (86%), this pattern remained stable over time and can be considered as good result of surgery, since the stump is continuously washed out by tributaries towards the tv valve. however, in remaining 14% of cases, a bad evolution towards the failing pattern (s4) was recorded over time. probably a spontaneous recanalization very likely unmasked the tv incompetence, causing turbulence. the third pattern (s3) should be considered as a warning pattern. in fact it could not be defined as failure yet, with an antegrade flow from the tributaries to gsv and then to the common femoral vein; but, under valsalva maneuver, the tv became refluxing and turbulence was recorded by dus. in this pattern, the patient should be strictly followed up. however, in our experience this pattern remained stable by two years of follow up. finally, in 6% of cases, lower than 8.3% reported by pichot and colleagues,7 surgery fails to restore the competence of tv, very likely due to high grade of dilatation or because of disruption of valve cusps (s4). this pattern is irreversible and might evolve to very large neovascular vessels (2/48). lefebrve-vilardebo17 showed that lymph nodes in the neighborhood of the ligated saphenous stump might actually contribute to the recurrence of disease. the presence of tiny veins (1-4 mm) passing through the surrounding lymph nodes was detected at postoperative dus examination of the groin, suggesting a role of lymph nodes in the neovascularization process. limitations of the study this main limitation of this study is that it is only a descriptive observational analysis, without any possibility to identify any patient or vein characteristic associated more with a specific pattern rather than another one. further investigations to identify anatomic and hemodynamic risk factors for persistent tv incompetence, even after surgery, should be evaluated, since most of vein surgery today is focused to spare the sfj. conclusions the evolution of the gsv stumps can be classified in four different patterns, where only s4 (incompetent tv at rest) should be considered failing outcome of surgery and periodically treated with foam under echo-guide. in s3 cases, a strict follow up is mandatory. references 1. stucker m, netz k, breuckmann f, et al. histomorphologic classification of recurrent saphenofemoral reflux. j vasc surg 2004;39:816-21. 2. geier b, stucker m, hummel t, et al. residual stumps associated with inguinal varicose vein recurrences: a multicenter study. eur j vasc endovasc surg 2008;36:207-10. 3. fischer r, linde n, duff c, et al. late recurrent saphenofemoral junction reflux after ligation and stripping of the greater saphenous vein. j vasc surg 2001;34:236-4. 4. chandler jg, pichot o, sessa c, et al. defining the role of extended saphenofemoral junction ligation: a prospective comparative study. j vasc surg 2000;32: 941-53. 5. casoni p, lefebvre-vilardebo m, villa f, corona p. great saphenous vein surgery without high ligation of the saphenofemoral junction. j vasc surg 2013;58: 173-8. 6. disselhoff bc, der kinderen dj, kelder jc, moll fl. five-year results of a randomized clinical trial of endovenous laser ablation of the great saphenous vein with and without ligation of the saphenofemoral junction. eur j vasc endovasc surg 2011;41: 685-90. 7. pichot o, kabnick ls, creton d, et al. duplex ultrasound scan findings two years after great saphenous vein radiofrequency endovenous obliteration. j vasc surg 2004;39:189-95. 8. pittaluga p, chastanet s, guex jj. great saphenous vein stripping with preservation of sapheno-femoral confluence: hemodynamic and clinical results. j vasc surg 2008;47:1300-4. 9. merchant rf, pichot o; closure study group. long-term outcomes of endovenous radiofrequency obliteration of saphenous reflux as a treatment for superficial venous insufficiency. j vasc surg 2005;42: 502-9 10. min rj, zimmet se, isaacs mn, forrestal md. endovenous laser treatment of the incompetent greater saphenous vein. j vasc interv radiol 2001;12:1167-71. 11. carradice d, mekako ai, mazari fa, et al. randomized clinical trial of endovenous laser ablation compared with conventional surgery for great saphenous varicose veins. br j surg 2011;98:501-10. 12. morrison n. saphenous ablation: what are the choices, laser or rf energy. semin vasc surg 2005;18:15-8. 13. proebstle tm, alm j, göckeritz o, et al. three-year european follow-up of endovenous radiofrequency-powered segmental thermal ablation of the great saphenous vein with or without treatment of calf varicosities. j vasc surg 2011;54:146-52. 14. rasmussen lh, lawaetz m, bjoern l, et al. randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins. br j surg 2011;98:1079-87. 15. de maeseneer m, pichot o, cavezzi a, et al. duplex ultrasound investigation of the veins of the lower limbs after treatment for varicose veins uip consensus document. eur j vasc endovasc surg 2011;42:89-102. 16. stonebridge pa, chalmers n, beggs i, et al. recurrent varicose veins: a varicographic analysis leading to a new practical classification. br j surg 1995;82:60-2. 17. lefebvre-vilardebo m. [vous avez dit “néovascularisation inguinale post-chirurgicale?] phlebologie 2001;54:253-4. [article in french] no n c om me rci al us e o nly hrev_master veins and lymphatics 2015; volume 4:5360 [page 58] [veins and lymphatics 2015; 4:5360] the discovery of the brain lymphatic system paolo zamboni translational surgery and vascular diseases center, university of ferrara, italy in the latest issue of nature antoine louveau and a team of collaborators of the university of virginia, published a breakthrough article for who is interested in lymphatics, with a clear and elegant description of the lymphatic system of the brain.1 surprisingly, few days later a group of helsinki confirmed with other experiments the existence of a cerebral lymphatics network connected with cervical nodes.2 despite the rapid popularity of this article it does not represent a revolutionary discovery, but rather an updated systematic description of connections and function of the lymphatic system in this particular anatomical district. it should be, in fact, recognized that a forgotten literature on durand fardel’s periarterial and perivenous virchow-robin’s spaces, recently turned into glymphatic system,3 exists from more than a century. however, this article permits to definitely overcome the neurocentric concept that lymphatic drainage of the central nervous system is confined to the meningeal compartment and there is a lack of lymphatic drainage in the brain parenchyma. the authors also better clarify the structure and the function of the so called glymphatic system, till now more supposed than proved.3 the group of the university of virginia clearly found the lymphatic system practically in the wall of the dural veins, and this testifies the functional and anatomical cross talk between the two systems, something which gives the title to our journal. moreover, they demonstrated with elegant images that interconnection of the lymphatic collectors are not just veins, but also the cerebrospinal fluid (csf) (figure 1), and the deep cervical lymphnodes and with the internal jugular veins, as well. what are the potential implications of this discovery? the main consequence is that the dogma of the immune privilege of the brain, as admitted by the authors themselves, dramatically falls down. we all studied that the brain is segregated from the immunitary point of view.4 the physical reason was just the lack of lymphatics, which means no t-cell gataway into and out of the brain. the demonstration of the central nervous system lymphatics warrants an urgent reassessment of the basic assumption in neuroimmunology. in fact, the immune privilege of the brain means that t-cell and antibodies found in the brain and/or in the csf are of brain autochthonous production. consequently, the presence of t-cells was considered of autoimmune origin. the new concept easily paves the way to reconsider the autoimmune etiology of a number of neuroinflammatory and neurodegenerative diseases, including multiple sclerosis, alzheimer’s disease, etc. of course, the interconnection of the brain lymphatics with both the nasal mucosa and the deep cervical lymph-nodes, as well, permits to understand that there is no segregation at all. to the contrary, t-cells but also viruses may easily circulate. moreover, the interconnection with csf clearly indicates that what we found in it cannot be more considered autochthonous. furthermore, in origin we know that manual lymphatic drainage is a valid rehabilitation method for treating lymphoedema. the challenge is: may this technique to be useful also for the brain? may the interconnection of the brain lymphatics with the deep cervical lymph-nodes, a draining route toward the thoracic duct, be improved? both articles really open new and stimulating questions, and this happens only when a discovery is a real scientific advancement. references 1. louveau a, smirnov i, keyes tj, et al. structural and functional features of central nervous system lymphatic vessels. nature 2015 [epub ahead of print]. 2. aspelund a, antila s, proulx st, et al. a dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. j exp med 2015 [epub ahead of print] 3. yang l, kress bt, weber hj, et al. evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of csf tracer. j transl med 2013;11:107. 4. antel j, birnbaum g, hartung h-p, eds. clinical neuroimmunology. boston: blackwell science; 1998. correspondence: paolo zamboni, translational surgery and vascular diseases center, university of ferrara, via aldo moro 8, 44124 cona (fe), italy. e-mail: paolozamboni@icloud.com received for publication: 10 june 2015. accepted for publication: 10 june 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright p. zamboni, 2015 licensee pagepress, italy veins and lymphatics 2015; 4:5360 doi:10.4081/vl.2015.5360 figure 1. schematic representation of the functional histology specimen showed in the nature article.1 the lymphatic system lines the venous dural sinuses and is closely interconnected with cerebrospinal fluid (csf) space, as well as with meningeal vessels. out of the skull the interconnection was found by the researchers of the virginia university both with the internal jugular vein and with the deep cervical lymph-nodes. no n c om me rci al us e o nly hrev_master veins and lymphatics 2013; volume 2:e8 [veins and lymphatics 2013; 2:e8] [page 23] experimental study on efficacy of compression systems with a high static stiffness index for treatment of venous ulcer patients anneke andriessen,1 martin abel2 1andriessen consultants, malden & umc st. radboud, nijmegen, the netherlands; 2medical & regulatory affairs, lohmann & rauscher, rengsdorf, germany abstract the experimental study measured interface pressure and static stiffness index of four different compression systems in fifty-two healthy volunteers. for the study interface pressure (3 cm ø probe was placed at the anatomical b1 point) was recorded on application of the compression systems every 15 min for 4 h, in supine, standing, while sitting and during walking. for this purpose a portable kikuhime (harada corp., osaka, japan) device was used. further static stiffness index (ssi) was calculated. the evaluated systems were: short stretch bandage system (ssb) rosidal sys (lohmann & rauscher, rengsdorf, germany), multi-layer bandaging (lsb) profore (smith & nephew, hull, uk), varistretch bandage (vsb) proguide (smith & nephew) and tubular compression (cs) rosidal mobil (lohmann & rauscher). the mean interface pressure of ssb, lsb and vsb was significantly higher (p<0.05) in each position measured over 4 h, compared to cs. in supine vsb showed high-pressure levels, up to 60 mmhg, which remained high. the other systems had more tolerable levels of about 30 mmhg. interface pressure exerted on limbs is an indicator of their clinical effect. the experimental study results showed different patterns of interface pressure and ssi, which may enable clinicians to predict the frequency of bandage application, supporting an adequate and safe choice of bandage system. introduction the paper was presented at the international compression club meeting in vienna 2012 and discussed an experimental study that was previously published.1 the study aimed to compare interface pressure and static stiffness index (ssi) of four different compression systems that are currently in use for venous leg ulcer and lymphedema treatment of the lower limbs. materials and methods for the experimental study fifty-two ambulatory adults with healthy legs, were recruited at random in the study center, after they had given informed consent.1 excluded were those with an allergy against one of the used materials; arterial occlusive disease (abpi less than 0.8); ulcers on the lower limb; lower limb edema; known history of dermatological problems such as eczema or cellulites. the evaluated systems were: short stretch bandage system (ssb) rosidal sys (lohmann & rauscher, rengsdorf, germany), multi-layer bandaging (lsb) profore (smith & nephew, hull, uk), vari-stretch bandage (vsb) proguide (smith & nephew) and tubular compression (cs) rosidal mobil (lohmann & rauscher). interface pressure (ip) (3 cm ø probe was placed at the anatomical b1 point) was recorded on application of the compression systems and every 15 min for 4 h, in supine, standing, while sitting and during walking. for this purpose a portable kikuhime (harada corp., osaka, japan) device was used. measure ments during walking were recorded while subjects walked on a treadmill for at least 5 min at normal pace. correspondence: anneke andriessen, zwenkgras 25, 6581 rk malden, the netherlands. tel. 31 24 3587086. e-mail: anneke.a@tiscali.nl key words: interface pressure, static stiffness index, compression for venous leg ulcers. conference presentation: part of this paper was presented at the international compression club (icc) meeting on stiffness of compression devices, 2012 may 25, vienna, austria (http://www.icc-compressionclub.com/). contributions: the authors contributed equally. conflict of interests: ma is an employee of lohmann & rauscher (rengsdorf, germany), the company that provided the study products. a limited educational grant was received from lohmann & rauscher for conducting the study. received for publication: 4 october 2012. revision received: 1 november 2012. accepted for publication: 15 november 2012. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright a. andriessen and m. abel, 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e8 doi:10.4081/vl.2013.e8 figure 1. mean interface pressure in supine, sitting, standing and walking (n=52). ip, interface pressure; ssb, short stretch bandage system; lsb, multi-layer bandaging; vsb, vari-stretch bandage; cs, tubular compression. figure 2. static stiffness index (n=52). ssb, short stretch bandage system; lsb, multi-layer bandaging; vsb, vari-stretch bandage; cs, tubular compression. no nco mm er cia l u se on ly primary outcome measure interface pressure measured in supine, sitting, standing and walking and ssi. parametric or non-parametric tests (spss: ibm corp., armonk, ny, usa) were used where appropriate. mann-whitney u or paired t-test were used for intragroup and per group comparisons of the ip measured in the different positions and over time. results the mean interface pressure of ssb, lsb and vsb was significantly higher (p<0.05) in each position measured over 4 h, compared to cs (figure 1). in supine vsb showed highpressure levels, up to 60 mmhg, which remained high. the other systems had more tolerable levels of 30 mmhg. measurements in sitting showed similar trends. all compression systems maintained pressure levels in walking of at least 40 mmhg (table 1). the ssi was the highest for ssb with 20 and remained 19 throughout the study period. lsb followed with an ssi of 18, reduced to 15, where the ssi for vsb went from 17 to 12 and cs with an ssi of 6 lagged behind (figure 2). discussion the ip for lsb and vsb in supine of ±60 mmhg were higher than usually reported. lsb and vsb are defined systems, ssb is a variety of compression systems. lsb has an elastic layer (extensibility >100%), ssb consists of short-stretch materials (extensibility±70%). by applying lsbs’ elastic layers over each other, with a cohesive bandage as the outer layer, the final system is stiffer.2 this was also shown in our study1 and is in line with what was demonstrated by mosti and partsch.2-5 in a clinical study6-8 two groups were treated with compression and one group received no compression. in selected patients ip and ssi was measured for the two compression systems lsb and ssb. the static stiffness index remained higher than 10 in both compression groups for one week, the duration of bandage application, despite of bandage pressure loss (figure 3). the reduction in ulcer area from weeks 12 to 24 in the lsb group and usual care group (moist wound healing dressings, no compression) was not significant (p=0.67 and p=0.16), where a statistically significant reduction in ulcer area was observed in the ssb group (p=0.047) (figure 4). both compression systems treated groups showed effective ulcer healing with faster and better ulcer area and pain reduction for ssb, which may be explained by the higher ssi of the system. limitations this was an experimental study on healthy conference presentation [page 24] [veins and lymphatics 2013; 2:e8] table 1. experimental study (n=52): interface pressure measured in supine and walking. mmhg ssb lsb vsb cs paired t-test supine walking supine walking supine walking supine walking mean 40.68 (±5.01) 56.11 (±5.01) 48.12 (±4.57) 69.59 (±6.24) 48.96 (±3.99) 66.21 (±4.02) 37.82 (±0.58) 40.04 (±1.77) supine: ssb, lsb, (±sd) vsb vs cs: p=0.05 median 41 (39-60) 57 (52-80) 50 (44-59) 73 (64-90) 51 (46-60) 69 (64-80) 40 (39-41) 42 (40-45) walking: ssb, lsb, (range) vsb vs cs: p=0.05 ssb, short stretch bandage system; lsb, multi-layer bandaging; vsb, vari-stretch bandage; cs, tubular compression; sd, standard deviation. figure 3. clinical study (n=321): interface pressure and static stiffness index. ip, interface pressure; ssi, static stiffness index; ssb, short stretch bandage system; 4lb, four-layer bandage system; sd, standard deviation. figure 4. clinical study (n=321): ulcer area reduction at 12 and at 24 weeks. ssb, short stretch bandage system; 4lb, four-layer bandage system; uc, usual care (a moist wound healing dressing and no compression); anova, analysis of variance; sd, standard deviation. no nco mm er cia l u se on ly conference presentation [veins and lymphatics 2013; 2:e8] [page 25] legs over a 4-h period where typically the systems are left in place for 3-4 days up to 1 week. moreover the device that was used to measure ip is not suitable to leave in place for over 4 h. based on our results it is not possible to predict what the pressure levels would be over this period on for instance venous leg ulcer patients with edema. however the reported results from a clinical study,6,7 suggest that when using the ssb and lsb compression systems in venous leg ulcer patients with edema, the ip levels are maintained at a therapeutic level over a week. for this study another, more suitable measurement device [picopress®, microlab elettronica sas, roncaglia di ponte san nicolò (pd), italy]3 was used to measure ip levels. this device can be left in place for several days up to a week, providing clinically relevant information.3 conclusions interface pressure exerted on limbs is an indicator of their clinical effect. the study results showed different patterns of interface pressure and ssi, which may enable clinicians to predict the frequency of bandage application, supporting an adequate and safe choice of bandage system. this approach may increase the patients’ participation in, and compliance with, compression therapy, thereby saving on costs and nursing time. references 1. wong iky, man mbl, chan osh, et al. interface pressure and static stiffness index of four compression systems. j wound care 2012;21:161, 164, 166-7. 2. mosti g, mattaliano v, partsch h. inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous reflux. phlebology 2008;23:287-94. 3. mosti g, partsch h. inelastic bandages maintain their hemodynamic effectiveness over time despite significant pressure loss. j vasc surg 2010;52:925-31. 4. mosti g, mattaliano v, partsch h. influence of different materials in multicomponent bandages on pressure and stiffness of the final bandage. dermatol surg 2008;34:6319. 5. partsch h. the use of pressure change on standing as a surrogate measure of the stiffness of a compression bandage. eur j vasc endovasc surg 2005;30:415-21. 6. wong iky, andriessen a, charles he, et al. randomized controlled trial comparing treatment outcome on quality of life of two compression bandaging systems and standard care without compression in patients with venous leg ulcers. jeadv 2012;26: 102-10. 7. wong iyk, andriessen a, lee dtf, et al. randomized controlled trial comparing treatment outcome of two compression bandaging systems and standard care without compression in patients with venous leg ulcers. j vasc surg 2012;55: 1376-85. 8. partsch h. the static stiffness index (ssi): a simple method to assess the elastic property of compression material in vivo. dermatol surg 2005;31:625-30. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2016; volume 5:5991 [page 22] [veins and lymphatics 2016; 5:5991] compression and deep vein thrombosis hugo partsch department of dermatology and angiology, medical university of vienna, vienna, austria introduction compression may have two beneficial effects in deep vein thrombosis (dvt): i) long term use may reduce the incidence and severity of a post-thrombotic syndrome (pts); ii) in the acute stage it alleviates pain and swelling. reduction of post-thrombotic syndrome based on meta-analyses wearing of compression stockings after dvt for 2 years reduces the incidence of pts.1,2 also previous american college of chest physicians (accp) guidelines have recommended compression after dvt for this indication.3 this suggestion has recently been changed, mainly due to the outcome of the sox trial, which was unable to find a reduction of pts, 2 years after dvt, when compression stockings were used in comparison to placebo stockings.4 this publication caused lot of discussions, in which especially the poor compliance wearing the stockings had been criticized.5 however, the most recent accp guideline states: in patients with acute dvt of the leg, we suggest not using compression stockings routinely to prevent pts (grade 2b). remarks: this recommendation focuses on prevention of the chronic complication of pts and not on the treatment of symptoms. for patients with acute or chronic symptoms, a trial of graduated compression stockings is often justified.6 it may be assumed that future guidelines will advocate a tailored regime suggesting compression for symptomatic patients as soon as data will be available.7 reduction of pain and swelling in the acute stage starting compression in the acute stage of dvt, at the same time as anticoagulation is a real cinderella indication, which tends to fall into oblivion. the description that strongly applied inelastic unna boot bandages (zinc paste invented by unna) lead to an immediate reduction of pain dates back more than 100 years ago.8 also swelling is immediately reduced, so that mobile patients are able to keep on walking. several famous european phlebologists followed the recommendation of treating dvt by compression in addition to anticoagulation (g. bauer, sweden; r. tournay, france; k. sigg, switzerland; f. haid-fischer, germany). however, this regime was based on experience only and not supported by scientific evidence. the introduction of low molecular heparin (lmwh) allowing safe and efficient anticoagulation by subcutaneous injections of fixed doses and avoiding intravenous infusions opened the possibility for home therapy. in our hands patients could stay ambulant without bed-rest due to the pain relieving effect of simultaneously applied good compression, without the risk of major pulmonary embolism.9 a randomized controlled three-arms study was started comparing bed-rest and no compression with compression stockings and with inelastic fischer bandages in patients with proximal dvt. since most patients did not want to take the risk of bed-rest and refused to sign the consent for the study plan, the study had to be stopped after 53 patients.10 all patients were mobile and received therapeutic doses of lmwh and overlapping vitamin k antagonists. one group received firmly applied unna-boot bandages (fischer-bandages),8 the second group, thigh-length compression stockings, and the third group had bed-rest and no compression. both compression groups were encouraged to walk. study duration was 10 days, starting on the day of admission to the hospital because of verified dvt extending into the thigh (n=37) or pelvis (n=16). pain was assessed by visual analogue scale and by a modified lowenberg-test. (assessing the tolerability of a pressure applied to both calves using a blood pressure cuff the difference between the tolerated pressure on the non-affected limb minus that on the leg with dvt gives a quantifiable parameter for pain). in addition, daily walking distances, quality of life and differences of leg circumferences were measured. repeated lung scans were performed as a safety feature. the firmly applied zinc paste bandages were wrapped over by inelastic textile bandages (rosidal k®; lohmann & rauscher ag, st. gallen, switzerland), and adhesive bandages were applied over the knee and thigh up to the groin (panelast® and porelast®; lohmann & rauscher ag). the initial resting pressure on the leg was >50 mmhg. these bandages stayed overnight and were changed every 2-3 days. thigh length compression stockings (23-31 mmhg) (sigvaris 503; sigvaris management ag, winterthur, switzerland) were also worn during night. in spite of the low number of recruited patients the outcome was convincing. there were statistically significant superior results for pain, swelling and quality of life favoring the compression groups in comparison to bed rest and no compression. globally, no significant difference was found between the efficacy of stockings and bandages. pain reduction was much faster with compression compared to bed-rest. one day after starting with inelastic fischer-bandages the pain level was in the same range as in the bed rest group after 5 days. more randomized clinical trials regarding the value of compression are rare. a study, concentrating on the post-thrombotic sequelae, after one year reported a faster reduction of clinical symptoms including pain and swelling if strong bandages were applied for one week in the acute phase of dvt in contrast to no compression.11 recently the authors of the sox trial have published a sub-analysis of their data concentrating on their findings after one month, concluding that compression stockings do not reduce leg pain in patients with acute proximal dvt.12 however, this conclusion is invalid, since treatment with compression started only 2-3 weeks after the onset of dvt, at which time acute symptoms have already disappeared.13 in conclusion new data are supporting the experience that good compression applied immediately is able to reduce pain and edema in dvt patients. future randomized trials should start in the acute phase of compression since we know that the clinical outcome in this acute phase will have a deciding influence on the development of pts. references 1. musani mh, matta f, yaekoub ay, et al. venous compression for prevention of postthrombotic syndrome: a meta-analysis. am j med 2010;123:735-40. 2. tie ht, luo mz, luo mj, et al. correspondence: hugo partsch, department of dermatology and angiology, medical university of vienna, baumeistergasse 85, a 1160 vienna, austria. e-mail: hugo.partsch@meduniwien.ac.at this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright h. partsch, 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5991 doi:10.4081/vl.2016.5991 no n c om me rci al us e o nly conference presentation [veins and lymphatics 2016; 5:5991] [page 23] compression therapy in the prevention of postthrombotic syndrome: a systematic review and meta-analysis. medicine (baltimore) 2015;94:e1318. 3. kearon c, akl ea, comerota aj, et al. antithrombotic therapy for vte disease: antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. chest 2012;141:e419s-94s. 4. kahn sr, shapiro s, wells ps, et al. sox trial investigators. compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. lancet 2014;383:880-8. 5. labropoulos n, gasparis ap, caprini ja, partsch h. compression stockings toprevent post-thrombotic syndrome. lancet 2014;384:129-30. 6. kearon c, akl ea, omelas e, et al. antithrombotic therapy for vte disease: chest guideline and expert panel report. chest 2016;149:315-52. 7. ten cate-hoek aj, ten cate h, tordoir j, et al. individually tailored duration of elastic compression therapy in relation to incidence of the postthrombotic syndrome. j vasc surg 2010;52:132-8. 8. fischer h. eine neue therapie der phlebitis. med klinik 1910;30. 9. partsch h. therapy of deep vein thrombosis with low molecular weight heparin, leg compression and immediate ambulation. vasa 2001;30:195-204. 10. blättler w, partsch h. leg compression and ambulation is better than bed rest for the treatment of acute deep venous thrombosis. int angiol 2000;22:393-400. 11. roumen-klappe em, den heijer m, van rossum j, et al. multilayer compression bandaging in the acute phase of deep-vein thrombosis has no effect on the development of the post-thrombotic syndrome. j thromb thrombolysis 2009;27:400-5. 12. kahn sr, shapiro s, ducruet t, et al. graduated compression stockings to treat acute leg pain associated with proximal dvt. a randomised controlled trial. thromb haemost 2014;112:1137-41. 13. partsch h. pain relief by compression in acute dvt. a critique of kahn et al. thromb haemost 2014; 112: 1137-1141. thromb haemost 2015;113:9067. no n c om me rci al us e o nly hrev_master veins and lymphatics 2012; volume 1:e6 [page 18] [veins and lymphatics 2012; 1:e6] ulcerated hemosiderinic dyschromia and iron deposits within lower limbs treated with a topical application of biological chelator eugenio brizzio,1 marcelo castro,2 marina narbaitz,3 natalia borda,2 claudio carbia,2 laura correa,4 roberto mengarelli,5 amalia merelli,2 valeria brizzio,2 maria sosa,6 biagio biancardi,7 alberto lazarowski2 1international group of compression and argentina medical association, buenos aires, argentina; 2department of clinical biochemistry, institute of pathophysiology and clinical biochemistry, school of pharmacy and biochemistry, university of buenos aires, argentina; 3pathology department hematology national academy of medicine, buenos aires, argentina; 4favaloro’s foundation, buenos aires, argentina; 5pontifical catholic university of argentina, buenos aires, argentina; 6italian hospital of buenos aires, argentina; 7faculty of pharmacy, university of naples, italy abstract the ulcerative haemosiderinic dyschromia of chronic venous insufficiency is difficult to heal and presents a high accumulation of iron. lactoferrin, a potent natural iron chelator, could help to scar this ulcerative haemosi derinic dyschromia. the objective of this study was to determine whether the topical application of a liposomal gel with lactoferrin favors scarring/degradation of the brown colored spot typical of ulcerative haemosiderinic dyschromia. nine patients with severe chronic venous insufficiency and ulcerative haemosiderinic dyschromia (ceap-c6), with a natural evolution of over 12 months, were included in the study. hemo chromatosis gene mutations were investigated. the levels of serum ferritin, transferrin saturation and blood cell counts were analyzed. the presence of hemosiderin was investigated through periulcerous and ulcer fundus biopsies carried out at baseline and 30 days after treatment with lactoferrin. the severity of the injuries (ceap classification) was evaluated at the beginning of and throughout the whole 3-month treatment period. no patient had received compression treatment during the three months previous to this therapy. significant improvement in these injuries, with a reduction in the dimensions of the brown spot (9 of 9) at day 90, and complete scarring with a closure time ranging from 15 to 180 days (7 of 9) were observed. the use of topical lactoferrin is a non-invasive therapeutic tool that favors clearance of hemosiderinic dyschromia and scarring of the ulcer. the success of this study was not influenced either by the hemochromatosis genetics or the iron metabolism profile observed. introduction chronic venous insufficiency (cvi) is one of the most significant health problems in developed countries. though the pathogenesis of skin changes and venous ulcers is not completely understood, they occur as a late consequence of chronic ambulatory venous hypertension, caused by outflow obstruction and reflux due to superficial or deep venous valve incompetence. ethological theories including fibrin cuffs or leukocyte entrapment by chronic inflammation have been suggested.1 haemosiderinic dyschromia (hd) of cvi is a pathological entity that features a brown colored spot resulting from the deposit of free iron within leg tissues. iron is a highly irritative element capable of stimulating free-radical release and of causing leg ulcers, thus producing an ulcerated hemosiderinic dyschromia (uhd). since it has been recognized as a grade iv cause of skin dyschromia according to ceap classification, and taking into account that these effects can be self-produced or generated by stimulation of melanin, there is an increasing interest in the role of iron tissue deposits caused by chronic venous disorders. according to this, a brown discoloration of the skin near the injury can be considered to be a typical sign of venous disease. it occurs when blood cells leak out of blood vessels. the hemoglobin from red blood cells is broken down into hemosiderin that is then permanently stored within the tissues. this can take place after a significant injury in the leg and is often worsened by an underlying venous problem.2,3 since extravasated blood cells with hemoglobin are phagocyted by tissue macrophages called siderophages, the accumulation of hemosiderin within the injury area is a characteristic feature of the disease, resulting in the brownish color of the skin.2 furthermore, urinary hemosiderin could be a biological marker for the clinical follow up of chronic venous insufficiency with haemosiderinic dyschromia.4 nearly 25% of absorbed iron is normally eliminated from the body by exfoliation of epidermal cells;5 therefore, iron accumulation in the skin should be secondary to any mechanism that may increase iron deposits before carrying out this exfoliation. iron is thought to be a co-factor or mediator of skin toxicity in a variety of pathological situations, including sunburn,6 porphyria cutanea tarda,7 inflammation,8 and skin cancer,9 as well as in hereditary hemochromatosis (hh).10 it is important to distinguish hd in cvi from hereditary hh because individual differences could be genetically determined by genes related to hh (h63d, s65c and c282y).11 lactoferrin (lfr) is a glycoprotein belonging to the family of transferrins, capable of binding to iron. both human and bovine lfr show a wide antimicrobial spectrum, against positive and negative gram bacterias, and certain viruses and fungi.12 the studies on lfr have focused on its ability to chelate iron in cases of hemosiderinic iron accumulation (ecchymosis, post sclerotherapy, cvi).12 the results of recent studies indicate that it is a powerful regulator of dermal fibroblasts, and that it promotes cutaneous wound healing; 13,14 correspondence: eugenio brizzio and alberto lazarowski, san martín 965, 1st floor (zip code 1004) buenos aires, argentina. tel. +54.11.4311.5559. e-mail: eugeniobrizzio@ciudad.com.ar; ebrizzio@fibertel.com.ar; eugeniobrizzio@gmail.com; alazarowski@gmail.com key words: ulcerated haemosiderinic dyschromia, liposomal lactoferrin, scarring, hemosiderin-ferritin. acknowledgments: the authors would like to thank p. girimonte for her assistance with the statistical analysis of the results. we also wish to thank the patients who made this study possible. conference presentation: part of the present study has been presented at the following congresses: i) xx argentine congress of hematology, october 18-22, 2011, mar del plata, argentina (submitted to the poster section); ii) iii world symposium of advances in phlebology and lymphology, november 10-12, 2011, buenos aires, argentina (awarded); iii) latin american congress of angiology and vascular surgery, november 24th, 2011, cartagena, colombia. received for publication: 26 july 2012. revision received: 19 september 2012. accepted for publication: 26 september 2012. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright e. brizzio et al., 2012 licensee pagepress, italy veins and lymphatics 2012; 1:e6 doi:10.4081/vl.2012.e6 no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e6] [page 19] however, this has been poorly researched. there is currently no efficient treatment for hd and associated ulcer in patients with cvi. in a recent systematic survey and meta-analysis, eight randomized clinical trials were identified comparing treatment with stockings and bandages. five studies revealed an advantage in the use of stockings over bandages, while three other assays showed no difference.15 our aim was to study the effect of liposomated bovine lactoferrin, locally applied on the surface of uhd, in 9 patients with long-lasting evolution of refractory cvi, selected from our previous study,16 and to evaluate its potential relation to the iron metabolism profile and mutations of hh genes.17 study design this was a prospective controlled pilot study performed on 9 selected patients with severe and persistent uhd of cvi, carried out according to the inclusion and exclusion criteria described below. all patients gave their signed individual consent to treatment with topical application of liposomated lfr and to undergo biopsy of two lesions. there were three evaluation time points: at 30, 90 and 180 days. the therapeutic protocol was presented for review by the independent court of ethics on march 5th 2010 and was accepted on april 23th 2010; the protocol was approved in accordance with the principles of the declaration of helsinki. the study used a database consistent with the results obtained during a 6-month followup period of 9 patients with recalcitrant venous ulcers. only one of them presented bilateral ulcers with similar severity of lesions in both legs. this was a pilot study and the data collected should be considered in this light. the main parameters controlled before and after treatment were: i) stratification of cvi (ecodoppler), and leg goniometry and edema; ii) severity of ulcerous injuries (color, ulcer areas, rate of scarring time); iii) pain and quality of life; iv) hemosiderin staining in biopsies and blood iron metabolism parameters; v) hematologic profiles; vi) iron profiles; vii) the presence of hh mutations as potential predictive parameters of evolution. inclusion criteria the main inclusion criteria were: i) patients over 18 years old; ii) unilateral or bilateral ulcers at the anteromedial part of the calf, of proved venous origin, confirmed by ecodoppler ultrasound; iii) surface larger than 3 cm² and smaller than 25 cm²; iv) presence of associated periulcerative haemosiderinic dyschromia; v) pre-existing ulcer with at least two months of evolution; vi) patients accepting to undergo treatment according to protocol; vii) each patient received a written report and signed their consent. exclusion criteria the main inclusion criteria were: i) presence of occlusive arterial pathology with a more than 0.8 arm/ankle index; ii) known allergies; iii) pregnancy; iv) life expectancy less than 12 months; v) severe diseases coexisting simultaneously with venous pathologies, e.g. cardiac or mental disorders, renal or hepatic insufficiencies, tumors, etc.; vi) symptomatic peripheral neuropathy, e.g. diabetic neuropathy; vii) patients with motor disabilities; viii) diabetes; ix) severe joint disease of the ulcerated leg, besides the ankle stiffness caused by venous ulceration. materials and methods patients nine patients were selected (3 males, 6 females); average age 63 years. a total of 10 ulcerated legs were studied (unilateral ulcers, n=8; bilateral ulcers, n=2). ecodoppler a sonoscape® colour ecodoppler s6 (sonoscape co. ltd., shenzhen, china) was used to confirm the venous vascular etiology of the ulcer and the stratification of patients according to the type of reflux observed. only one baseline control was performed at the moment of admission. stratification of patients was carried out according to the type of reflux observed, such as superficial, perforating, deep, or their combined forms as superficial + perforating, perforating + deep, superficial + perforating + deep. lesion evaluation time from the onset of the cvi, the evolution of the hemosiderinic dyschromia, and the ulcer development were all recorded. since skin pigmentation as a brown discoloration near the lesion is a typical feature of hd in case of venous ulcers, a visual scale of brown color was used to follow up treatment. baseline and weekly controls were carried out. we used an analogical visual arbitrary numbered scale of brown (figure 1) that allowed us to build a follow-up chart and to identify any improvement in hd. wound size is a basic parameter used to evaluate the success of treatment. the planimetric visitrak® smith and nephew device (smith and nephew, hull, uk) was used. volume was obtained through perimeters measured at 4 segments of the leg: 12 cm from hallux extremity, and 10, 20 and 30 cm from the floor (figure 2a and b).18-19 goniometry was measured using the model described by cleusa belczak (figure 3). 20 pain was measured at baseline and after four weeks of treatment using the arbitrary numerical likert scale from 1 to 5, where 1 indicates the lowest intensity of pain and 5 the highest one.21 the quality of life questionnaire in chronic lower limb venous insufficiency (civiq) was evaluated as previously described.22 venous blood samples for determining hematimetric parameters as well as molecular studies were drawn in 2 separate collection tubes containing potassium ethylene diamine tetraacetic acid (k3-edta), while those for determining biochemical parameters were drawn in tubes with serum separators. serum was freshly separated from venous blood samples by centrifugation at 1800 g for 10 min at room temperature. all fractioned serum samples and those for molecular studies were stored frozen at -20°c for three months before assaying. hematimetric parameters were evaluated on fresh samples immediately after blood sample collection; full blood cell counts were studied by sysmex xt-1800 (roche, penzberg, germany). serum iron (sfe, mg/dl), total iron-binding capacity (tibc, mg/dl), transferrin saturation (sat-trf %) and serum ferritin (sf, ng/ml) were assayed using a cobas 6000 autoanalyzer system (roche). figure 1. arbitrary identification of color scale used. no nco mm er cia l u se on ly article [page 20] [veins and lymphatics 2012; 1:e6] hfe genotyping samples: five drops of 25 ul of anticoagulated blood with k3-edta were collected on whatman filter paper no. 1 (5¥5 cm) and stored at room temperature in a paper envelope dna extraction: dna was extracted by the modified boom method.23 two drops of dried blood from filter paper of each sample were cut with a scalpel and placed on 4.5 ml of lysis buffer. after 4 h of gentle shaking, the paper was carefully discarded and the dna was extracted in the supernatant as previously described.23 dna extracts were stored at -20°c. amplification and detection: the polymerase chain reaction (pcr) mixture was prepared in separate tubes for the study of mutations in exons 4 and 2, respectively, at a final volume of 50 ul and a final concentration of 1x taq buffer, 0.2 mm dntp, 2.5 mm mgcl2, 0.5 u of taq polymerase (invitrogen corp., carlsbad, ca, usa) and 0.2 um of each primers (invitrogen). we used 5 ul of dna extract per sample. the sequences of the primers used were: i) exon 4 (cys282tyr mutation) forward: 5’tggcaagggtaaacagatcc reverse 5’ctcaggcactcctctcaacc (390 bp); ii) exon 2 (mutations his63asp and ser65cys) forward: 5’acatggttaaggcctgttgc reverse 5’gccacatctggcttgaaatt (208 bp). for both constructions of primers, amplification conditions were 35 cycles with an annealing temperature of 63°c. then 15 ul of pcr products were digested with 2 u of rsa i for codon 282, bcl i for codon 63 and hinf i for codon 65 (new england biolabs, ipswich, ma, usa) overnight, according to the manufacturer’s instructions. the digestion products were run on 3% agarose gel (invitrogen) for 2 h at 120 volts, with ethidium bromide for viewing under uv light. this allowed us to distinguish wild-type (wt), heterozygous (ht) and homozygous (ho) genotypes for each mutation with the following cutting patterns:24,25 rsa i (cys282tyr): wt 250 pb/140 pb, ho 250 pb/111 pb/29 pb, ht 250 pb/140 pb/111 pb/29 pb; bcl i (his63asp): wt 138 pb/70 pb, ho 208 pb, ht 208 pb/138 pb/70 pb; hinf i (ser65cys): wt 147 pb/60 pb, ho 207 pb, ht 207 pb/147 pb/60 pb. biopsy handling: all patients were treated with subcutaneous local administration of 1% sterile xilocaine. after 10 min, an approximately 12 mm long and 3 mm wide rectangle of tissue was excised to include the surrounding intact skin, the ulcer edge, and the ulcer base. in order to compare changes on both anatomic and hemosiderin staining patterns, biopsies were taken at two different contiguous sites for initial and end-point samples, respectively.26 biopsy histochemistry: each biopsy was immediately divided lengthways. one half was fixed in cold 4% paraformaldehyde in phosphate buffered saline and the other was snapfrozen in optimal cutting temperature over liquid nitrogen for immunocytochemistry. after 24 h, fixed tissues were embedded in paraffin wax and sectioned at 4 m. hematoxylin & eosin and perls’ prussian blue methodswere used to stain alternate sections.27 operational protocol: the product, a gel containing bovine lfr liposomated to 3%, placed on a 15¥20 cm sterile paraffin dressing (tulle gras) made of open weave gauze, with 0.5% chlorhexidine acetate, an antiseptic with a broad spectrum (bactigras® plaque, smith and nephew), was locally applied every day for four weeks (first end point). it was applied twice a week during the second and third months using an additional compression by means of a multilayer bandage from the very first day, assembled with 3 short 8 cm and 10 cm elastic bandages (fisiodur®, zuccari srl, trento, italy). the multilayer bandage was applied in a figure-of-eight with turns that regularly crossed one another, with a resting pressure of 40 mmhg and 5-7 mmhg of static stiffness, as previously described.28 at each medication session, the ulcer was cleaned using gauzes impregnated with prontosan® solution (b. braun medical inc., bethlehem pa, usa) followed by administration of simple occlusive medication. results patients nine patients were selected from a cohort of 55 patients who had previously completed the aforementioned comparative study of lowstrength medical compression stockings with bandages for treating recalcitrant venous ulcers,16 after a long period without showing any improvement in the ulcers’ features (e.g. dimensions, color intensity of dyschromia), as well as pain and civiq. of the 9 independent cases analyzed, 5 corresponded to primary (p) ulcers and the remaining 4 to recidivating (r) ulcers. ninety percent of the patients included in this study presented dynamic static alterations of plantar support, 4 patients with pes cavus (grades ii and iii), another 4 with flat feet (grades ii and iii), and the remaining patient without any foot disorder. there was equal distribution of lower limb ulcers between both legs (right n=5, left n=5), taking into account that one patient had bilateral ulcers that both presented the same degree of severity (table 1). stratification of refluxes through ecodoppler ecodoppler confirmed the venous vascular etiology of the ulcer (figure 4). no patients presented purely deep reflux. one case exhibited an altered reflux due to the combination of the three systems associated with a severe hemodynamic condition (table 2). lesion evaluation range of duration of cvis was 48-560 months, of hemosiderinic dyschromia 15-240 months, and of ulcers 2-54 months (table 1). in order to perform an evolutive control of the hemosiderinic dyschromia, we used an analogical and arbitrary visual numbered scale of the color brown, and built a chart of color evolution. therefore, the real color intensity of the skin was compared to the intensities of the aforementioned color scale (table 3). this scale figure 2. (a) patient’s leg with (b) schematic representation of cylindrical volume of each area (1-4). modified from rossi et al.29 figure 3. belczak’s model of goniometry. no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e6] [page 21] showed a starting point with an average intensity of 18.7 and decreased to an average intensity of 7.2 at week 12 (p<0.001) (figure 5). an approximately 50% decrease in color intensity was observed at week 4. measurement of the area of the ulcer the area of the ulcer and the scarring rate were checked at study start and at weekly intervals, and observations were recorded. during the initial control, dimensions of ulcers ranged from 3.3 to 23.6 cm. in 8 of 9 patients (9 of 10 ulcers), the area involved decreased significantly (p<0.001) (table 4 and figure 6), and in 7 patients, the healing rate reached 80% of the ulcers at the 6-month follow up (table 5). only one patient, who had abandoned the trial, showed a transient increase in the size of the surface of the ulcer, which returned to baseline at month 6. volumetric perimeter: control of edema perimetral control of foot and leg was transformed to volume in cm3 as previously described.18-20 with the exception of case no. 3437 (corresponding to the patient with bilateral ulcers) whose values were approximately 9500 cm3, the remaining cases presented values ranging from 3000 cm3 to 5000 cm3 and a mild decrease in the edema volume was observed (table 6). goniometry was measured at baseline and after 30 days to check flexion (flx) and extension (ext) movements. a favorable evolution of the tibioastragaline joint could be observed at the expense of an increase in flexor and extensor excursions without any additional treatment (table 7). pain and chronic lower limb venous insufficiency controls we used the numerical likert scale, most commonly seen as a 5�point scale (0=no pain, 5=worst possible pain). in 5 patients, the maximum level of pain (grade 5) was observed at the initial control; this was later reduced to grade 1 after four weeks of treatment. as far as the remaining patients are concerned, the level of the likert scale diminished 1 point during the same period (table 8). the survey of quality of life (civiq), the baseline control and the tests performed during weeks 4, 8 and 12 showed an improvement at all levels. it could be observed that, at all times, the average scoring of the civiq scale (total score) in patients with ulcers closed at week 12 was lower than the average scoring in patients with unclosed ulcers (p<0.05) (table 9). blood tests: hematimetric and iron metabolism profiles normal results of basal control (1st) and after four weeks (2nd) of treatment on hematimetric parameters and platelet counts were observed in all cases (data not shown), and iron metabolism profile (table 10). interestingly, while transferrin sat (%) decreased in 7 of 9 cases, ferritin increased in 6 of 9. hfe genotyping only one of the 9 patients (case no. 3334) was heterozygous for the mutant h63d gene (table 10). coincidentally, the patient presented a high level of ferritin (222 and 244 µg/ml). table 1. main features of patients’ lesions. no patients were previously treated by surgical or sclerotherapy procedures. case no. laterality duration cvi duration interval duration primary cavus bmi (months) dyschromia (months) ulcer age or recurrent and/flat feet (months) (months) 3446 r 180 22 20 2 p fc normal 3437r r 180 60 24 36 r fc ob.3 3437l l 180 60 30 30 r fc ob.3 3283 l 336 36 34 2 r fc ob.1 3334 r 276 48 46 2 r fc over weight 3161 l 192 84 36 48 r normal normal 3441 l 60 54 --54 p ff normal 3451 r 48 15 2 13 p ff ob.2 3274 l 560 60 57 3 p ff ob.2 3449 r 360 240 236 4 r fc normal r, right; l, left; cvi, chronic venous insufficiency; p, primary; r, recurrent; bmi, body mass index; ob, obesity. figure 4. color ecodoppler: reflux in great saphenous vein. no nco mm er cia l u se on ly article [page 22] [veins and lymphatics 2012; 1:e6] ecodoppler for this patient evidenced reflux on the 3 systems, superficial, perforating and deep reflux mentioned above. biopsy histochemistry biopsy features of borders and ulcer bed: samples of two control biopsies (initial and after 4 weeks of treatment) were obtained from the periulcerous area in 10 ulcers, and additional samples from the ulcer bed were obtained in another 2. histological features (figure 7) and hemosiderin staining (figure 8) were evaluated before and after treatment. before treatment, the histological analysis showed the presence of fibrin cuffs, small vessels, and extravasation of red blood cells, fibrosis and a chronic inflammatory pattern (figure 7a). perls’ prussian blue staining showed superficial and deep high cumuli of hemosiderin in the border and fundus of the ulcer (figure 8a). after four weeks of treatment, extravasated red blood cells and fibrosis were still present; however, certain neovascular structures as well as a repairing inflammatory pattern were observed (figure 7b). in some cases, perls’ prussian blue staining seemed to have decreased (figure 8b). discussion ochre dermatitis is a secondary pigmentary disorder of venous stasis in which the increase in intravascular pressure and endothelial alterations cause extravasations of erythrocytes, hemosiderin-laden macrophages, and melanin deposits. it is associated with longterm and high care costs, with an equally high incidence of recurrence, and a significant proportion of negative patient outcomes.29 in our study, all 9 patients were selected from a previous study because they had ulcers and hemosiderinic dyschromia, both associated to refractory ulcer. wound repair depends on neoangiogenesis and activation of a local immune response, as well as on the presence of growth factors, including epidermal growth factor, transforming growth factor b, and basic fibroblast growth factor.30,31 it has been recently suggested that systemic or topical drugs acting in the wound repair and regeneration processes could be promising and useful agents in the treatment of chronic venous ulcers.32 however, in a previously reported systematic review performed by bradley et al., 16 randomized controlled trials were identified that compared topic agents (growth factors, cell suspensions, free-radical scavengers) versus placebo for treating cvi ulcers, concluding that there was insufficient evidence to recommend any particular agent.33 the main finding was that topic application of liposomated lfr allowed a fast and progressive table 2. stratification of refluxes through ecodoppler (type) and frequencies (no.) of pure or mixed forms of reflux. systems type no. superficial reflux only one system 1 perforating reflux only one system 3 deep reflux only one system 0 mixed superficial and perforating reflux two systems 3 mixed perforating and deep reflux two systems 1 mixed superficial, perforating and deep reflux three systems 1 table 3. brown color scale: colorimetric evolution. weeks case no. baseline 1 2 3 4 8 12 3446 26 17 13 11 9 7 7 3437r 23 23 22 11 9 8 8 3437l 25 18 17 14 11 10 9 3283 17 10 9 8 7 3334 19 18 17 14 11 10 8 3161 8 7 5 5 5 5 5 3441 18 17 14 14 13 8 5 3451 16 15 14 11 10 8 7 3274 18 16 14 11 10 8 7 3449 17 15 14 13 13 11 9 r, right; l, left. table 4. evolution of ulcerous area in cm2 during the first six months of follow up. case no. study start month 1 month 2 month 3 month 4 month 5 month 6 3446 3.3 0.0 3437r 6.5 0.1 0.1 0.0 3437l 12.8 10.7 8.8 8 5.7 3.2 0.0 3283 4.5 5.8 7.2 8.3 4.5 deserted 3334 3.1 0.5 0.2 0.1 0.0 3161 6.0 5.1 7.5 6.4 4.7 2.7 0.0 3441 19.9 8.8 0.6 0.0 3451 23.6 11 3.5 2.1 0.0 3274 3.6 0.8 1.8 0.3 0.5 0.2 0.0 3449 9.6 6.2 6.7 6.2 5.2 4.9 00 r, right; l, left. table 5. time (months) taken to achieve complete closure of the 10 lesions from 9 patients. time (months) number closed lesions total 1 1/10 1 3 2/10 3 6 6/10* 9 *one patient left the study. no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e6] [page 23] reduction in the dimensions of the area of the ulcer in 9 of 9 patients and complete closure in 7 of 9 cases. the 90 days of evolution evidenced an important improvement in the injuries, with a reduction in the intensity of the brown color of the spot (9 of 9) and time to complete scarring ranging from 15 to 180 days (7 of 9). it is important to emphasize that the patients belonged to the group of refractory cases included in the previous study already mentioned.16 this assay showed that 50% of ulcers showed complete closure using medical compression stockings, and 67% of complete closure with multilayer bandages, after 180 days. one of the most remarkable findings was the significant decrease, in all cases, of the brown color of the hd and the size of the ulcerous areas (figures 5 and 6), with a concomitant goniometric improvement (table 7), and complete closure of lesions in 7 cases after six months of treatment. the rate of healing was independent of baseline or recurrent ulcers (figure 5). in all patients, clinical improvement of the wounds (10 ulcers) was associated with a significant decrease in pain and improvement in quality of life, except in one case (*case no. 3161) due to a domestic accident on the lesion, which showed no clinical improvement and led to the patient discontinuing treatment (figure 6, tables 8 and 9). all biopsies showed changes in cytological patterns (figure 7). in several cases, a decrease was seen in the high level of stainfigure 5. variation in brown color scale values during the treatment. figure 6. ulcer’s areas diminution during six weeks of follow up. table 6. edema control in cm3: volumetric variation in leg edemas. case no. basal week 1 week 2 week 3 week 4 week 8 week 12 3446 4227 4127 4089 4072 3958 3932 3886 3437r 9457 9409 9678 9623 9562 9549 9605 3437l 9963 9856 9777 9670 9581 9588 9540 3283 4215 4122 4092 4061 4011 3999 3980 3334 4747 4680 4565 4548 4495 4424 4366 3161 3163 3056 3431 3214 3125 3008 2998 3441 4149 4011 4020 3977 3959 3884 3892 3451 4480 4314 4241 4204 4115 4097 4161 3274 4261 4008 3878 4129 4114 4059 3993 3449 4737 4512 4498 4451 4388 4275 4174 r, right; l, left. table 7. baseline-final goniometry. goniometric values before and after 30 days of treatment. case no. bg (flx) fg (flx) bg (ext) fg (ext) 3446 12° 12° 30° 42° 3437r 10° 19° 22° 25° 3447l 9° 10° 22° 24° 3283 5° 12° 25° 35° 3334 10° 12° 30° 35° 3161 10° 12° 19° 28° 3441 3° 10° 37° 40° 3451 9° 12° 22° 24° 3274 10° 11° 20° 23° 3449 9° 10° 15° 30° r, right; l, left; bg, baseline; fg, final goniometry; flx, flexion; ext, extension. no nco mm er cia l u se on ly article [page 24] [veins and lymphatics 2012; 1:e6] ing for hs in periulcerous and ulcer fundus biopsies present during the initial control (figure 8) and this associated with a significant improvement in the edema and ulcerous areas (figure 9) after treatment. iron deposits in the skin of patients with cvi cause readily visible hd (brown colored dermal areas) that always surrounds ulcers. the origin of increased iron loads in these lesions lies in the extravasations of red blood cells during significant venous stasis. erythrocytes are degraded by resident dermal macrophages, and iron is incorporated into ferritin which, in time, changes to hs according to progressive iron overload.30,32 furthermore, the urinary excretion of hemosiderin described in these patients4,33 suggests that the phenomenon of leg hemosiderin deposits could be of significance on the entire body.34,35 however, in contrast with this hypothesis, in 1988 ackermann found a 20-fold higher average concentration of iron in lower limbs affected by venous ulcers as compared to the upper arms of the same subjects.2 the distribution of high levels of ferritin staining in leg ulcers of patients with cvi were reported to be located intra and extracellular in the matrix, as compared with normal skin tissue with considerably less alterations or nonevident alterations at all.11 however, the systemic parameters of iron metabolism observed in our study (table 7) did not seem to influence either the severity of hd nor the evolution of treatment with local lfr. furthermore, the abnormal levels of ferritin observed in some patients did not limit the previously mentioned improvement in the ulcers. however, it is important to note that potential co-morbidities could be associated to systemic iron overload. one case that presented an altered reflux caused by the combination of the three systems associated with a severe hemodynamic condition was also a carrier of an hfe gene mutation (heterozygous), evidencing high levels of serum ferritin (222 and 244 ng/ml), and suffered a sudden death. in another case with elevated serum ferritin (405 and 355 ng/ml) the patient experienced heart insufficiency and later stroke. finally, the patient with bilateral ulcers also exhibited high serum ferritin values (233 and 251 ng/ml). we still do not know with certainty if ferritin could constitute a prognostic evolutive parameter, but its association to the clinical evolution observed in 3/9 patients suggests that it should be included in follow-up protocols. because all parameters studied including ulcer lesion features, as well as quality of life (civiq) and pain (likert’s scale) were improved after treatment, topic application of liposomed lf could be a new therapeutic strategy, particularly in patients with refractory ulcers and hd associated secondary to chronic venous insufficiency. figure 7. (a) histological features before treatment: presence of fibrin sleeves, small vessels, extravasations of red blood cells, fibrosis, chronic inflammatory pattern. (b) histological features after treatment (4 weeks): presence of new vascular structures, extravasations of red blood cells, fibrosis and granulation tissue-granulation, chronic repairing inflammatory pattern. figure 8. baseline sample (a) showed high hemosiderin concentration (local iron overload) with (b) an evident reduction in hemosiderin staining after four weeks of treatment. table 9. positive chronic lower limb venous insufficiency score: variation between baseline and final values were observed in all cases except in one patient (*) who discontinued treatment. case no. baseline final b-f 3446 35 33 2 3437 83 75 8 3283 66 59 7 3334 53 47 6 3161* 49 53 -4 3441 73 60 13 3451 89 80 9 3274 67 60 7 3449 71 66 5 b, baseline; f, final. *one patient left the study. table 8. pain control using the likert scale comparing baseline values with those obtained at week 4. case no. baseline week 4 3446 1 1 3437r 5 1 3437l 5 1 3283 5 3 3334 3 2 3161* 2 3 3441 5 2 3451 5 1 3274 2 1 3449 5 1 r, right; l, left. *one patient left the study. no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e6] [page 25] as regards its iron binding properties, lfr differs from serum transferrin in its higher iron binding affinity and unique ability to retain iron over a broad ph range.1 the protective effects of topic lfr on induced dermatological allergic process was demonstrated experimentally.36 similar results were obtained in a study carried out on human volunteers, treated by topical administration of the contact allergen and using purified recombinant human lfr.37 although originally identified as an abundant protein in milk secretions, lfr is mainly expressed by surface epithelia and secreted into the mucosal environment. however, further research is needed to clarify whether local iron mobilization, free radical scavenging and induction to tissue repair are simultaneously staged by the multiple properties of lf. conclusions our results suggest that the topical use of lfr could be a potential non-invasive therapeutic tool that favors clearance of hd and a faster closure of ulcers, with concomitant relief or disappearance of pain, and consequent improvement in quality of life in patients with chronic venous insufficiency. further research is needed to confirm these results by prospective randomized controlled studies. references 1. raju s, neglen p. chronic venous insufficiency and varicose veins. n engl j med 2009;360:2319-27. 2. ackerman z, seidenbaum m, loewenthal e, rubinow a. overload of iron of patients with varicose ulcers: possible contributing role of iron accumulation in progression of the disease. arch dermatol 1988;124:1376-8. 3. allegra c, antignani pl, bergan jj, et al. international union of phlebology working group. the “c” of ceap: suggested definitions and refinements: an international union of phlebology conference of experts. j vasc surg 2003;37:129-31. 4. piotrowicz r, grzela t, jawień a, kuligowska-prusińska m. urine haemo siderin: a marker of chronic venous insufficiency. acta angiol 2009;15:101-7. 5. weintraub l, demis d, conrad m, crosby w. iron excretion by the skin selective localization of iron in epithelia cells. am j pathol 1965;46:121-7. 6. bissett dl, chatterjee r, hannon dp. chronic ultraviolet radiation induced increase in skin iron and the photo protective effects of topically applied iron chelators. photochem photobiol 1991;54:215-23. 7. takeshita k, takajo t, hirata h, et al. in vivo oxygen radical generation in the skin of the protoporphyria model mouse with visible light exposure: an l-band esr study. j invest dermatol 2004;122:1463-70. 8. gira ak, casper ka, otto kb, et al. induction of interferon regulatory factor 1 expression in human dermal endothelial cells by interferon-gamma and tumor necrosis factor-alpha is transcriptionally regulated and requires iron. j invest dermatol 2003;121:1191-6. 9. bhasin g, kausar h, sarwar alam m, athar m. progressive iron overload enhances chemically mediated tumor promotion in murine skin. arch biochem biophys 2003;409:262-73. 10. chevrant-breton j, simon m, bourel m, ferrand b. cutaneous manifestations of figure 9. comparison of severity of lesion before (a, c) and after (b, d) treatment. (a and b) size of ulcers and (c and d) edema. intensity of hemosiderin staining. decreasing dimensions of edema and ulcers correlate with a lower staining hemosiderin observed after treatment (a and b). table 10. iron metabolism profile. case no. iron m/dl tibc m/dl transferrin ferritin sat. (%) ng/ml 1° 2° 1° 2° 1° 2° 1° 2° 3446 38 53 361 253 10.5 20.1 25 23.8 3437 61 58 302 306 20.1 19 233 251 3283 60 74 263 265 23.5 27.9 117 126 3334 73 53 325 382 22.4 18.9 222 244 3161 57 48 297 311 19 15.4 82 72.9 3441 52 44 309 325 16.8 13.5 26 31.3 3451 73 70 198 212 36.8 33 405 355 3274 128 120 296 301 43 40 197 201 3449 72 66 250 251 28.8 26.2 112 117 tibc, total iron binding capacity. no nco mm er cia l u se on ly article [page 26] [veins and lymphatics 2012; 1:e6] idiopathic hemochromatosis. study of 100 cases. arch dermatol 1977;113:161-5. 11. zamboni p, tognazzo s, izzo m, et al. hemochromatosis c282y gene mutation increases the risk of venous leg ulceration. j vasc surg 2005;42:309-14. 12. valenti p, berlutti f, conte mp, et al. lactoferrin functions: current status and perspectives. j clin gastroenterol 2004;38 suppl 6:s127-9. 13. tang l, wu jj, ma q, et al. human lactoferrin stimulates skin keratinocyte function and wound re-epithelialization. br j dermatol 2010;163:38-47. 14. engelmayer j, blezinger p, varadhachary a. talactoferrin stimulates wound healing with modulation of inflammation. j surg res 2008;149:278-86. 15. brizzio e, blättler w, rossi g, et al. healing venous ulcers with different modalities of leg compression. unexpected findings of a pilot study. phlebologie 2006;35:249-55. 16. brizzio e, amsler f, lun b, blättler w. comparison of low-strength compression stockings with bandages for the treatment of recalcitrant venous ulcers. j vasc surg 2010;51:410-6. 17. blättler w, lüscher d, brizzio e, et al. healing of chronic venous leg ulcers could be affected by an interaction of the hemochromatosis gene polymorphism hfe h63d with the strength of compression treatment a re-analysis of patients from previous studies. wound repair regen 2012;20:120-4. 18. perrin m, guex jj. edema and leg volume: methods of assessment. angiology 2000;51:9-12. 19. rossi g, idiazabal g. mathematical model to obtain the volume of the lower limb. int angiol 2005:3 suppl 1:110. [abstract]. 20. belczak ceq. fisiologia do sistema venoso. in: thomaz jb, belczak ceq (eds.). tratado de flebología y linfología. rio de janeiro: editorial rubio; 2006. pp 37-70. 21. likert r. a technique for the measurement of attitudes. archiv psychol 1932;140:1-55. 22. launois r, reboul-marty j, henry b. construction and validation of a quality-oflife questionnaire in chronic lower limb venous insufficiency (civiq). qual life res 1996;5:539-54. 23. boom r, sol c, salimans m, et al. rapid and simple method for purification of nucleic acids. j clin microbiol 1990;28:495-503. 24. baptista-gonzález ha, rosenfeld-mann f, trueba-gómez r, et al. association of hfe mutations (c282y and h63d) with iron overload in blood donors from mexico city. ann hepatol 2007;6:55-60. 25. oliveira vc, caxito fa, gomes kb, et al. frequency of the s65c mutation in the hemochromatosis gene in brazil. genet mol res 2009;8:794-8. 26. herrick se, sloan p, mcgurk m, et al. sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. am j pathol 1992;141:1085-95. 27. bancroft j, gamble m (eds.). theory and practice of histological techniques bancroft & gamble. 6th edition. london: churchill-livingstone, elsevier health sciences; 2008. 28. brizzio e, idiazabal g. multilayer system. rev acta flebol 2003;3:65-8. 29. beebe-dimmer jl, pfeifer jr, engle js, schottenfeld d. the epidemiology of chronic venous insufficiency and varicose veins. ann epidemiol 2005;15:175-84. 30. eming sa, kieg t, davidson jm. inflammation in wound repair: molecular and cellular mechanisms. j invest dermatol 2007;127:514-25. 31. werner s, grose r. regulation of wound healing by growth factors and cytokines. physiol rev 2003;83:835-70. 32. palfreyman s, king b, walsh b. a review of the treatment for venous leg ulcers. br j nurs 2007;16:s6-14. 33. bradley m, cullum n, nelson ea, et al. systematic reviews of wound care management: (2) dressings and topical agents used in the healing of chronic. health technol assess 1999;3:1-35. 34. zamboni p, scapoli g, lanzara v, et al. serum iron and mmp-9 variations in limbs affected by chronic venous disease and venous leg ulcers. dermatol surg 2005; 31:644-9. 35. zamboni p, izzo m, tognazzo s, et al. the overlapping of local iron overload and hfe mutation in venous leg ulcer pathogenesis. free radic biol med 2006;40:1869-73. 36. zweiman b, kucich u, shalit m, et al. release of lactoferrin and elastase in human allergic skin reactions. j immunol 1990;144:3953-60. 37. griffiths ce, cumberbatch m, tucker sc, et al. exogenous topical lactoferrin inhibits allergen-induced langerhans cell migration and cutaneous inflammation in humans. br j dermatol 2001;144:715-25. no nco mm er cia l u se on ly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: la technique start (sclerotherapy in tumescent anaesthesia of reticular veins and telangiectasias) by ramelet aa. phlebologie 2012 (also appeared as: sclerotherapy in tumescent anesthesia of reticular veins and telangiectasias. dermatol surg 2012;38:748–51.) stefano ricci abstract having observed that treating telangectesias during the same phlebectomy session gave better results, the authors began to associate to the sclerotherapy (polidicanol foam 0.25-0.50%) a tumescence made with ringer solution, in some cases adding lidocaine-epinephrine. this is carried out either before, during or after sclerotherapy, usually with a 20-50 ml syringe or by a perfusion pump. after the procedure, the patient rests for a few minutes, and then puts on 20-30 mmhg stockings; these will be used for three weeks. during the last six years, 300 patients presenting refractory telangectasias (not disappearing after 3 treatments) or large telangectatic areas otherwise needing several sessions, were selected. patients who preferred to receive the sclerotherapy treatment in local anesthesia were also included. the results were very good; the majority of the patients needed only one session, and a stable outcome was achieved. complications, such as hematoma, thrombosis, pigmentation, small necrosis and matting, although a possible complication with polidocanol, were more frequent than usual, probably due to the higher risk associated with this difficult pathology. the efficacy of this technique may be related to the high perivenous pressure achieved during and after treatment, lasting at least an hour, similar to that suggested by thibault and parsi (i.e. infiltration of the saphenous space after saphenous injection). comment by stefano ricci in the field of telangectasias, one of the most difficult areas of phlebology, novelties are rare, and when one is announced, it is usually associated to some expensive technology. that is why the simple method suggested by ramelet is particularly interesting: it is easy, not expensive, rational and (according to the author) effective. my personal experience of sclerotherapy in areas previously treated with phlebectomy confirms that the fading effect on telangectasias is enhanced. in my mind, this has been related to a sort of reaction (edema, hyperemia, inflammatory activation) of treated tissues making the sclerosis more efficient, but the tumescence theory is possibly another aspect of this. it would be interesting to know, from the author’s experience, if also other types of sclerotherapy (liquid, scleremo) behave similarly. chromated glycerine for example, being more gentle, could cause less inconvenience than polidicanol in foam. finally, a better definition of refractory telangectasias would be interesting, not forgetting that areas that underwent several previous treatments may respond positively to further treatment for cumulative effect. reply by the author i have used start with scleremo or liquid polidicanol without problems, but i particularly like foam, a matter of choice and habit. the definition of refractory telangectasias is difficult. refractory to what? to not repeating the treatment? because it has been badly managed? is inadequate? in order to simplify, i mean refractory to several sessions by an experienced physician. [top] hrev_master veins and lymphatics 2013; volume 2:e12 [veins and lymphatics 2013; 2:e12] [page 37] the use of strapping to increase local pressure: reporting of a sub-bandage pressure study alison hopkins,1 fran worboys,1 hugo partsch2 1accelerate cic, london, uk; 2private practice, vienna, austria abstract high compression is the gold standard for venous ulcer management. this brief report presents the results of a sub-bandage pressure study that investigated the pressures received from compression therapy in the region of the retromalleolal fossa. the study tested the hypothesis that therapeutic compression is not achieved behind the malleolus. the results confirm this, showing that less that 5-mmhg sub-bandage pressure is achieved despite high compression at the b1 level. this report demonstrates that the application of novel strapping below the malleolus substantially increases the compression at rest, standing and dorsiflexion. the clinical implications of this are discussed. introduction the development of the strapping technique has been discussed and presented previously.1 this technique was developed in response to the clinical complexities seen in lower limb ulceration where the ulcers are on the foot or behind the malleolus in the retro malleolal fossa. these sites typically prove difficult to heal with standard high compression therapy. this small study tested the hypothesis that standard high compression does not apply adequate pressure in this region; that therapeutic compression is only achieved at b1 or gaiter area. standard compression therapy is ineffective in the retro-malleolal fossa region due to bandage hammocking from the heel to the malleolus. this study aimed to test this hypothesis and provide some evidence for the clinician and patient experience of this novel technique. materials and methods the sub-bandage pressures were obtained using a picopress® [microlab elettronica sas, roncaglia di ponte san nicolò (pd), italy] with probes at standard b1 plus the retromalleolus fossa, both medially and laterally. cohesive inelastic compression (actico, lohmann & rauscher gmbh & co. kg, neuwied, germany) was applied using a standard regime of 10 cm spiral or a non-standard 8cm in a figure of 8 from the toes. these regimes were compared with additional strapping. strapping was applied in a fan distribution1 (figure 1). subbandage pressures were collated at resting, standing and at dorsiflexion. results the mean pressures at b1 using cohesive inelastic regime were 42 mmhg at rest and 62 mmhg on standing. figure 2 demonstrates the range of sub-bandage pressures exhibited from the probe placed behind the malleolus. when the probe was placed in the inner/medial or outer/lateral retromalleolal fossa, the pressures were under 5 mmhg at rest, standing and on dorsiflexion. with the application of strapping, pressures in this region increased, ranging from 25 mmhg to 48 mmhg (figures 2-4). correspondence: alison hopkins, accelerate cic, mile end hospital, bancroft road, london e1 4dg, uk. tel. +44.0208.223.8331 fax: +44.020.8223.8863. e-mail: alison.hopkins2@nhs.net key words: venous ulceration, compression, stiffness, sub-bandage. conference presentation: part of this paper was presented at the international compression club (icc) meeting on stiffness of compression devices, 2012 may 25, vienna, austria (http://www.icc-compressionclub.com/). contributions: ah, fw, co-developer of the novel strapping technique, investigator and analysis; hp, advised in study design, investigation and results. conflict of interests: the authors declare no potential conflict of interests. received for publication: 31 october 2012. revision received: not required. accepted for publication: 22 january 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright a. hopkins et al., 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e12 doi:10.4081/vl.2013.e12 figure 1. fan strapping. figure 2. range of sub-bandage pressures. no nco mm er cia l u se on ly conference presentation [page 38] [veins and lymphatics 2013; 2:e12] discussion and conclusions this simple study confirmed the hypothesis that standard high compression does not provide compression to the retromalleolal area despite achieving high pressures in the b1 area. thus this region does not receive therapeutic compression. the use of a strapping technique has been shown to significantly increase compression to this area. the authors contend that this is of clinical significance. where there is non-healing ulceration below the ankle and on the foot, this technique targets that area. high compression can be focused on the site without resorting to increasing compression through multiple layers of bandage from toe to knee; thus management is tailored to the patient and limb improving tolerance of treatment. patients report that they feel the additional pressure from the straps, that it promotes a support to the ankle and offers pain relief. this novel technique impacts on compression stiffness and also assists in reshaping the foot and anatomical shape of the malleolal fossa; the latter has often been lost through edema and reduced ankle range of motion. the pressures demonstrated at the ankle region through the use of the strapping dispute the promotion of standardized compression regimes for all patients. the strapping technique was developed in a primary care trust. the authors claim this is a key factor in having a venous ulcer prevalence of 0.14 per 1000.2 references 1. hopkins a, worboys f, bull r, farrelly i. compression strapping: the development of a novel compression technique to enhance compression theory and healing for ‘hard to heal’ leg ulcers. int wound j 2011;8:474-83. 2. hopkins a, worboys f, posnett j. low wound prevalence and cost burden: the impact of a multidisciplinary wound specialist team. ewma j 2012;12:18-9. figure 3. lateral ankle, no straps. figure 4. lateral ankle, with straps. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2016; volume 5:5989 compression after vein harvesting for coronary bypass oscar maleti department of vascular surgery, hesperia hospital, modena, italy introduction using the saphenous vein for venous or coronary bypass is like inviting cinderella to the royal ball because, instead of being ablated, it is used as a tool for revascularization. the saphenous wall is particularly useful in this role because it hardly dilate. the low incidence of post-arterialization dilatation is indirect evidence that the wall dilatation that occurs in varicose veins is due to parietal stress, which is correlated with turbulence rather than with increased pressure. though the saphenous vein is the best material for bypass interventions, on the other side it is difficult to harvest. there are different kinds of harvesting, depending on the type of skin incision, long or short, or performed in endoscopy. saphenous vein harvesting saphenous harvesting can be performed by means of open or endoscopic surgery. the open technique involves a long incision or multiple incisions. the long incision (figure 1) improves the graft visibility, is more rapid and improves long-term graft patency, but it is associated with increased skin healing difficulty. the endoscopic surgery improves with multiple incisions (figure 2), but this technique requires a longer operation and the reduced graft visibility is correlated with reduced long-term graft patency. the leg skin healing is faster compared to the first procedure. considering that this technique is slower and more expensive, it is not currently applied. the site of incision is important: at thigh level healing is usually better than at leg level; however, the discrepancy in caliber at thigh level, forces us to choose leg level. the incidence of global complications is higher in women and the total complication rate is extremely variable, from 1% to 24%. possible complications correlated to saphenous vein harvesting are shown in table 1. certain patient characteristics may increase the harvesting complications rate; such features are age, dystrophic lesions, and associated vascular diseases (arterial, venous and lymphatic disease). age and dystrophic lesions increase the time of incision healing, while obesity increases edema and postoperative cellulitis. an associated arterial disease does not present particular problems in patients with an ankle-brachial pressure index (abpi) 0.5-1 but in cases of abpi less then 0.5, problems of incision healing can occur correlated to suture, wound care and compression (figure 3). an associated venous disease presents two possible problems: the absence of a donor segment or the unsuitability of the donor segment in patients with chronic venous insufficiency (cvi). in the first case an alternative donor site is sought, while in cvi the patient will require adequate postoperative compression. harvesting in patients with associated lymphatic disease is particularly dangerous due to the increased risk of lymphedema worsening. diagnostic approach any candidate for saphenous harvesting should be submitted to preliminary ultrasound evaluation; this is able to detect arterial disease and cvi, and can also evaluate abpi, femoral lesions (useful in catheterisation) and saphenous mapping (useful in guiding the incision). in particular circumstances, supplementary diagnosis such as arteriography or venography may be necessary. procedural strategy to reduce harvesting complications there is no correlation between postoperative edema and diabetes, the use of diuretics, low-sodium diet, poor-skin healing and incision length; however, the postoperative edema and the healing-reduction rate are correlated with the surgical technique employed and with postoperative treatment. regarding the surgical technique, it is preferable to avoid any border skin damage and to perform a single layer suture (figure 4). compression therapy is crucial for reducing postoperative complications and should take account of the principal features of these patients: coagulation is normal; the patient remains in the supine position for two days; in the sitting position on the third postoperative day; in the standing position on the fourth postoperative day. an anti-thrombotic elastic stocking is well tolerated by the patient, but this device exerts low compression at the saphenous-vein harvesting site. the use of short-stretch bandaging (concentric compression) has the advantage of being modifiable but it must be performed by experienced personnel and must be renewed daily. the application of eccentric compression at the harvesting site has the advantage of exerting specific compression where needed, reducing the risk of hematoma (figure 5), and it is also applicable in patients with arterial disease. this kind of compression must also be performed by experienced personnel, and it is time consuming. crucial points to remember in postoperative compression are: bandage pressure within the limits of patient pathology; protect the skin; protect areas at risk of decubitus; remove and check bandage on second postoperative day. after discharge, the elastic stocking should be maintained for four weeks, as the third and fourth weeks are a crucial period in skin healing. conclusions although it has been always considered of secondary importance and thus neglected, proper harvesting at the saphenous vein site plays a crucial role in candidates for coronary bypass operation. correct management of the harvesting site and effective postoperative control of hemostasis and edema by means of compression therapy considerably reduces the length of the hospital stay and related costs. correspondence: oscar maleti, department of vascular surgery, hesperia hospital, via arquà, 80/a, 41125 modena, italy. e-mail: oscarmaleti@gmail.com this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright o. maleti, 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5989 doi:10.4081/vl.2016.5989 table 1. possible complication correlated to saphenous vein harvesting. edema early late (4 weeks) lymphedema hematoma erythema infection bad incision healing saphenous vein neuralgia stump deep venous thrombosis cellulitis [veins and lymphatics 2014; 3:5989] [page 17] no n c om me rci al us e o nly conference presentation [page 18] [veins and lymphatics 2016; 5:5989 figure 1. open technique: long incision. figure 2. open technique: multiple incisions. figure 3. bad healing in patient with arteriopathy. figure 4. bad healing of the incision due to margins damage. figure 5. hematoma due to wrong compression. no n c om me rci al us e o nly hrev_master veins and lymphatics 2017; volume 6:6628 [page 12] [veins and lymphatics 2017; 6:6628] thonic bandage: bridging a gap for self-bandaging and homecare pierre gonon ceo thonic innovation, monistrol sur loire, france the science of bandaging is well documented. hysteresis and stretchability are technical specifications which are easily measured in laboratories and allow practitioners to anticipate the effects the bandages will have on a patient’s limb. the recent development of simple devices has opened a new field of investigation with the possibility to measure the sub-bandage pressures and quantify the static stiffness index (ssi). this increasing knowledge and understanding of bandages characteristics has allowed the development of numerous guidelines for the management of conditions such as lymphoedema and venous leg ulcers (vlus) and they all come to the same conclusion that compression bandages must be applied by trained staff.1 the authors of the european dermatology forum’s guideline for diagnostics and treatment of vlus2 who reviewed studies using a whole range of different bandaging systems even noticed that it made no difference which bandage was used provided it was correctly applied. this is a confirmation of what many practitioners feel, i.e. bandaging is not only a science but also an art. it also means that if all available bandaging systems can be efficient, the fundamental question every prescriber should ask themselves when prescribing a bandage is who is going to apply the bandage i am prescribing? when the staff in specialist care centers have the skills and the time to apply compression bandages correctly, this question takes a whole new dimension when it comes to what is happening in primary care where self-bandaging is promoted or, more importantly, when the bandages are applied usually by primary care nurses at the patients’ homes. the argument of primary care nurses applying bandages and reaching much lower vlus healing rates at 6 months when compared to specialist centers (45% vs 70%)3,4 can probably be brought down to 2 main issues: guidelines and training. the publication and regular update of guidelines for the management of vlus does not seem to be sufficient to ensure standard and quality care to patients.5 this can probably be partly explained by the perceived contradictions between recommendations from different guidelines,6 such as the need for daily skin care in the management of lymphoedema1,7 vs the effective oedema reduction achieved with bandages applied for 4 days.1 training programs allow primary care nurses to really improve their bandaging skills but the challenge seems to be the maintenance of these skills over time: nurses who had improved their bandaging skills with training went back to their initial level after 6 to 10 weeks.8 the workload these primary care nurses have to face can probably explain this. although non disease nor treatment specific, a survey conducted in 2013 among district and community nurses in the uk9 showed that 81% of them had correspondence: pierre gonon, ceo thonic innovation, 43120 monistrol sur loire, france. e-mail: pierre.gonon@thonic.care this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright p. gonon, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6628 doi:10.4081/vl.2017.6628 figure 1. thonic bandage static stiffness index interface resting/working pressures measured with picopress on 5 healthy volunteers (courtesy by dr j.p. begnini and dr j.f. uhl). figure 2. application of thonic bandage on lower limb. no n c om me rci al us e o nly conference presentation [veins and lymphatics 2017; 6:6628] [page 13] worked an average of 80 minutes extra-time per 7-9 hour shift, with 75% reporting they had left necessary activities undone. this overload of work on primary care nurses, which seems to be common in many countries, cannot be ignored and leads to the need of simpler and safer bandaging systems that can also be applied for selfbandaging. the evolution in practice from multi-layer bandaging systems to simpler 2 layer systems in the recent years is clearly a sign of this need. thonic bandage’s simple design, which combines innovatively the fundamentals of compression therapy (inelastic and elastic materials; figure 1), allows the simultaneous application of both components (figure 2) which not only reduces the application time but makes it also easier to apply. not having to worry about which bandage goes against the patient’s skin might sound trivial but it will make a major difference for patients, untrained practitioners, and trained practitioners under heavy workloads. with thonic bandage, they don’t even have to worry about which side goes against the skin as they are both 100% cotton, and therefore extremely comfortable. thonic bandage technical design also allows a safer application as the stretchability of the elastic material is mechanically limited, thus reducing the risks of patients or untrained professionals applying dangerously high pressures by over stretching it. finally, thonic bandage is washable and reusable which makes it extremely cost-efficient and eco-friendly. thonic bandage is therefore the solution to bridge the gap between specialist care and homecare bandaging, including self-bandaging. references 1. international lymphoedema framework. position document. best practice for the management of lymphoedema; 2nd edition. available from: http://www.woundsinternational.com/m edia/issues/210/files/content_175.pdf 2. neumann m, cornu-thénard a, jünger m, et al. evidence based (s3) guidelines for diagnostic and treatment of venous leg ulcers. jeadv 2016;30:1843-75. 3. brown a, bums e, chalmers l, et al. effect of a national community intervention programme on healing rates of chronic leg ulcer: randomised controlled trial. phlebology 2002;17:47-53. 4. cullum n. nelson ea, flemming k, sheldon t. systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy. health technol assess 2001;5:1-221. 5. franks pj, barker j. management of patients with venous leg ulcers: challenges and current best practice. wounds austr ewma j 2016;16:1. 6. scott ia, glasziou pp. improving the effectiveness of clinical medicine: the need for better science. med j austr 2012;196:304-8. 7. lymphoedema framework. best practice for the management of lymphoedema. international consensus. london: mep ltd.; 2006. 8. feben k. how effective is training in compression bandaging techniques? br j community nurs 2003;8:80-4. 9. ball j, philippou j, pike g, sethi j. survey of district and community nurses in 2013 report to the royal college of nursing. london: nnru, king’s college london employment research ltd.; 2013. no n c om me rci al us e o nly hrev_master veins and lymphatics 2016; volume 5:5983 [veins and lymphatics 2014; 3:5983] [page 7] compression treatment following polytrauma and in endocrinopathies mieke flour phlebology and chronic wounds clinic, vascular centre, university hospital, st. raphaël (kuv), leuven, belgium management of polytrauma patients will aim as much as possible at salvation of limbs and limb function if possible. the same applies to surgical reconstruction, for example of deglovement injury. limb saving flaps and grafts may lead to complex loco-regional situations, with non-homogenic hardness or elasticity, fragility of tissues and dysfunctional skin. inevitable damage to nerves, blood vessels or lymphatics prolongs healing or results in stiff scarred parts while other sites may be swollen (figure 1). sometimes, flaps and grafts appear to be undermined due to difficulties concerning adherence to the underlying tissues. scarring may further impair elasticity or skin and limb functions. following closure or healing of skin defects, rehabilitation exercises must start without compromising the fragile skin and eventually orthoses/prostheses will have to be accommodated. therefore, compression treatment is sometimes needed to reshape or to protect the limb. the mobility and the need for compression may not be equal in the different compartments of the limb to be treated, and often compression devices will have to be adapted towards a combination of different materials and techniques, in order to deliver appropriate local pressure values. if the shape of the post-traumatic limb is too difficult to accommodate with standard devices, a silicone orthosis might help to reshape the leg in order to permit bandaging or donning of a compression stocking (figure 2). at the same time this orthosis will equalize consistency of tissues and protect utterly fragile parts. the endocrinopathies considered in relation to compression therapy are mainly diabetes, thyroid disorders, morbid obesity and the metabolic syndrome, as they induce skin changes prone to collect and retain edema fluid, as well as vascular changes leading to hypertension and endothelial dysfunction. in peripheral arterial insufficiency, such as in hypertension, diabetes, peripheral arterial occlusive disease, it is important to keep in mind the territories of the affected angiosomes in order to adapt pressures accordingly. compression affects the venous, arterial, lymphatic and capillary circulation. not only the mechanical effects but also metabolic and behavioral changes on the cellular level have been described for endothelial cells, circulating leukocytes, or fibroblasts on the level of the microcirculation, being it primarily in phlebological patients. it has been shown that in patients with mixed disease [ankle-brachial index (abi) 0.5-0.8] compression enhances arterial circulation by removal of edema through reduction in capillary filtration, increasing lymphatic drainage, a shift of fluid to non-compressed areas, and a breakdown of fibrosclerotic tissue (due to inflammatory mechanisms in venous disease). endothelial dysfunction is strongly associated with both type-1 and -2 diabetes mellitus. in diabetic patients, the attention is cautiously focused on the micro-and macroangiopathy and on a peripheral sensory neuropathy considering the failure of perception under inappropriately high-pressure values. multiple abnormalities in the skin microcirculation of the foot have been described in diabetics with neuropathy, and controversial results depending on the methods used are sometimes difficult to interpret.1 peripheral autonomic neuropathy impacts on the regulation of flow in the small vessels of the skin including the lymphatics. these subjects may present edema due to several organ complications like heart or kidney failure, swelling secondary to the medication to treat these, or caused by the diabetic tissue alterations of the skin. advanced glycation endproducts (and lipoxigenation), celland matrix alterations as well as deposition of a.o. amyloid [and glycosaminoglycans (gags)] make the skin and collagenous tissues thickcorrespondence: mieke flour, schoonzichtlaan 43, b-3020 herent, belgium. tel. +32.478.566780. e-mail: mie.flour@skynet.be this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright m. flour, 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5983 doi:10.4081/vl.2016.5983 figure 1. disfigured and non-homogenous limb following polytrauma: fragility of grafted areas and loss of function. figure 2. a silicone orthosis might help to reshape the leg in order to permit bandaging or donning of a compression stocking. no n c om me rci al us e o nly conference presentation [page 8] [veins and lymphatics 2014; 3:5983] ened, stiff/less mobile, while at the same time there is retention of fluids leading to edema. furthermore, there are advanced fructosylation endproducts, which actually have a greater affinity binding to proteins than glucose and follow a similar pattern in the production of the reactive oxygen species. this huge waxy skin in diabetes not only is at risk for injury leading to blisters or wounds, it is also more prone to inflammation in the context of the dysregulated diabetes (figure 3). therefore, compression treatment may be indicated to lower the water content of skin and subcutaneous tissues. although diabetes is considered as a relative contra-indication for compression treatment of limbs, many have clinical experience of the benefit of compression in these patients and some authors have published beneficial results in diabetic patients without obvious vascular compromise.2 in a more recently published study of wu et al., mild compression therapy (18-25 mmhg) decreased swelling in diabetes patients with lower extremity edema without compromising vascularity.3 interpretation should be cautious considering some weaknesses of this publication: this study is a pilot, uncontrolled study, including a low number of participants. vascular status was tracked via abi (which in diabetics is not always reliable), and edema was measured via tape measurement of circumference at difficult anatomical sites like ankles and mid-foot. the myxedematous skin in thyroid disorders may present specific skin lesions which are due to the storage of large amounts of proteoglycans or mucin deposition in the reticular middle and lower dermis, also responsible for the yellowish color of the skin in these situations. deposited gags promote dermal edema by promoting the retention of fluid in the skin. the edema is doughy, with a manifest pitting sign. compression therapy will expel or displace edema fluid and diminish inflammatory erythema, but since the underlying mechanism does not itself respond to pressure, this symptomatic treatment has to be maintained. in morbid obesity and the frequently associated metabolic syndrome, edema may be attributed to pretibial mucin deposition on the shins, known as pretibial myxedema.4 the patients with morbid obesity frequently present with bilateral lower extremity pitting edema (sparing the feet and ankles) of gradual and painless onset. the waxy brownish erythematous plaques are found primarily on the shins, and the semitranslucent papules due to mucin deposition at the superficial papillary dermis and around the vessels may easily develop vesicles when fluid accumulation separates the epidermis from the underlying dermis (figure 4). one of the many synonyms given to this entity is chronic obesity lymphedematous mucinosis. it has been reported that there is an association between lymphedema in pretibial myxedema and mucin deposition.5 references 1. zimny s, dessel f, ehren m, et al. early detection of microcirculatory impairment in diabetic patients with foot at risk. diabetes care 2001;24:1810-4. 2. belcaro g, laurora g, cesarone mr, et al. microcirculatory effects of elastic stockings in diabetic microangiopathy: a 24 week study. j cardiovasc surg 1993;34: 479-82. 3. wu sc, crews rt, najafi b, et al. safety and efficacy of mild compression (18-25 mmhg) therapy in patients with diabetes and lower extremity oedema. j diabetes sci technol 2012;6:641-7. 4. tokuda y, kawachi s, murata h, saida t. chronic obesity lymphooedematous mucinosis: three cases of pretibial mucinosis in obese patients with pitting oedema. br j dermatol 2006;154:157-61. 5. bull rh, coburn pr, mortimer ps. pretibial myxooedema: a manifestation of lymphoedema? lancet 1993;341:403-4. figure 3. diabetic thick waxy skin due to deposition of glycosaminoglycans and advanced glycation endproducts. figure 4. pretibial myxoedema and effect of compression therapy. no n c om me rci al us e o nly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: volume displacements from an incompetent great saphenous vein during a standardised valsalva manoeuvre by lattimer cr, kalodiki e, azzam m, geroulakos g. acta phlebologica 2012;13:25-30. stefano ricci abstract reflux duration longer than 0.5 s is the cut-off point for the diagnosis of valvular incompetence. it is induced by a calf compression/release maneuvre (ccrm) in a weight-loaded position, with a full venous reservoir. ccrm is a pre-valve challenge test; reflux stops when the reservoir is full. in contrast, a valsalva maneuvre (vm) is a post-valve challenge test and also a validated technique to induce reflux. it is performed in a supine position, when the venous reservoir is only partially filled. the authors measured the volume of blood displaced during a standardized vm within an incompetent gsv (18 patients c2, reflux until the popliteal crease). a standard vm was performed by taking a deep breath during 3 s, a strain during the next 3 s, and then a relaxation during the final 3 s. gsv diameters during stain and relaxation were measured just distal to the sfj. volume flow in cc/min (time average mean velocity x diameter) multiplied by 3/60 gave volume displacement in 3 s. a median of 25 ml blood was displaced into the gsv over 3 s during straining with only 9 ml blood out of the gsv during the following 3 s of relaxation. as far as the volume is concerned, the different physical properties of foam must be referred to and the displaced foam volumes are likely to be lower. during ultrasound guided foam sclerotherapy (ugfs), vm is unavoidable (leg movements, cough, head lifting, strains, stocking application) and bolus displacement of foam into deep veins, and blood/foam mixing may cause concern over safety and efficacy. protocols should be formulated to minimize the vm risks (stocking application, avoid standing, talking and coughing soon after the injection). putting on a below-the-knee stocking before the procedure may be of benefit. this study has also shown that reflux duration following a vm can be determined by the physician and not by the pathology of the disease. comment by stefano ricci at the end of the ugfs procedure, the gsv is submitted to a spasm of unknown but relatively long duration as a direct effect of the foam on the muscular layer of the vein. when this occurs, the volume of the affected gsv is markedly reduced. therefore, when the patient gets up and begins to walk, the vm is likely to displace a substantially reduced volume. for this reason, this interesting study cannot apply directly to the ugfs procedure. however, a vm might affect subsequent recanalization. if this is true, the vm should also be studied in the standing position, because this is more representative of the venous circulation in everyday life. the benefit of the stockings, possibly analyzed during vm, is cited in the abstract but unfortunately is not described in the paper; this is a pity. finally, the 4 patients with gsv reflux at a standing compression/relaxation maneuvre but with negative vm in a supine position probably had a competent terminal valve, as this is commonly found in approximately 30% of cases of gsv incompetence. reply by the author (lattimer) foam sclerotherapy causes substantial venospasm of the gsv and ricci correctly concludes that foam displacement, back and forth across the sfj during a vm, may be minimal or even non-existent. the reported results apply to blood, not foam. the hemodynamic properties of foam in vivo after sclerotherapy are not known and this needs to be the subject of future research. a vm is likely to be more detrimental during the injection than after the onset of venospasm. the purpose of a partially-applied graduated compression stocking, up to the level of the sclerotherapy injection site, was to avoid any strain the patient may exert in providing a counterforce during the initial application of the stocking by the physician. we did not evaluate a vm with a stocking in place. this may have reduced the volume displaced through a reduction in the gsv calibre and the venous reservoir. instead, we assessed peak velocity and volume flow across the sfj during the application of a compression stocking.1 lattimer et al. discussed foam-induced venospasm. we agree that a competent terminal valve is the likely explanation for the absence of gsv reflux during a vm in the presence of significant reflux after manual ccrm. this discrimination is an essential step in the evaluation of patient profile prior to saphenous conservation surgery. references 1. lattimer cr, azzam m, kalodiki e, geroulakos g. hemodynamic changes at the saphenofemoral junction during the application of a below-knee graduated compression stocking. dermatologic surgery 2012. [in press] [top] hrev_master veins and lymphatics 2015; volume 4:4851 [veins and lymphatics 2015; 4:4851] [page 7] a phlebo-lymphology humanitarian trip to matagalpa, nicaragua sergio gianesini,1 attilio cavezzi,2 giovanni mosti,3 lorenzo tessari,4 francesco zini,5 simone urso,6 fausto campana,7 mirko tessari,1 patrizia dalla caneva,1 freddy espinoza,8 ruth rocha,8 diana neuhardt,9 eric mowatt-larssen,10 joe zygmunt,11 susan cortesi,12 terri morrison,12 nick morrison12 1vascular disease center, university of ferrara, italy; 2eurocenter venalinfa, san benedetto del tronto (ap), italy; 3angiology department, clinica md barbantini, lucca, italy; 4glauco bassi foundation, trieste, italy; 5surgical department, città di parma private hospital, parma, italy; 6phlebology department, prof. nobili private hospital, castiglione di pepoli (bo), italy; 7vascular medicine, bufalini hospital, cesena, italy; 8fara foundation, matagalpa, nicaragua; 9compudiagnostics, phoenix, az, usa; 10the vein specialists of monterey, monterey, ca, usa; 11veinz phlebology consulting, kure beach, nc, usa; 12morrison vein institute, tempe, az, usa abstract amigos de salud and vene e linfatici foundation took part in a volunteer medical trip in nicaragua. a detailed description of the provided healthcare is reported. background chronic venous disease (cvd) is an extremely widespread pathology, affecting up to 60% of women and 56% of men in the industrialized caucasian race. with the bias of extremely sparse literature about the topic, the population in limitedresource countries seem to be less prone to this disorder.1,2 nevertheless, worrisome data in the few investigated resource-poor population have recently emerged regarding the most advanced stages of the disease, including venous ulcers.3 under-estimated co-morbidities such as infections, diabetes, arterial disease and trauma have been identified as determinants of this burden.4 a dysfunctional lymphatic system and its pathophysiology are directly related to the venous pathophysiology. even more than this, when lymphatic system is affected, skin infections may more easily occur, which eventually establishes a vicious circle in the venouslymph drainage impairment. phlebo-lymphatic disease (pld) mismanagement, together with lack of appreciation of its co-factors, severely impacts patients in underdeveloped areas. the real drama lies inside the relatively easy avoidance of this scenario by means of adequate disease management. indeed, severe pld can lead to disabling conditions such as infections, impaired ambulation and even limb amputation. moreover, considerable working days are lost, potentially severely impacting the social life. nevertheless, the modern scientific and therapeutic achievements of the industrialized countries have not yet reached the poor countries, leaving these populations in a vicious circle of severe impairment of quality of life and indeed economic distress. amigos de salud activities amigos de salud is a non-profit organization, which for the last 25 years, by means of medical volunteer trips, has been providing diagnostic and therapeutic interventions for local people in central and south american countries (costa rica, ecuador, nicaragua, peru; http://www.amigosdesalud.org/). the international medical team pays its own travel, covering all their own expenses, assembling all the needed equipment and providing industry contacts that can eventually support the poorest population healthcare, as well as scholarships and food programs. together with the medical team, invaluable help is provided by nurses, assistants, interpreters and family members of the healthcare team. all together this extra group becomes fundamental to the realization of the whole humanitarian act. this year amigos de salud supported medical activities in matagalpa, nicaragua, in collaboration with the italian foundation vene e linfatici, gathering some medical and nonmedical personnel dedicated to the care of venous and lymphatic diseases (figure 1). thanks also to the conjunction with a local foundation, an american/italian team of eleven expert phlebologists was in charge of the treatment of 846 cvd patients for a total of 942 lower limbs. amigos de salud and vene e linfatici foundation 2014 medical support in nicaragua population recruitment and demographics in the months prior to the arrival of the volunteer medical group, two physicians of the local nicaraguan foundation screened 1000 patients coming from different regions of the country, exhibiting signs of cvd and complaining of the related symptoms. within this population, 117 patients presented with an active ulcer, of which 10 were bilateral. the two local assessors excluded 50 patients because of major co-morbidities that were considered to significantly increase the risk of post-procedural complications. on the patients’ procedural day 104 patients missed the appointment because of unavailable economic funding to cover the trip to the hospital. of the residual 846 patients examined and treated by the amigos de salud team, 74 were males (8.74%) and 772 were females (91.25%) (figure 2). the patients’ age is reported in table 1. correspondence: sergio gianesini, vascular disease center, university of ferrara, via aldo moro 8, 44128 cona (fe), italy. e-mail: sergiogianesini@hotmail.com key words: volunteer, medical trip. conflict of interest: none acknowledgements: the volunteer members of amigos de salud and vene e linfatici foundation express their deep gratitude for the passionate work that was done and that is still going on by dr ruth rocha and dr freddy espinoza, together with all the members of the local fara foundation (http://www.farafoundation.org), and it’s directors, marcela cisne, manny and maria farahani. moreover, extreme gratitude is expressed also in favour of the industries that supported the volunteer medical trip (in alphabetic order): angiodynamics, cook medical, eufoton, farmax, flebysan, gloriamed, hk surgical, juzo, kreussler, lohmann-rauscher, medi, mycli, sigvaris, std pharmaceuticals, techlamed, 3m, trafita-terason. received for publication: 30 november 2014. accepted for publication: 29 january 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s. gianesini et al., 2015 licensee pagepress, italy veins and lymphatics 2015; 4:4851 doi:10.4081/vl.2015.4851 no n c om me rci al us e o nly technical note [page 8] [veins and lymphatics 2015; 4:4851] of the 846 treated patients, 688 (81.32%) were never treated before, while 158 (18.67%) had recurrent or residual disease. management of the diagnostic and therapeutic process over the course of the 6 working days the american-italian team was able to provide all the following diagnostic and therapeutic procedures to the previously screened patients: i) specialist clinical and colour-duplex ultrasound investigation; ii) ultrasound-guided foam sclerotherapy; iii) preliminary saline flush followed by ultrasound-guided foam sclerotherapy; iv) endovenous laser ablation; v) laser assisted foam sclerotherapy; vi) catheter directed foam sclerotherapy; vii) ulcer debridement and advanced medication; viii) compression therapy; ix) hook phlebectomy. in three cases a sapheno-femoral junction high ligation was performed without major or minor complications at one-month follow-up. all the screened patients underwent a clinical and cdu assessment by the american/italian team member. patients then underwent the therapeutic procedure directly with the examiner physician, or were sent to colleagues who were ready to offer another kind of technical therapeutic option, whenever more appropriate for that specific case. once treated, in case of an ulcer presence, the patient was sent to the physician in charge of treating the ulcer itself. the age of this ulcer subgroup population ranged from 30 to 84 years. the ulcer etiology was: superficial cvd (36.9%), deep cvd (25.8 %), deep and superficial cvd (33%), not determined (4.3%). the average ulcer area was 60 cm2 (ranging from 1 to 460 cm2), with an onset going back from 3 to 420 months. an active inflammatory ulcer was reported in 69.9% of cases, while 28% already presented granulation and 2.1% re-epithelization. all the patients were treated by surgical debridement, advanced dressings and inelastic bandages. a second wound healing session was possible and performed just in 8.6% of cases. all of them demonstrated improvement from the inflammatory to the granulation state. in table 2 numbers of performed procedures are reported. quite impressively, neither minor nor major peri-procedural complications were spontaneously reported by the patients, whereas two minor post-phlebectomy hematomas and a postsclerotherapy superficial thrombophlebitis were identified by the treating physicians. post-procedural management a post-procedural elastic stocking of proper size, length (below or above-knee) and comfigure 1. amigos de salud and vene e linfatici foundation group. figure 2. first patients joining the fara foundation clinic in early morning. no n c om me rci al us e o nly technical note [veins and lymphatics 2015; 4:4851] [page 9] pression class (15-20, 20-30, 30-40 mmhg) was donated and applied to all the patients (figure 3). after the treatments, the two nicaragua physicians were available to follow-up and assist all the patients within the local foundation clinic whenever needed, even after the american-italian team’s departure. at one-month follow-up the two physicians were visited by 72 (7.6%) patients. the reasons for the patients returning to the clinic following the original treatment are reported in table 3. further to the patients listed above, so far (november 2014) the doctors from the local clinic are still weekly medicating and bandaging 75 out of the initial 117 active ulcers. considerations on the nicaragua 2014 experience despite the short (6 days) commitment to the volunteer medical trip, the medical team was able to provide phlebological health-care to a large number of patients. the 18.67% patients exhibiting residual/ recurrent disease illustrates the need to establish local follow-up expertise, enabling the local physicians to treat signs and symptoms of recurrences at the very early stages. in this way it would be possible to complete the first therapeutic act, guaranteeing the longest disease-free time possible. the 12.34% (104 out of 950) patients who had to drop out because of unavailable economic funding to cover the trip to the clinic is illustrative of the poverty afflicting these regions. these data highlight the need to provide further support to increase the potentially treatable population, which may benefit from such volunteer medical trips. the presence of a well-trained and experienced medical and support team, together with an adequate fundraising campaign and the availability of very generous industry support allowed the creation of a temporary phlebological unit. a high level diagnostic and therapeutic approach was put in place in the local clinic, reaching standards typical of western country health providers. general considerations on volunteer medical trips in poorly resourced countries a major possible cause of drop out from the check up and treatment is the lack of nearby health structable 1. treated population age. age (years) 14-25 26-35 36-49 50-60 61-74 >75 0.7% 8.3% 32.2% 30.9% 22% 5.9% table 2. performed therapeutic procedures. procedures number of treated cases % ultrasound-guided foam sclerotherapy 605 63.8 preliminary saline flush followed by ultrasound guided foam sclerotherapy 45 4.7 endovenous laser ablation 96 10.1 laser assisted foam sclerotherapy 39 4.11 catheter directed foam sclerotherapy 15 1.6 ulcer debridement, advanced medication 117 12.3 hook phlebectomy 15 1.6 high-ligation 3 0.3 compression (bandaging) 130 13.7 figure 3. amigos de salud members teaching elastic stockings compression to the patients. table 3. issues leading the patients to come back for a visit at one-month follow-up. patient issue male female check-up 10 pain 2 14 superficial thrombophlebitis 4 40 post procedural skin lesion 2 no n c om me rci al us e o nly technical note [page 10] [veins and lymphatics 2015; 4:4851] tures and obviously the lack of sufficient funds for the necessary travel to the clinic. the local physicians who are involved in the patients’ management all year long are particularly devoted to their humanitarian mission in favour of this poor population. nevertheless, the overwhelming amount of work and the need to be a multi-specialty physician can result in complex management of all patients’ needs especially their pld. reports on social health data in underdeveloped countries are lacking, leading to an unclear scenario of the on-going critical situations and actual needs.5 this kind of data collection could also shed some light on those cofactors in pld development that are not commonly known in industrialized countries. conclusions the 2014 medical volunteer trip of the amigos de salud and vene e linfatici foundation team to matagalpa resulted in an effective and safe diagnostic and therapeutic approach to nearly 850 patients affected by various, mostly severe, stages of cvd. notwithstanding the objective limitations encountered during this experience, the medical and non-medical personnel was able to deliver proper care to 846 patients affected by varices, ulcers, lymphedema, post-thrombotic syndrome, venous malformations. further developments of similar humanitarian phlebology trips, such as adequate provisional of economical support for educational and diagnostic/therapeutic needs, are to be expected. references 1. beebe-dimmer jl. the epidemiology of chronic venous insufficiency and varicose veins. ann epidemiol 2005;15:175-84. 2. milic dj. prevalence and socioeconomic data in chronic venous disease: how useful are they in planning appropriate management?. medicographia 2011;33:253-58. 3. shukla vk, mumtaz a, gupta sk. wound healing research: a perspective from india. int j lower extremity wounds 2005;4:7-8. 4. nag f, de a, hazra a, et al. chronic venous ulceration of leg associated with peripheral arterial disease: an underappreciated entity in developing country. int wound j 2014;11:546-9. 5. http://chileangringo.blogspot.it/2009/05/ latin-america-gdp-pp.html no n c om me rci al us e o nly alessandro rasman reflections on the canadian study by traboulsee et al. prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study sandro mandolesi,1 aldo d’alessandro,2 tarcisio niglio,3 michele rossi 4 1 department of cardio-vascular and respiratory sciences, la sapienza university, rome; 2 department of neuroscience, imaging and clinical sciences, g. d’annunzio university, chieti-pescara; 3 istituto superiore di sanità, rome; 4 radiology department sant’andrea, la sapienza university, rome, italy. correspondence: sandro mandolesi, e-mail: s.mandolesi@email.it acknowledgments: the authors wish to thank doctor alessandro rasman for his collaboration. preface by p. zamboni the editorial how to objectively assess primary venous obstruction published in the last 2014 issue of veins and lymphatics (http://dx.doi.org/10.4081/vl.2014.4195) stimulates an intense scientific debate even involving the social networks. strictly correlated to such an open scientific discussion we herein receive a letter condensing thoughts again about the traboulsee et al.’s paper published on the lancet. 1 letter 1. there is a conflict of interest as the first sponsor is the multiple sclerosis society of canada and other foundations, we do not know who they represent is also not reported how much it cost the study; 2. if as it appears on the paper the doctors or technicians ultrasonographers who carried out the ultrasound were trained by zamboni, why they found 0% of reflux and 0% of stenosis in the jugular of patients with ms?? no paper, even the most deductive in literature, reports such as it is statistically impossible; 3. zamboni can confirm attendance and technical preparation of all sonographers of the three structures that examined the ms patients?? they never speak of hemodynamic stenosis or total compressions of jugular veins (present in our statistics, respectively, in 13% and 48% of patients). 2 4. why they discarded the radiographic evaluation of the patients studied in orthostatic position by saying that the internal jugular veins usually collapse in the upright position, with blood redirected to the azygous vein and vertebral veins. it must be inferred that they did not show narrowings; it is a motivation not clear as they could evaluate all other hemodynamic parameters (reflux, stasis and compensatory circles). in addition to what sample, healthy or pathological, the vessels were collapsed and what correspondence was between venography and the results of the ultrasound in orthostatic? a vessel collapsed indicates that does not pass the blood in its interior how has been explained this anti-physiological event throughout the sample? because it would mean that normally in orthostatic we have the internal jugular closed; 5. why are not reported the venographic results of the azygos vein? they have not even found one lesion on this vessel? 6. the abnormal collaterals were not to our knowledge still encoded by a consensus (they identify the number and caliber: if one is present must be of a size at least 50% greater than the vessel near, if two or more even if they have a smaller caliber vessel near side are pathological; 7. they do not relate the amount of contrast medium injected, but only the pump flow ml/sec (missing for many seconds is the duration of infusion), do not say if this amount was the same in subjects with ms and in those of control or if it is changed in the same subject or in different spots and possibly why; 8. given the very high position of the catheter should be discarded as parameters of the study both collateral circulation and reflux otherwise always visible if the pressure and the amount of contrast is higher than the pressure of the outflow known in the sample examined, the one studied in supine position, is almost 0; 9. at what stage of respiration was injected contrast after inspiration or expiratiion and was performed at the same stage in all patients? 10. in which position of the head were performed contrastographic spots? in the same position on all vessels? and if rotation of the head in which, intra or extra rotation, with respect to the vessel in question? see our publication on the compression of the jugular veins; 2 11. what radiographic have used the anteroposterior, lateral, both etc?; 12. why were not reported pressure measurements? they do not report as have been performed, even monitoring during the inspiratory-expiratory cycle? 13. this paper takes account of the hemodynamic events of phlebographic examination narrowing with abnormal flow and those morphological narrowing unreliable because not yet defined for venography. also the narrowing >50% can go from 51 to 99% with a completely different hemodynamic impact. in the paper have not been stratified ranges for example up to 80% and over 80%. the altered discharge of the contrast medium with a delay time greater than 4 seconds is present on an internal jugular in 89% of patients with ms and in only 5% of the controls. 3 furthermore, in the recent study from manconi on the respiratory index (roc curve 97%) positive test (which corresponds to a hindered discharge vessel) is 4 times greater in subjects with ms compared to healthy ones); 4 14. we judged on haemodynamically significant narrowing to be present if at least one of the following was recorded: reflux persistent retrograde flow of most of the contrast bolus after injection was completed); stasis (contrast was present 4s after the injection); or abnormal collaterals (one or blackberries vessels >50% the size of the adjacent primary vessel, or two or will more collateral vessels present at <50% the size of the adjacent primary vessel). in this study were placed on the same level three completely different hemodynamic conditions and were not differentiated in the statistical evaluation. making this soup a normal subject with reflux was equated to one that has both stasis, both reflux and collateral circulation!!!!! see table 2; 15. the results of table 6 indicate that stenosis >50% is an unusable data as always present in equal measure (74%) in subjects positive at ultrasound (ccsvi present) than negative (ccsvi absent); the serious thing of this unification that are grouped in ccsvi positive subjects with ms, siblings and normal subjects that have almost the same percentage of 40% (see table 4) and the same is done to form the negative group: this is a pretty tricksy! statistically; 16. where were detected stenosis in j1, j2 or j3? 17. there have been differentiated anatomical stenosis from those compressive extravascular? 18. with a mean disease duration of 13 years is statistically impossible to have an edss of 2.7 (in our sample of about 1000 patients with a mean duration of 12.6 years, we have 4.5 of edss); 19. the criteria used to evaluate the ccsvi score appear to be those of 2009; why they have not used up to date versions of the international consensus of 2011? 5 20. the literature data tell us that the morphological lesions stenosis venographic (not those us because do not find?!?!?!) examined and evaluated have no value if they are not associated with a hemodynamic effect of contextual obstacle at vessel outflow (delay time greater than 4 sec). also there can be many false negatives because analyzing habitually anteroposterior if the vessel is compressed on this plane contrast fills equally around the lumen and stenosis is undetectable and only the annular stenosis are always visible; 21. they claim that venography is the gold standard, however, after discarding those orthostatic; 22. they have detected a significant inter-observer variability between centers involved in the study also took good for all data; 23. they preliminary matter that the study was done on three centers except merge two together in the final examination of the data; what would change from statistical point of view, keeping it separate? 24. where they found all these healthy and asymptomatic who have come to make a venography? they paid and who paid for them has a conflict of interest? statistical considerations 25. given the multiplicity of variables (and the inherent variability of the individual variables), the sample should be larger. at least twice that used; 26. there is no study of the quality of the data collected in most centers. it is not specified whether the equipment were the same and as they were calibrated. in a study of such structure would have to apply a meta-analysis and not simple tests of analysis of variance after forced amalgamation of data from different centers; 27. there is no study on the proper randomization before the study. changes related to sex and age alone suffice to require such analysis; ratings on the abstract 28. interpretation at the end of the abstract that chronic cerebrospinal venous insufficiency occurs rarely in both patients with multiple sclerosis and in healthy people is false!!! because in table 3 is present in 44% in those with ms and 37% in healthy people. that narrowing >50% is very frequent (74%) both in patients with sclerosis and in healthy only indicates that it is not a valid criterion to differentiate the two groups and was not to be used as discriminating. they have missed the aim of the study who wanted to investigate whether the blocking of the veins was specific to the multiple sclerosis as it has not been studied blocking of the venous drainage with ultrasound (found in 8%) and the one with venography in the two groups, but rather the stenosis that in ultrasound was never identified as such but simply as anomalies within the vessel and in venography as stenosis >50% which as we have previously reported is not a hemodynamic parameter, but morphological and frequently reflected in both healthy subjects and multiple sclerosis. moreover stenosis >50% associated with hemodynamic abnormalities reported in the study was a soup of three hemodynamic conditions of which the one valid definition to be used by itself (delay time >4 sec) was not considered. references traboulsee al, knox kb, machan l, et al. prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their sibilings, and unrelated healthy controls: a blinded, case control study. lancet 2014;383:138-45.[crossref] [pubmed] mandolesi s, manconi e, niglio t, et al. incidence of anatomical compressions of the internal jugular veins with full block of their flow in patients with chronic cerebro-spinal venous insufficiency and multiple sclerosis. in: allegra c, antignani pl, eds. proc. 21st eurochap-iua european chapter congress of the international union of angiology. sept 28-oct 1, 2013, rome, italy. turin: ed. minerva medica; 2013. pp 12-17. available from: http://wm7.email.it/webmail/wm_5/redir.php?http://filesformailing.minervamedica.it/volumi/eurochap.pdf veroux p, giaquinta a, perricone d, et al. internal jugular veins out flow in patients with multiple sclerosis: a catheter venography study. j vasc interv radiol 2013;24:1790-7.[pubmed] cadeddu f. fisiologia e fisiopatologia della insufficienza venosa cerebrospinale: proposta di nuovi criteri diagnostici. tesi di dottorato. università di cagliari; 2014. available from: http://veprints.unica.it/960/1/phd_thesis_cadeddu.pdf zamboni p, morovic s, menegatti e, et al. screening for chronic cerebrospinal venous insufficiency (ccsvi) using ultrasound-recommendations for a protocol. int angiol 2011;30:571-97. erratum in: int angiol. 2012;31:201.[abstract] [pubmed] [top] hrev_master veins and lymphatics 2016; volume 5:5980 [page 2] [veins and lymphatics 2016; 5:5980] inflammation and compression: the state of art daniela ligi, lidia croce, ferdinando mannello department of biomolecular sciences, university of urbino carlo bo, urbino (pu), italy chronic venous leg ulcer affects around 12% of the adult population in the western world,1 with significant expenditures and high social and economic impact. the leading hemodynamic cause is represented by venous hypertension, affecting the venous macroand micro-circulation, which is able to induce morphologic, functional and biochemical alterations in postcapillary venules and in the surrounding tissue microenvironment.2 in this regard, inflammatory processes by leukocytes and macrophages affect the venous endothelium, promoting a complex succession of events involving the activation of adhesion molecules, chemokines, cytokines, growth factors, and proteases which cause endothelial dysfunction and dysregulation, compromising tissue integrity and finally lead to dermal damage and ulcer development.3 a critical aspect for treating venous leg ulcer is correcting the abnormal venous hemodynamics by compression therapy. in fact, compression therapy has been widely recognized as the cornerstone in the management of chronic venous insufficiency (cvi), clinical condition resulting from venous hypertension secondary to superficial or deep venous valvular reflux and/or obstruction.4 compression can be achieved using compression bandaging, compression pumps, or graduated compression stockings, which, by decreasing ambulatory venous hypertension in the area, counteract the chronic inflammation in the tissues and finally aide healing processes.5 it has been shown that ulcer dressings create and maintain a moist environment on the ulcer surface, promoting autolytic debridement, angiogenesis and a more rapid formation of granulation tissue, favoring keratinocytes migration and finally accelerating healing of wounds, even if different wound dressings must be used according to the ulcer stages.6 in the recent revision of the society for vascular surgery and american venous forum guidelines on management of venous leg ulcers performed by the international union of phlebology, it has been highlighted that …in a patient with a venous leg ulcer without arterial involvement or peripheral neuropathy, it is recommend strong compression pressure (>40 mmhg resting pressure at the ankle) over low compression pressure to increase venous leg ulcer healing rate... suggesting grade 1 and level of evidence b.7 moreover, it has been provided evidence that strong (>40 mmhg) compression is more effective than low (<20 mmhg) compression in promoting ulcer healing, including also that ...in a patient with a healed venous leg ulcer, the compression therapy decreases the risk of ulcer recurrence... (grade 2 and level of evidence b).7 unfortunately, venous leg ulcer recurrence ranges between 30-70%, and other modalities in therapy along with the compression therapy are required. the goal for adjuvant products is to promote the shift from an inflammatory chronic wound to a reparative wound that will promote provisional extracellular matrix deposition and re-epithelialization. there are many products on the market that can be used as adjuvants to compression therapy; in this respect, it has been highlighted that …for long-standing or large venous leg ulcer, we recommend treatment with either pentoxifylline, micronized purified flavonoid fraction or sulodexide, all used in combination with compression therapy (grade 1; level of evidence b);7 however, it must be recognized that there is a paucity of clinical trials that have evaluated the clinical effectiveness of specific products with clearly defined end points, and most importantly a healed venous leg ulcer with a low recurrence rate. despite the treatment modalities are aimed at reducing venous hypertension, some therapies, although widely used, only provide short-term improvement of the edema but do not provide long-term benefits.8 chronic venous disease and cvi are characterized by an increase in ambulatory venous pressure but the different symptoms and signs clearly show that there is an inflammatory state secondary to venous hypertension, which leads to venous wall and valves injury.1 several studies were performed to assess and demonstrate the efficacy of compression treatment in the management of chronic venous leg ulceration. an interesting randomized controlled trial published in 2004, comparing compression treatment alone or in combination with superficial venous surgery, demonstrated that 24-week healing rates were similar in the compression-surgery vs. compression alone groups, but 12-months ulcer recurrence rates were significantly reduced in the compression-surgery patients, suggesting, from a clinical point of view, that most patients with chronic venous ulceration will benefit from the combination of therapies added to simple surgery.9 it has also been demonstrated that significantly less legs in the compressionsurgery treated patients developed perforator incompetence in comparison to the group treated with compression alone, offering more protection against developing new perforator incompetence.10 although a plethora of studies have identified up-regulation of various pro-inflammatory cytokines in fluid collected from venous leg ulcers,11 and even if the compression therapy results in healing of most venous leg ulcers, the biomolecular mechanism(s) responsible for this effect is not well understood. in this respect, an interesting study performed on biopsies from ulcerated tissue from non-healing chronic venous insufficiency affected patients treated with high-compression therapy revealed that compression therapy (with 3-layer or 4-layer compression bandage system for 4 weeks) resulted in healing coupled with reduced pro-inflammatory cytokines [e.g., interleukin (il)-1�, interferong, granulocyte-macrophage colony-stimulating factor] and higher levels of the anti-inflammatory cytokine il-1ra.12 similarly, it has been previously reported that wound healing of venous ulcers treated with compression therapy correlated with decreasing serum levels of tumor necrosis factor-a and vascular endothelial growth factor13 and increasing exudate levels of transforming growth factor-b�1.14 moreover, it is well known that an alteration of the proteolytic and anti-proteolytic balance is significantly implicated in chronic wound initiation and progression. in this regard, it has been investigated in venous leg ulcer tissues the effect of sustained limb compression of 30 mmhg (or greater) for 4 weeks on ulcer healing rates, demonstrating that stromelysin matrix metalloproteinase (mmp)-3, collagenase mmp-8 and gelatinase mmp-9 were significantly reduced after the compression treatment, and suggesting that a down-regulation of proteinases in ulcer tissue microenvironment by compression may represent a possible mechanism (in conjunction to the decrease of inflammation) to counteract the progression of cvi and improve venous ulcer healing.15 more recently, it has been reported that venous ulcers treated with a multi-layer bandaging system showed decreased plasma levels of mmp-9, timp-1, and mmp-2/timp-2 ratio in healed wounds.16 finally, a recent randomized placebo-controlled trial assessed the efficacy of elastic compression stocking to prevent post-thromcorrespondence: ferdinando mannello, department of biomolecular sciences, university of urbino carlo bo, via aurelio saffi 2, 61029 urbino (pu), italy. e-mail: ferdinando.mannello@uniurb.it this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright d. ligi et al., 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5980 doi:10.4081/vl.2016.5980 no n c om me rci al us e o nly conference presentation [veins and lymphatics 2016; 5:5980] [page 3] botic syndrome; although the study showed several bias weakening the entire protocol, their results suggested that elastic compression did not prevent post-thrombotic syndrome, not supporting routine wearing of elastic compression stocking after deep vein thrombosis.17 noteworthy is the scarce presence of biomolecular evidence of elastic compression efficacy on swelling and inflammation, suggesting that further studies are needed to clarify the mechanisms of stocking efficacy in down-regulation of hemodynamic and inflammatory processes implicated in cvi and deep venous thrombosis. for what concerns the future perspectives, on the basis of previous studies performed in animal models18 and human cell lines,19,20 it is noteworthy that glycosaminoglycans in conjunction to compression therapy may improve ulcer healing,21 due to their effectiveness in down-regulating the release of cytokines, chemokines and leukocyte colony stimulating factors from human macrophages and in modulating the inflammatory pathways. the effects of glycosaminoglycans could actually enhance the effects of compression therapy on inflammation mediators. references 1. raffetto jd, mannello f. patho-physiology of chronic venous disease. int angiol 2014;33:212-21. 2. raffetto jd. which dressings reduce inflammation and improve venous leg ulcer healing. phlebology 2014;29:157-64. 3. mannello f, raffetto jd. matrix metalloproteinase activity and glycosaminoglycans in chronic venous disease: the linkage among cell biology, pathology, and translational research. am j transl res 2011;3:149-58. 4. kolluri r. management of venous ulcers. tech vasc interv radiol 2014;17:132-8. 5. carr sc. diagnosis and management of venous ulcers. perspect vasc surg endovasc ther 2008;20:82-5. 6. mosti g. wound care in venous ulcers. phlebology 2013;28:79-85. 7. mosti g, de maeseneer m, cavezzi a, et al. society for vascular surgery and american venous forum guidelines on the management of venous leg ulcers: the point of view of the international union of phlebology. int angiol 2015;34:202-18. 8. raffetto jd, eberhardt rt, dean sm, et al. pharmacologic treatment to improve venous leg ulcers healing. j vasc surg venous lymphatic disorder 2015 [epub ahead of print]. 9. barwell jr, davies ce, deacon j, et al. comparison of surgery and compression with compression alone in chronic venous ulceration (eschar study): randomized controlled trial. lancet 2004;363:1854-9. 10. gohel ms, barwell jr, wakely c, et al. the influence of superficial venous surgery and compression on incompetent perforators in chronic venous leg ulceration. eur j vasc endovasc surg 2005;29:78-82. 11. mannello f, ligi d, canale m, raffetto jd. omics profiles in chronic venous ulcer wound fluid: innovative applications for translational medicine. exp rev mol diagn 2014;14:737-62. 12. beidler sk, douillet cd, berndt df, et al. inflammatory cytokine levels in chronic venous insufficiency ulcer tissue before and after compression therapy. j vasc surg 2009;49:1013-20. 13. murphy ma, joyce wp, condron c, bouchier-hayes d. a reduction in serum cytokine levels parallels healing of venous ulcers in patients undergoing compression therapy. eur j vasc endovasc surg 2002;23:349-52. 14. gohel ms, windhaber ra, tarlton jf, et al. the relationship between cytokine concentrations and wound healing in chronic venous ulceration. j vasc surg 2008;48:1272-7. 15. beidler sk, douillet cd, berndt df, et al. multiplexed analyses of matrixmetalloproteinases in leg ulcer tissue of patients with chronic venous insufficiency before and after compression therapy. wound repair regen 2008;16:642-8. 16. caimi g, ferrara f, montana m, et al. behaviour of the plasma concentration of gelatinases and their tissue inhibitors in subjects with venous leg ulcers. clin hemorheol microcirc. 2015;60:309-16. 17. kahn sr, shapiro s, wells ps, et al. compression stockings to prevent postthrombotic syndrome: a randomized placebo-controlled trial. lancet 2014;383:880-8. 18. tong m, tuk b, hekking im, et al. heparan sulphate glycosaminoglycan mimetic improves pressure ulcer healing in a rat model of cutaneous ischemia-reperfusion injury. wound repair regen 2011;19:505-14. 19. mannello f, medda v, ligi d, raffetto jd. glycosaminoglycan sulodexide inhibition of mmp-9 gelatinase secretion and activity: possible pharmacological role against collagen degradation in vascular chronic diseases. curr vasc pharmacol 2013;11: 354-65. 20. mannello f, ligi d, canale m, raffetto jd. sulodexide down-regulates the release of cytokines, chemokines and leukocyte colony stimulating factors from human macrophages: role of glycosaminoglycans in inflammatory pathways of chronic venous disease. curr vasc pharmacol 2014;12:173-85. 21. mannello f, ligi d, raffetto jd. glycosa minoglycan sulodexide modulates inflammatory pathways in chronic venous disease. int angiol 2015;33:236-42. no n c om me rci al us e o nly stefano ricci comment to: anatomy of the hunter’s canal and its role in the venous outlet syndrome of the lower limb by uhl jf, gillot c. phlebology 2014 sep 10 [epub ahead of print] stefano ricci abstract one hundred limbs of 50 non-embalmed cadaveric subjects (mean age of 82) were studied by injection of the venous system of the lower limbs with green neoprene latex. a realistic 3d reconstruction of the whole venous network with an accurate morphological description was obtained by 200 phlebographies and 100 ct venograms. the outlet of the hunter’s canal, located at the medial aspect of the lower thigh, is narrowed by a tendinous band, the vastoadductor membrane, joining the vastus medialis to the adductor longus. the roof of the canal is made by the vastus medialis muscle, the floor by the adductors, and it is closed medially by the sartorius muscle. a musculotendinous band, the vastoadductor membrane, arose from the adductor magnus muscle, joining the adductor tendon to the vastus medialis. the vascular pedicle being tightened inside this small fibrous space changes its direction to go from the thigh to the popliteal fossa: this explains the frequent kink or plication of the vein, compressed at the posterior aspect of the canal, while the artery is located at the anterior aspect of the canal. the saphenous nerve is located deeply next to the collateral canal and perforates the muscular fascia at the lower third of the thigh. it runs subcutaneously parallel to the tendon of the adductor longus. the femoral vein is located more posteriorly and is frequently narrowed at this level by the edge of the vastoadductor membrane. the reason for venous compression is the reduced width and stiffness of this part of the canal, surrounded by fibrous stiff structures. the vein at this level could be easily compressed in the posterior angle of the hiatus, commonly tightened by a calcified artery. physiological hypothesis: the cadaveric simulations demonstrated that contraction of the adductor longus closes the hiatus, and contraction of the adductor magnus opens it. during the impulsion phase of the step (extension of the thigh), the systole of the calf muscle pump pushes the blood up into the femoral vein. at this time, the adductor longus is relaxed and the adductor magnus contracts, which opens the hunter’s hiatus. during thigh flexion, at the beginning of the step (suspension phase), the calf is relaxed and the adductor longus is in tension, which closes the hunter’s hiatus. this event could be important for the prevention of venous thrombosis of the femoropopliteal axis. in the sitting position, the adductor longus muscle relaxes and the adductor magnus is shortened, which closes the outlet of the hunter’s canal, leading to venous compression. different possible derivative routes in case of stenosis of the hunter’s canal are possible: i) the axial vein located along the ischiatic nerve; ii) the deep femoral vein with a low popliteal communicating branch; iii) the venous arcades of the vastus medialis; iv) and especially the dilated arcades of the semimembranosus muscle. these act like a safety valve, derivating the blood of the popliteal vein to the deep femoral vein, bypassing the hunter’s canal stenosis. in clinical practice, a venous examination should systematically include an evaluation below the semimembranosus muscle at the posteromedial aspect of the thigh, 10 cm up to the knee joint, close to the midline: the presence of dilated arcades is a sign of stasis, and probably of femoral compression of the hunter’s outlet. comment by stefano ricci this interesting paper should be considered as the sequel of the one, from the same authors, just analyzed in this same bibliolab: anatomy of the veno-muscular pumps of the lower limb phlebology online first, published on january 10, 2014. in that instance the adductors canal’s possible obstruction (functional or organic) was only recalled, while in this paper it is described at great length. very clear images are supplied that greatly help in understanding this difficult and scarcely attended subject. after this lecture it comes natural to suspect an adductors canal obstruction in many unexplained clinical situations that we often encounter in our clinical practice. the one that is the most intriguing as far as superficial venous network is concerned, is the case when a reflux at the sapheno-poplitel junction (spj) is transmitted to the giacomini vein (in a centripetal direction) and consequently to the great saphenous vein (gsv). often in these cases the gsv is incompetent as a consequence of the overload. typically, the spj reflux is present also during muscles contraction (the so called systolic phase) giving evidence of an insufficient draining capacity of the deep system, the giacomini acting like a derivative route, although not mentioned in the paper’s bypassing routes. probably a complete dynamic (but not easy) study of the hunter’s canal in these cases would reveal, at least, a relative obstruction. the same anatomical presence of the giacomini vein (gv) could be (inversely) correlated to the deep veins system efficiency: the gv is present only in subjects with deep veins relatively difficult drainage. finally, some spj interruption recurrences and popliteal fossa perforator post op. appearances could be explained in the same way. [top] hrev_master veins and lymphatics 2015; volume 4:5012 [veins and lymphatics 2015; 4:5012] [page 39] the role of magnetic resonance imaging in assessing venous vascular abnormalities in the head and neck: a demonstration of cerebrospinal venous insufficiency in a subset of multiple sclerosis patients e. mark haacke,1,2 sean k. sethi,1 jing jiang,1 ying wang,1 david t. utriainen1 1magnetic resonance innovations, inc.; 2department of radiology, wayne state university, detroit, mi, usa abstract the study of chronic cerebrospinal venous insufficiency (ccsvi) and its impact on the development and progression of multiple sclerosis (ms) remains controversial. although the initial thrust in evaluating ccsvi was with ultrasound, other modalities including magnetic resonance imaging (mri) have been used to study venous vascular abnormalities. this review focuses on the findings of a number of past mri studies including a look at a combined study of four previous works with a cohort of 559 ms patients regarding structure and function of the extra-cranial vasculature. strengths and limitations of each paper are discussed which give insight into conflicting reports of venous abnormalities in ms patients and healthy controls. guidelines for data acquisition and analysis for future studies related to extra-cranial structure and flow, both arterial and venous, are discussed. this includes the grading of stenosis of the internal jugular veins (ijvs) as well as normalized flows through major veins of the neck. the lack of agreement between most studies is likely due to inconsistent data acquisition and incomplete data analysis. our own work over four independent sites shows good agreement, indicating that there is a high incidence of stenosis and structural venous abnormalities in the ms population and that this change results in reduced outflow of the ijvs and increased collateralization of venous return to the heart compared to healthy controls. introduction from the onset of the description of multiple sclerosis (ms) to the more current autoimmune descriptions, there has been a belief that the venous system is involved in the pathogenesis of ms. few argue that ms lesions are venocentric, but the implications of this finding are unclear. some believe that, from a mechanical point of view, venous hypertension should lead to venocentric lesions.1 a more modern view invokes a venous involvement of the small veins or venules in the pathophysiology of the disease in an attempt to explain how it might be auto-immune in nature. it has also been suggested that blood flow plays a critical role in the ability of the brain to maintain neuronal myelination.2 the use of contrast agents in magnetic resonance imaging (mri) has proven useful in the study of ms. it is apparent from the observed contrast leakage into the cerebral parenchyma for some lesions that there is disruption of the blood brain barrier, but many auto-immune models do not take into account the potential endothelial dysfunction or potential mechanical damage to these veins. from an mr imaging standpoint, a number of studies have observed a reduction in cerebral blood flow in the lesions of relapsing remitting ms patients.3 understanding the role, which cerebral blood flow plays, especially the venous involvement, is now at a critical divide. many questions have arisen which require further assessment, such as: what is the source of the venous involvement? and is it related to the pathogenesis of the disease? or is the presence of abnormal venous flow just a comorbidity with an autoimmune source of the disease? still, it is important to consider that there are many vascular situations with abnormal venous flow that can lead to neurological effects.2,4,5 although groups in the past have demonstrated major involvement of the venous system with ms,6,7 the first clinical attempt to deal with the abnormal vasculature specifically for ms came from the work of paolo zamboni.8 he recognized that there were extra-cranial venous structural and flow abnormalities that, in themselves, created a highly resistive secondary network of collateral flow that might explain upstream effects on the venous system in the brain. this extra-cranial effect had been noticed previously in patients with paraplegia and quadriplegia by aboulker et al. in the early 1970s.9 over the first half of that decade, they treated many patients who had stenoses of the jugular, azygous, subclavian and iliac veins as well as the vena cava. both groups found that treating the veins could have a significant affect in relieving symptoms of their patients, but only for a fraction their patients. still, in some cases the benefit was clear. the initial investigative work of zamboni et al. was based on the use of ultrasound (us) as an imaging tool to probe the venous flow. from this work, he determined a set of five criteria that he believed could be related to abnormal structure and function (flow) of the extra-cranial and intra-cranial venous system.8 unfortunately, over the last few years, different groups have been unable to replicate his work or each other’s work with the results representing a broad range of patients and normal controls who may meet these criteria.10-18 this has resulted in a controversial scientific debate between different groups research findings.19 currently, there is no consensus as to whether these criteria are valid or not. this may be, in part, due to the fact that us is highly operator-dependent. the importance for ms patients is not whether us works or not, but rather: are there venous vascular abnormalities in patients with ms? in this review, we will address an alternate approach to us by means of analyzing the vasculature of the head and neck quantitatively using mri. a major advantage of mri is that it allows evaluation of the structural patency and correspondence: e. mark haacke, magnetic resonance innovations, inc., 440 east ferry street, detroit, mi 48202, usa. tel.: +1.313.758.0065 fax: +1.313.758.0068. e-mail: nmrimaging@aol.com key words: multiple sclerosis; flow quantification; chronic cerebrospinal venous insufficiency; magnetic resonance imaging. acknowledgements: the authors would like to thank mr innovations india; dr. naftali raz, dr. ana daugherty and dr. phil levy from wayne state university for usage of some of their healthy control data; and giacomo gadda from the university of ferrara, for his assistance in preparing some of the figures and their statistics. contributions: the authors contributed equally. conflict of interests: the authors declare no potential conflict of interests. funding: research reported in this publication was supported in part by the national heart, lung, and blood institute of the national institutes of health under award number r42hl112580; as well as national institutes of health award number 5r01md005849. the content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the national institutes of health. received for publication: 31 january 2015. revision received: 27 march 2015 accepted for publication: 30 march 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright e.m. haacke et al., 2015 licensee pagepress, italy veins and lymphatics 2015; 4:5012 doi:10.4081/vl.2015.5012 no n c om me rci al us e o nly article [page 40] [veins and lymphatics 2015; 4:5012] dimensions of the head and neck vasculature and brain parenchyma as well as imaging flow data in minutes. for the flow data, the in-plane resolution is collected around 0.5 mm2 so a clearly defined cross sectional area (csa) can be found easily for all major vessels (arteries and veins) and the blood flow into the brain and out of the head-neck system into the heart can be quantified. this can be accomplished at both 1.5 t and 3.0 t for all manufacturers and, once a given protocol has been established, the results will be operator-independent. a number of groups have tried using mri to study the anatomy and/or flow of the vessels in the neck with varying degrees of success.10,1215,20-31 again, as in us, the results between studies are not consistent. part of the problem here is not the methodology; rather it is either the incompleteness of the studies and/or the associated processing of the data. the purpose of this review is to understand, if possible, why that might be the case by evaluating not only how the data were collected by each group but also how they were analyzed. in the end, we recommend a user-friendly, widely available mri protocol that, with a fairly complete analysis of the data, may offer the ability for both healthy controls and ms patients to be carefully and consistently studied across different sites. materials and methods recommended imaging protocol to study venous abnormalities in ms patients, both the anatomy and flow of the vessels must be investigated with the patient in the supine position. the evaluation of the vascular anatomy of the head and neck can be done using either coronal 3d time-resolved contrast-enhanced (ce) mr arteriovenography (mrav) with coverage of the carotid arteries and internal jugular veins (ijvs), or by using transverse 2d time-of-flight (tof) venography. both should provide coverage from at least the level of the aortic arch to the sigmoid sinuses. the 3d ce mrav requires the timed use of a contrast agent. the time resolution for this 3d coverage should be only a few seconds (less than 10 s and preferably less than 5 s to capture the arterial phase clearly) per slab. acquiring many time points will take between one and two minutes if the late phase venous information is desired. the 2d tof mrv of the neck does not require the use of a contrast agent, however, the signal is dependent on the velocity of blood flow exceeding a threshold (the slice thickness/echo time) and takes longer to acquire. mr flow quantification is finding a new life using 4d flow quantification which provides a 3d representation of flow dynamics throughout the cardiac cycle.32 the resulting data makes it possible to estimate pressure gradients along the vessels. the 4d flow measurements have also been shown to have accuracy and precision for both arterial and venous flows at varying velocity encodings which is promising for future applications studying venous stenosis and abnormal flow patterns.33 the technique has also been used in combination with computational fluid dynamics to validate 3d printed phantoms of vascular structures.34 however, this technique requires substantial time to collect and process. still, for now, in the best interests of a clinically oriented research protocol, simplicity and speed are of great concern. the data which are collected should be easy to interpret and any post-processing which is needed, whether it is 3d modeling or functional quantitative measurements, should require minimal user input and minimal time. therefore, our recommendation is to use 2d phase-contrast (pc) flow quantification (fq) bearing in mind that as mr technology becomes faster, 4d methods will eventually become viable. generally, 2d fq is readily available from all mr manufacturers. the acquisition time is usually only 2 or 3 min depending on resolution and cardiac period. flow throughout the cardiac cycle can be obtained roughly every 30 to 40 ms. in order to provide an adequate mapping of blood flow, data from at least two levels should be collected. the first slice should be set perpendicular to the flow of the ijvs and carotid arteries at the level cranial to the ijv valve and caudal to the carotid bifurcation (preferably at the c5/c6 level). the second slice should be set perpendicular to the flow of the ijv and carotid arteries at the level caudal to the vertebral arteries exiting of the vertebral column and cranial to the carotid bifurcation by over a few centimeters (preferably at the c2/c3 level).35,36 the velocity encoding (venc) should be set to 50 cm/s; this is to ensure sufficient signal-to-noise ratio in slower flowing veins. any aliasing that occurs from the faster carotid artery flow during peak systole can be unwrapped using simple algorithms. this sequence does not require the administration of a contrast agent. putting all components of a standard (conventional) neuro-imaging protocol together with the suggested flow protocol discussed above can be done in stages. a versatile protocol containing sequences which can be acquired on nearly any magnet is ideal, and the required core sequences and admitted variations both with and without contrast are discussed in the recent paper by zivadinov et al.37 recommended analysis of the data ideally, data should be processed by individuals trained in using an acceptable software package for processing flow data. this software should be capable of reliable measures of cross sectional area and flow in both positive and negative directions. if both 2d and 3d mrav data are collected, the coronal 3d contrast enhanced data can be reformatted to match the 2d tof mrv data.25 usually available software packages detect the vessel boundaries automatically and provide a means to modify the boundary if the user so chooses. some definition of stenosis is required and we recommend that vessels with a csa less than 25 mm2 at or caudal to the c3 level and less than 12.5 mm2 cranial to the c3 level be denoted as stenotic.20-22,25,35,36,38 lack of visibility of the ijvs in all imaging modalities with clear visualization of surrounding vasculature in a segment should be referred to as atresia, and lack of visibility observed throughout the entire vessel length as aplasia. if a venc of 50 cm/sec is used and aliasing occurs in either the arteries or veins, a phase unwrapping algorithm must be available or used when the flow velocity exceeds 50 cm/s. in order to create an across system and across sequence robust result, we recommend normalizing the ijv flow to the arterial sum (ta) of the common carotid and vertebral (va) arteries at the c5/c6 level and the internal carotid and va at the c2/c3 level. this normalization will also account for variations in total flow into and out of the brain among subjects. the ratio between the ijv carrying the higher flow, considered the dominant jugular (dj), and the lower flow, considered the subdominant jugular (sdj) should then be calculated. all such measurements should be evaluated by each processor. a processor can be considered reliable if the intra-class correlation statistic [icc(2)] for an individual vessel measurement is greater than 0.85. finally, we recommend evaluating two populations: stenotic and non-stenotic for both the ms and healthy control (hc) groups. differences that might not otherwise be apparent can become evident such as the number of stenotic (st) and nonstenotic (nst) cases in each group and the flow associated with st and nst individuals. our experience over four independent studies covering 559 multiple sclerosis cases in our own work in this area, we used spin (signal processing in nuclear mr; mr innovations, inc., detroit, mi, usa) software and had six processors trained so that their data analysis had an icc of 0.85 or better for all quoted flow measures. spin has a built in anti-aliasing algorithm. vessel boundaries are calculated using a full width at half maximum algorithm.39 we analyzed the following flow indices: total ijv flow normalized to total arterial flow (tijv/ta), sub-dominant ijv normalized to dominant ijv (sdj/dj), and sub-dominant ijv normalized to total arterial (sdj/ta) at both the c2/c3 and c5/c6 neck levels. a general linear model (glm) was used to differentiate normalized ijv no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:5012] [page 41] flow between groups (st, nst, and hc), controlling for age and sex and a univariate glm was used to allow paired t-tests to study group differences. to determine the discrimination of these measures between disease states, a receiver operating characteristic (roc) curve analysis was performed. optimum roc sensitivity and specificity was determined as the point with the least distance from the coordinate (0,1) with sensitivity as the y-axis and 1-specificity as the x-axis. statistical significance for both the student’s t-test and the area under the curve evaluation was determined using p<0.05. a chisquare test for proportion was used to test the number of st cases between the groups with significance of p<0.05. results our recent work25 using the mr protocol introduced above to assess ijv structure and function showed lower tijv/ta blood flow in the ms group (138 subjects) compared to a group of healthy controls (67 subjects). more specifically, this ms group was divided into stenotic (72 subjects) and non-stenotic (66 subjects) giving three groups of roughly equal size st ms, nst ms, and hc. significant flow differences were found in the ijvs between the ms and hc groups. this research showed significant differences between the st-ms group and the hc group, between the st-ms and the nst-ms groups, and no differences in flow between the nst-ms group and the hc group. the largest difference in tijv/ta flow between the st-ms and hc groups was observed below the cut-off of 0.66 for c2/c3 and 0.62 for c5/c6. that is, the percentage of st-ms patients below these cutoff values was much larger than that of the nst-ms or hc populations. when applying these thresholds to the hc and ms groups, 4/67 (6%) of the hc group and 51/138 (37%) of the ms group fall below those two boundaries. of the ms group, 44/72 (61%) st-ms and 7/68 (11%) nst-ms subjects fell under the cut-offs indicating a disparate flow behavior between the two groups. the first flow related study on ms from our group found that 136 (68%) out of 200 ms patients showed the presence of anatomic abnormalities, including stenosis or atresia, in the ijvs.22 in this study the flow measurements were reported for c5/c6 neck level only and were normalized as tijv/ta. the result was compared to the normalized ijv flows reported by doepp et al.40 for 50 healthy controls. the nst-ms behaved similar to the hc, however, the st-ms had significantly reduced ijv flow. the sdj/dj index was calculated, and it was found that 67% had flow in the subdominant ijv less than 3 ml/s and a sdj/dj ratio less than 1/3. the next study found 79% of the stenotic group had a sdj/ta flow of less than 20%, a tijv/ta of less than 50% and/or a sdj/dj flow ratio of less than 1/3.21 similar findings were seen in a fourth study where out of 323 ms patients, 223 (69%) had a stenosis.20 the tijv/ta was significantly lower at both c2/c3 and c5/c6 neck levels in the st-ms group compared to the nst-ms group, with 56+/-26% and 51+/-23% compared to 85+/-13% and 73+/-12% respectively. in order to better demonstrate the validation of cross-site studies employing the same protocol and processing, a meta-analysis was done on the data from the four previously mentioned studies20-22,25 plus our available database yielding a total of 559 ms cases and 95 hc. the flow data were reprocessed using spin software rather than flow-q software. in this large group analysis, it is clear from the mrv and flow data that there are venous structural abnormalities in both the hc and ms populations, and that primary outflow obstruction will lead to collateralization of flow to the heart. a summary of each type of stenosis, atresia, and aplasia is given in table 1. more than half (61.8%, 346/559) of the ms group showed abnormal vasculature using both the 2d tof mrv and 3d ce mrav data, whereas, only 11 of 49 hc (22.4%, 46 subjects did not have venographic imaging to review) showed abnormal vasculature. a goal in this meta-analysis was to determine if these structural and functional changes could still separate the hc and ms groups. examples of the appearance of venous abnormalities with a description of the collateralization of flow are shown in figure 1 for both ms and hc. to better understand how the structural changes have affected the venous drainage, an roc analysis was performed to compare the ms and hc groups, as well as the st-ms and hc groups, to determine if a significant separation in flow patterns could be observed. all cases were plotted comparing the normalized ijv flows at c2/c3 vs c5/c6 levels and are shown in figure 2a and b. based on the distribution of flows between groups, the optimum cutoff for tijv/ta for categorizing the most st-ms subjects while categorizing the least hc for the c5/c6 level was 61% yielding a sensitivity of 0.80 and specificity of 0.62 and for the c2/c3 level the optimum cutoff was 73% yielding a sensitivity of 0.74 and specificity of 0.71. the ms subjects tend to show a larger variety of compensation which involves reflux of flow through the common facial vein out of the ijv and into superficial collaterals, bypassing any stenosis in the ijv through neighboring collaterals, and other large shifts of outflow into and out of the ijvs. the number of st-ms, nst-ms, hc, and total ms cases that fall below both thresholds is 192/346 (55.5%), 23/213 (10.8%), 12/95 (12.6%), and 215/559 (38.5%). of the st-hc cases, 6/11 (54%) fall below both thresholds; it is noteworthy that these cutoffs are similar to sethi et al.25 lastly, none of the hc showed any tijv/ta below 25% for both c5/c6 and c2/c3 neck levels. in figure 2c and d, the ms patients are broken into two groups (upper or lower level stensosis) for each of the left and right jugular veins. it can be seen that the healthy controls tend to sit in the middle of the plots while many of the ms patients are bunched toward or along the axes due to their slower flow in one vein. to better understand the role of stenosis, we evaluated the flow data as a function of stenosis location. for example, if there is an upper neck level stenosis of the left ijv (lijv), how is flow redirected and is there a change in the paired non-stenotic right ijv (rijv)? the stenosis level was considered table 1. stenosis type by group. ms (559) (ms %) hc (49) hc (%) stenosis type 346 61.8% 11 22.4% ll rijv stenosis 133 23.8% 4 8.2% ul rijv stenosis 93 16.6% 1 2.0% ll lijv stenosis 158 28.3% 7 14.3% ul lijv stenosis 115 20.6% 4 8.2% ll rijv atresia 6 1.1% 0 0.0% ul rijv atresia 17 3.0% 1 2.0% ll lijv atresia 13 2.3% 0 0.0% ul lijv atresia 33 5.9% 0 0.0% rijv diffuse stenosis 8 1.4% 0 0.0% lijv diffuse stenosis 21 3.7% 0 0.0% rijv aplasia 1 0.2% 0 0.0% lijv aplasia 2 0.4% 0 0.0% ms, multiple sclerosis; hc, healthy control; ll, lower level; rijv, right internal jugular vein; ul, upper level; lijv, left internal jugular vein. for the hc, 46 subjects were part of a different study which did not include venography. note in the last 8 narrowing or stenotic categories, there are 101 ms cases or 18% while in the hc there is only 1 case or 2%. no n c om me rci al us e o nly article [page 42] [veins and lymphatics 2015; 4:5012] either a single point in the upper or lower neck and if it was in the rijv or lijv. figure 2c and d show the distribution of each type of stenosis and the affect it has on c2/c3 and c5/c6 flows in both ijvs. it is reported in the literature and generally known that the rijv is dominant to the lijv in over half the population, a smaller group has co-dominant ijvs, and an even smaller group shows lijv dominance. figures 2c and 2d demonstrate this trend as seen in the hc nst as showing the rijv with higher flow (about 1/3 of that in the lijv). if we have an upper or lower lijv stenosis this will reduce the flow in the lijv, we only see a slight increase, if any, through the rijv. this indicates there may be collateralization on the left side. however, when there is a rijv upper neck level stenosis it reduces the outflow through the ijv and increases it through the lijv dramatically, clearly separating this group from the hc. the same is seen in a lower rijv stenosis but to a lesser extent. therefore, it appears that a stenosis in one jugular vein only will redirect flow to the other, or vice versa. discussion one of the key issues in this review is to consider why results from many groups using mri are so disparate. many of the studies thus far are not an exact recapitulation of the original us methods proposed by zamboni,8 but generally look for the hallmarks of chronic cerebrospinal venous insufficiency (ccsvi) which are venous structural and flow abnormalities using several different methods of data collection and analysis. we wish to promote a more uniform data collection and analysis so that groups around the world can easily compare their results and hopefully draw more consistent conclusions. many investigators have spent a lot of time on their studies but do not collect all relevant data or do not process the data they have collected consistently. some examples from the recent literature are presented below. studies from buffalo neuroimaging and stanford using ordinal internal jugular vein assessments after the original ccsvi study, zivadinov and colleagues published five studies using 2d tof mr venography and 3d tricks sequences on a 3t scanner.13,27,28,31,41 in all of their studies, the morphology of the ijvs was classified using an ordinal scale: absent, pinpoint, flattened, crescentic, and ellipsoidal in which absent and pinpoint were considered abnormal. when evaluating the ijv, the narrowest point along the inferior and superior part of the segments was considered. asymmetries were also assessed in the ijvs and vertebral veins; prominent venous collaterals were noted. any collaterals that were >5 mm in diameter (or 7 mm for the segment of the inferior segment of the external jugular vein) were noted as prominent. in the first pilot study by hojnacki et al.41 with 10 ms and hc, us and selective venography were used and compared to the mri modalities with respect to sensitivity and figure 1. examples of 3d contrast-enhanced (ce) magnetic resonance arteriovenography (mrav) of multiple sclerosis (ms) patients and healthy controls (hc). a) hc with normal appearing internal jugular vein (ijv) (arrows) with some collateral enhancement. the ijvs in this hc carry the dominant outflow towards the heart. b) hc with abnormal appearing ijvs with bilateral lower level stenosis (arrows). the ijv flows normalized to the total arterial input at the c2/c3 and c5/c6 levels are 27% and 24%, respectively, a trend which is seen in many hc where flows are consistent between levels. compensation appears to divert venous flow to the para-spinal and deep cervical veins through the anterior condylar confluence. c) ms patient with bilateral lower level stenosis (arrows) of the ijv. it closely resembles the hc in b with 32% of flow through the ijv and 44% through the para-spinal and deep cervical veins at the c5/c6 level. d) ms patient with diffuse stenosis of the left ijv and a tight stenosis of the right ijv at the lower neck level. the outflow at the c2/c3 level through the right ijv is 70% of total arterial inflow, while at the c5/c6 neck level it is reduced to 9%. the right anterior jugular vein (ajv, white arrow) carries 52%, indicating that the outflow through the ijv at the upper neck was redirected through the common facial vein as an anastomosis to the ajv. this type of primary compensation due to structural anomalies can be seen when there is high flow at the upper neck level and low flow at the lower neck, or when an upper level stenosis prevents inflow from the sigmoid sinus and the common facial vein reconstitutes high flow into the ijv at the lower neck level. e) ms patient without stenosis in the right ijv, however, as in d, the flow is redirected to the ajv (white arrow) via the common facial vein connection near the c4 vertebrae level. this indicates that there may be other structural or functional abnormalities which are not clearly evident in the ce mrav which result in quantitative changes in flow. f) ms patient with a tight stenosis at the lower neck level. the flow is redirected to the external jugular vein (ejv) via multiple anastomoses at different levels of the neck (white arrows). at the c2/c3 level the right ijv carries 42% of total arterial input; however at the c6 level it carries a negligible amount. at the c2/c3 level the right ejv carries 16% and by the c5/c6 level this increases to 52%. no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:5012] [page 43] specificity of diagnosing ccsvi. the sensitivity and specificity for detecting ijv abnormalities for 3d tricks were 31% and 100%, and 25% and 100% 2d tof respectively. mrv methods were shown to have lower sensitivity and specificity compared to us and selective venography; thus, mrv methods were concluded to have limited value when studying ccsvi. lack of experience and evaluation standards using mrv were cited as drawbacks to the study. further, the methods were noted to not have the resolution to depict intraluminal and vessel wall anomalies such as septa, webs, annulus, etc. no saturation pulse was used in the 2d tof imaging, which may miss bidirectional or reflux flow. the second study by zivadinov et al.31 was a longitudinal study among 10 ms and 6 hc subjects. catheter venography (as gold standard) and us were performed for comparison. for detecting ijv anomalies, low specificity was noted between two mrv techniques (30-40%) and catheter venography, while high specificity (99%) was noted; this contrasts with the work of the previous study. this protocol did not screen for any secondary venous collaterization. zivadinov’s third study involving 57 ms patients and 21 hc found no differences between the two groups in using the mrv methods, thus not supporting the results of zamboni who was able to distinguish ms from hc with certainty using us. no differences in venous collateral prominence or ijv asymmetries were found between ms and hc subjects.13 two additional studies by dolic et al.27,28 were done: one using a multimodal approach to evaluating ccsvi (mrv and us), and one using the same methods to evaluate the frequency of venous intraluminal and extraluminal abnormalities. the first study showed no differences in flow morphology using tof and tricks imaging between ms and hc, even though differences were found in us.28 in the latter study, no differences in ijv appearance were found between ms and hc using the mrv methods; in the ms group alone, however, progressive ms subjects showed more ijv abnormalities in mrv compared to non-progressive ms subjects.27 combining modalities increased the specificity for screening for ms, but the sensitivity remained low indicating only a subset of the ms patients may present with vascular pathology. while all five of these studies did not find any differences in ijvs between the two groups, this study was strictly an anatomical one and did not include phasecontrast flow quantification or csa using mri. some of the pitfalls of the analyses are detailed in work by rahman et al.38 and sethi et al.25 two additional mr venography studies were from the stanford group. the first study by zaharchuk and colleagues42 compared 2d tof mrv and 3d tricks with contrast venography in ms patients (no controls were used). ijv calibers were assessed with 2d tof at three different neck levels and scored ordinally as follows: 0 for normal round or ovoid, 1 for mild flattening, 2 for moderate flattening, and 3 for severe flattening or lack of visualization. the presence of collateral veins was assessed using a similar ordinal method with a score of 0 being none or minimal and 3 being most prominent. contrast venography was used as a standard to compare with the mri images. they found that the most common stenoses were in the upper (c1-c2) and lower (c6-t2) segment of the ijv. though good agreement was seen in the upper and mid-portions of the neck between 2d tof mrv and contrast venography, poor agreement was noted in the lower neck level (c6-t2). they also concluded that this may be due to turbulent or slow flow which may underestimate the ijv area in 2d tof mrv. collaterals were best visualized in tricks as their slow flow may not generate signal in 2d tof mrv. the second study by mctaggart et al.43 used similar mr venographic methods to assess ijv stenosis and venous collaterals in 19 patients with ms and 20 healthy controls. it proved to be one of the first studies that noted differences in the ijvs with respect to mrv; more specifically, the ms group showed greater flattening compared to the healthy control group, however, they did not show differences in the presence of venous collaterals in 3d tricks. both the stanford studies and the zivadinov studies did not use quantitative csa measurements for comparing jugular veins, nor did they use flow quantification for comparison. structural-focused studies rahman et al.38 assessed 170 ms and 40 hc figure 2. a) internal jugular vein (ijv) flow normalized to arterial flow for the c5/c6 neck level plotted against the c2/c3 neck level for cases with venography only. b) ijv flow normalized to arterial flow for the c5/c6 neck level plotted against the c2/c3 neck level for all cases. threshold lines of total ijv flow normalized to total arterial flow (tijv/ta) at c6<0.61 and tijv/ta at c2<0.73 are drawn (dotted lines). c-d) left (lijv) vs right (rijv) distribution of the normalized internal jugular veins flow at the lower level (c5/c6) and upper level (c2/c3) in subjects with different types of obstruction and in healthy controls (hc). normalization for the c5/c6 flow is referred to the sum of common carotid artery and vertebral artery measured at the same level. nst, non-stenotic; st, stenotic; ms, multiple sclerosis; ll, lower level; ul, upper level. no n c om me rci al us e o nly article [page 44] [veins and lymphatics 2015; 4:5012] subjects using 2d tof mrv and 3d tricks using a quantitative measure of csa for the ijvs.22 a larger csa was observed in the 3d tricks data compared to the 2d tof mrv data. a number of anomalies were noted in the ms group such as atresia, aplasia, diffuse or tight stenosis, and ectasia caused by compression from the carotid arteries. generally the anatomy was depicted more completely using 3d tricks compared to 2d tof mrv. this is because if the vessel is patent the contrast agent will show signal even if there is slow flow, whereas in 2d tof little signal is generated for slow flow. cases in which flow may jet down the side of the vessel may present with a smaller area size or pinpoint in 2d tof mrv compared to 3d tricks, in which the entire lumen may be seen (this may be the cause of the larger csa in 3d tricks). while this study neither proved nor refuted the ccsvi hypothesis, it did bring interesting dimension on how to use both the 2d and 3d methods in a complimentary way. one of the first papers using mr anatomic and flow data was presented by sundström et al.26 who looked at flow at the c2/c3 level for 21 ms patients and 20 healthy controls at 3t. they found a trend toward lower total cerebral blood flow in the ms cases. however, upon normalization of the total ijv flow to the total cbf they found both groups had an average of 70% although the spread in these normalized flows ranged from 0.12 to 0.97 for the ms group and 0.32 to 0.87 in the control group. it is important to note that they reported separately left and right ijv normalized flows, which makes it comparable to previous studies looking at dominance patterns of ijv flow. however, the limited size of the group makes it impossible to draw any conclusions as to whether having normalized total ijv flow less than 60% is abnormal or not. they also showed several cases with reflux and stenosis (3 ms patients no hc). wattjes et al.14 studied 20 ms patients and 20 hc at 3 t and found no cases with reflux. however, no quantitative flow data is given in this paper. they note that 50% of ms patients had stenosis and 40% of hc using a 50% stenosis rule. there is no surprise in this finding given that they did not use an absolute measure of cross sectional area (see the discussion under rodger et al.12 as to why this choice of 50% is inappropriate for veins). doepp et al.15 presents a more balanced view by reporting the level of stenoses. they studied 40 patients at 1.5 t using mrv to assess ijv stenosis, and found 12 had narrowing greater than 50% (relative to maximal csa), 19 between 50 and 80% and 9 greater than 80%. flow, however, was measured using doppler between intervertebral segments c4/c5 or c5/c6. they showed that there is a significant difference in total ijv flow between those with no stenosis and those with a stenosis greater than 80% (but not between those with no stenosis and those with 50 to 80% narrowing). specifically, they quote total ijv flow for the non stenotic group as 616 +/40 ml/min for standard error of the mean (p=0.02) and, for the greater than 80% group, they quote ijv flow as 381+/-75 ml/min for standard error of the mean (p=0.01). clearly, there is a significant difference for total ijv flow between the non-stenotic and high-grade stenotic groups, even though their method of stenosis assessment is different from ours. their conclusion then is very similar to ours although our stenosis cutoff was based on a 25 mm2 csa. macgowan et al.30 measured arterial and venous blood flow for 26 ms adolescent patients and 26 age-matched normal controls. they found there was a trend for reduced flow in the left internal jugular vein but that the difference was not significant. however, they did not classify patients as stenotic or non-stenotic. the measured average arterial flow was 754 ml/min (including the common carotid and vertebral arteries). they did not compare total jugular flow between groups. rodger et al.12 measured venous blood flow in 100 ms patients and 100 normal controls. they quote left and right jugular flow but do not quote arterial flow. they did not compare total jugular flow between groups, they did not normalize the flow and they did not sub-categorize patients into stenotic or non-stenotic groups. since ccsvi is about abnormal total jugular flow, both the previous two papers failed to quote the most critical piece of information. further, the variation in total ijv flow may well be much less than either jugular alone and hence may lead to a clear difference in their two populations. in fact, both found a trend to lower lijv flow in the ms population but they did not normalize their data to arterial flow. further sub-categorizing the data into stenotic and non-stenotic types has the potential to separate that sub-population of ms patients with abnormal flow more clearly. if the data were to be re-analyzed, both these studies may well validate the findings discussed in our meta-study in this paper, that st-ms patients have significantly reduced total ijv flow. another recent paper by traboulsee et al. compares mr with catheter venography.11 they use a percentage definition of stenosis for veins similar to that used in evaluating carotid arteries (which have geometrically consistent csa from the subclavian to the bifurcation). this is not appropriate for veins because they can flare out at the base near the subclavian vein and are quite variable in size throughout their course. several other groups have used the more realistic definition of stenosis as a vessel csa falling below a fixed threshold of either 25 mm2 22 or 30 mm2 8 at or below c3/c4 and 12.5 mm2 at or above c2/c3.22 traboulsee et al. make the claim that there is no difference in stenosis rates between hc and ms patients, with a stenosis rate of 74% in ms patients and 70% in hc.11 their study defined ijv stenosis as a narrowing of more than 50% of the widest vessel segment below the mandible. in a recent abstract, we showed that if our data were re-analyzed using this percentage approach, we would have found 83% of ms patients and 44% of hc were stenotic suggesting that the percentage definition of stenosis for veins is unrealistic.25 costello et al. did a large study of 120 ms patients and 60 hc with us and mr.10 they found no evidence of ccsvi for either group. they also found no differences in measured narrowings using ce mrav between the groups. however, they included the criteria greater than 50% stenosis rather than the absolute 25 mm2 or 30 mm2 suggested in recent years since, as discussed earlier, greater than 50% stenosis is not appropriate for veins. no mr flow measurements were done in this study. likewise, jurkiewicz et al. found no differences in stenosis or csa between 21 ms patients and 19 hc in children.23 no flow measurements were done in this study. to demonstrate this problem, we re-analyzed our own data from the four previous studies20-22,25 to show the number of cases from each group as a function of percentage stenosis. figure 3 shows a percentage of the ms and hc groups that are stenotic using a variable csa at the c5/c6 neck level. at a csa ≤25 mm2, none of the hc classify as stenotic for the rijv, while 4% of the hcs meet this criteria for the lijv. of the ms group, 24% of them classify as stenotic for the rijv, and 38% of them meet this criterion for the lijv. in general, more ms patients are classified as stenotic even as the csa cutoff value increases. the strongest separation between ms and hc occurs for narrowing less than 25 mm2. clearly the choice of an absolute cutoff makes more sense in studying stenoses in veins. kramer et al., compared catheter venography (cv) and ce mra in 99 subjects.44 no significant pressure gradients were seen (but they used greater than 3 mm hg as their criteria for significant changes). a subset of 39 patients received both ce-mra and cv. stenosis measurements between mr and cv were in good agreement. as far as expected pressure changes are concerned, a recent computational fluid dynamics paper showed that the presence of stenosis can lead to pressure increases of up to 2.5 mmhg which for veins represents a major increase in pressure across a stenosis.45 changes also occur in the superior sagittal sinus and straight sinus and, therefore, may affect the venous pressure changes in the basal ganglia and midbrain, areas where no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:5012] [page 45] increases in iron deposition are seen for ms patients. the real question is: what constitutes a major change in pressure for the venous system? the work by el-sankari and colleagues was more flow-orientated rather than anatomical.29 their group studied primary and secondary venous flow, arterial flow, and cerebrospinal fluid (csf) flow using mri flow quantification. they did not note any flow reductions in the ijv, nor did they find any differences in the oscillating properties of the venous flow curves. however, they did note reduced arterial perfusion in ms patients, as well as decreased csf dynamic oscillations in ms. in summary, apart from the work of feng, utriainen, sethi and haacke,20-22,25,35 none of these other papers has a complete set of anatomic and quantitative flow data at c2/c3 and c5/c6. many of the papers do not discuss total jugular flow or normalized jugular flow, or they use an incorrect assessment of the cross sectional area for stenosis as being 50% of maximum jugular area. in sethi et al., the sensitivity and specificity of the ability to use an anatomic assessment to predict abnormal flow were 0.78 and 0.76 at the c5/c6 neck level; at c2/c3 it was 0.84 and 0.68, respectively.25 what this means is that we can predict with at least 78% certainty that an ms patient that we classify as stenotic will have a normalized jugular flow lower than 62% at the c5/c6 neck level. we have established similar cut-offs for sensitivity and specificity with our group metaanalysis presented in the results section. as for the anatomical information seen with mri, there appears to be a variety of stenosis types for ms patients as shown in table 1. notably, the atresias, diffuse stenoses, and aplasia cases are only seen in the ms group. there are other considerations that relate to the vascular system. these include evidence of iron in the basal ganglia and midbrain,46 venocentric ms lesions,6 abnormal cerebrospinal flows,47,48 abnormal perfusion,3 and more recently evidence for significant reductions in cerebrovascular reserve in ms patients suggesting that there is a change in the brain’s ability for ms patents to respond to challenges that alter blood flow.49 several other relevant studies considered the effects of inspiration on flow measurements. kudo et al.50 studied the use of 2d pc mr venography and 2d pc flow images to measure flow changes in the ijv in 107 subjects with lacunar infarction. they found that during deep inspiration that 57 (36) subjects had decreased signal on the right (left) sigmoid sinus while 12 (33) had increases on the right (left). they found a decrease in flow velocity in 92 (70) subjects in the right (left) sigmoid sinus and an increase in the remaining subjects. mehta et al.51 studied 15 volunteers, they also showed that during deep inspiration there is a reduction in dural sinus flow. in the mr studies discussed above, breath-hold or valsalva maneuvers were not part of the protocol during imaging. using 3d contrast enhanced mrav and specially placed saturation bands, paksoy et al.52 demonstrated in three cases that flow reversal in the inferior petrosal sinus is due to a compression of the brachiocephalic vein preventing proper outflow in the lijv. impaired venous flow may not be limited to ms. in a recent study from our group by liu et al.24 looking at idiopathic parkinson’s disease (ipd), the appearance of veins using tof mrv, pc mri flow at the c2 neck level, and lesion loads in t2 flair were compared between 23 ipd patients and 23 age matched hc. the result differs from what was observed with the large group analysis of ms subjects in that the major flow abnormalities seemed to be a lack of flow in the left transverse sinus and left ijv. this abnormal venous outflow correlated with the t2 lesion loads. although the criteria differed from the analysis done on ms subjects, it does imply that venous vascular abnormalities may be found within sub-populations of other neurological and neurodegenerative diseases. jang et al.53 recently reviewed 2d tof mra data for 3475 patients from a general radiological database. in their assessment, they assessed the ijvs and the dural sinuses for venous reflux defined as tubular highintensity signal in the presence of in-slab saturated arteries. they found 1.6% of the sample showed venous reflux flow, and all instances were on the patients’ left side. generally, the reflux finding was more prevalent in females, and in older patients. it is notable that in the cohort with reflux, the following symptoms were presented: ischemia (39.3%), intracranial arterial stenosis (14.3%), headache (10.7%) and dizziness (8.9%). tof is very useful in qualitatively detecting smaller vessels that are hard to measure quantitatively with phase-contrast flow mri, however, in cases where the reflux may be too slow in which a velocity does not meet a certain threshold, no signal will of present in tof. some of the limitations in many of these studies include the drawbacks of using mrv methods.13,31,41 most notably, the low resolution prohibits it from viewing intraluminal abnormalities such as valves, septa, flaps, and annuli. the venous appearance can also depend on hydration status, head and neck coil positioning, transmural pressure, and respiratory phase. another limitation of the proposed mri protocol is its inability to directly visualize many intraluminal obstacles, such as membranous webs, septum, and malfunctioning valves, which have been observed as being prevalent in the ms population. while the resulting flow changes can be measured using 2d flow quantification, the implementation of 4d flow quantification will provide a more comprehensive assessment of pressure and flow changes directly at these points of obstruction. it is also pertinent to note that while imaging modalities have their unique strengths and weaknesses, a strong protocol may be derived from their combination or fusion, such as us and mri. lastly, the division of subjects into stenotic and non-stenotic subgroups may figure 3. the percentage of the multiple sclerosis (ms) and healthy control (hc) groups (data from sethi et al.25) which are stenotic when using a variable cross sectional area (csa) rather than a fixed csa to measure lower level stenosis. rijv, right internal jugular vein; lijv, left internal jugular vein. no n c om me rci al us e o nly article [page 46] [veins and lymphatics 2015; 4:5012] invoke criticism by those directly comparing ms and healthy controls. the rationale behind dividing the group, is that the flow distribution in the ms population is very large, but we recognized that the spread of healthy controls and non-stenotic ms is a tight group, therefore we reiterate that the abnormalities we are finding in both flow and anatomy are in a subset of the ms group, and not representative of the entire spectrum of the disease. conclusions despite the fact that there are many papers published on venous effects in ms patients in mri, the only consistent data appears to come from breaking the ms population into stenotic and non-stenotic groups and then performing specialized flow processing in each group. the basic findings are that far more ms patients show anatomical abnormalities for the jugular veins and that the total jugular flow in the stenotic ms patients is significantly less than that in the non-stenotic and healthy control group. we recommend that all mr-related investigations collect high resolution mr venographic anatomic and flow data for the dural sinuses and jugular veins and that not just individual jugular flow but total jugular venous flow and normalized jugular flow be evaluated at both the c2/c3 and c5/c6 levels. references 1. schelling f. damaging venous reflux into the skull or spine: relevance to multiple sclerosis. med hypotheses 1986;21:141-8. 2. haacke em, beggs cb, habib c. the role of venous abnormalities in neurological disease. rev recent clin trials 2012;7:100-16. 3. law m, saindane am, ge y, et al. microvascular abnormality in relapsingremitting multiple sclerosis: perfusion mr imaging findings in normal-appearing white matter. radiology 2004;231:645-52. 4. haacke em. chronic cerebral spinal venous insufficiency in multiple sclerosis. expert rev neurother 2011;11:5-9. 5. dake md, zivadinov r, haacke em. chronic cerebrospinal venous insufficiency in multiple sclerosis: a historical perspective. funct neurol 2011;26:181-95. 6. tan il, van schijndel ra, pouwels pj, et al. mr venography of multiple sclerosis. ajnr am j neuroradiol 2000;21:1039-42. 7. adams cw. perivascular iron deposition and other vascular damage in multiple sclerosis. j neurol neurosurg psychiatry 1988;51:260-5. 8. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:392-9. 9. aboulker j, bar d, marsault c, et al. [intraspinal venous hypertension caused by muliple abnormalities of the caval system: a major cause of spinal cord problems]. chirurgie 1977;103:1003-15. 10. costello f, modi j, lautner d, et al. validity of the diagnostic criteria for chronic cerebrospinal venous insufficiency and association with multiple sclerosis. cmaj 2014;186:e418-26. 11. traboulsee al, knox kb, machan l, et al. prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, casecontrol study. lancet 2013;383:138-45. 12. rodger iw, dilar d, dwyer j, et al. evidence against the involvement of chronic cerebrospinal venous abnormalities in multiple sclerosis. a case-control study. plos one. 2013;8:e72495. 13. zivadinov r, lopez-soriano a, weinstockguttman b, et al. use of mr venography for characterization of the extracranial venous system in patients with multiple sclerosis and healthy control subjects. radiology 2011;258:562-70. 14. wattjes mp, van oosten bw, de graaf wl, et al. no association of abnormal cranial venous drainage with multiple sclerosis: a magnetic resonance venography and flowquantification study. j neurol neurosurg psychiatry 2011;82:429-35. 15. doepp f, wurfel jt, pfueller cf, et al. venous drainage in multiple sclerosis: a combined mri and ultrasound study. neurology 2011;77:1745-51. 16. doepp f, paul f, valdueza jm, et al. no cerebrocervical venous congestion in patients with multiple sclerosis. ann neurol 2010;68:173-83. 17. monti l, menci e, piu p, et al. a sonographic quantitative cutoff value of cerebral venous outflow in neurologic diseases: a blinded study of 115 subjects. ajnr am j neuroradiol 2014;35:1381-6. 18. baracchini c, perini p, calabrese m, et al. no evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset. ann neurol 2011;69:90-9. 19. zamboni p, menegatti e, occhionorelli s, salvi f. the controversy on chronic cerebrospinal venous insufficiency. veins and lymphatics 2013;2:e14. 20. feng w, utriainen d, trifan g, et al. characteristics of flow through the internal jugular veins at cervical c2/c3 and c5/c6 levels for multiple sclerosis patients using mr phase contrast imaging. neurol res 2012;34:802-9. 21. feng w, utriainen d, trifan g, et al. quantitative flow measurements in the internal jugular veins of multiple sclerosis patients using magnetic resonance imaging. rev recent clin trials 2012;7:117-26. 22. haacke em, feng w, utriainen d, et al. patients with multiple sclerosis with structural venous abnormalities on mr imaging exhibit an abnormal flow distribution of the internal jugular veins. j vasc interv radiol 2012;23:60-8 e1-3. 23. jurkiewicz e, kotulska k, nowak k, et al. mr venography in children and adolescents with multiple sclerosis does not show increased prevalence of extracranial veins anomalies. eur j paediatr neurol 2014;18:218-22. 24. liu m, xu h, wang y, et al. patterns of chronic venous insufficiency in the dural sinuses and extracranial draining veins and their relationship with white matter hyperintensities for patients with parkinson’s disease. j vasc surg 2015;61: 1511-20.e1. 25. sethi sk, utriainen dt, daugherty am, et al. jugular venous flow abnormalities in multiple sclerosis patients compared to normal controls. j neuroimaging 2014 [epub ahead of print]. 26. sundström p, wåhlin a, ambarki k, et al. venous and cerebrospinal fluid flow in multiple sclerosis: a case�control study. ann neurol 2010;68:255-9. 27. dolic k, marr k, valnarov v, et al. sensitivity and specificity for screening of chronic cerebrospinal venous insufficiency using a multimodal non-invasive imaging approach in patients with multiple sclerosis. funct neurol 2011;26:205-14. 28. dolic k, marr k, valnarov v, et al. intraand extraluminal structural and functional venous anomalies in multiple sclerosis, as evidenced by 2 noninvasive imaging techniques. ajnr am j neuroradiol 2012;33: 16-23. 29. elsankari s, baledent o, van pesch v, et al. concomitant analysis of arterial, venous, and csf flows using phase-contrast mri: a quantitative comparison between ms patients and healthy controls. j cereb blood flow metab 2013;33:1314-21. 30. macgowan ck, chan ky, laughlin s, et al. cerebral arterial and venous blood flow in adolescent multiple sclerosis patients and age-matched controls using phase contrast mri. j magn reson imaging 2014;40:341-7. 31. zivadinov r, galeotti r, hojnacki d, et al. value of mr venography for detection of internal jugular vein anomalies in multiple sclerosis: a pilot longitudinal study. ajnr am j neuroradiol 2011;32:938-46. 32. stankovic z, allen bd, garcia j, et al. 4d flow imaging with mri. cardiovasc diagn ther 2014;4:173-92. no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:5012] [page 47] 33. tariq u, hsiao a, alley m,et al. venous and arterial flow quantification are equally accurate and precise with parallel imaging compressed sensing 4d phase contrast mri. j magn reson imaging 2013;37:1419-26. 34. anderson jr, diaz o, klucznik r, et al. validation of computational fluid dynamics methods with anatomically exact, 3d printed mri phantoms and 4d pcmri. conf proc ieee eng med biol soc 2014;2014:6699-701. 35. utriainen d, feng w, elias s, et al. using magnetic resonance imaging as a means to study chronic cerebral spinal venous insufficiency in multiple sclerosis patients. tech vasc interv radiol 2012;15: 101-12. 36. utriainen d, trifan g, sethi s, et al. magnetic resonance imaging signatures of vascular pathology in multiple sclerosis. neurol res 2012;34:780-92. 37. zivadinov r, bastianello s, dake md, et al. recommendations for multimodal noninvasive and invasive screening for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency: a position statement of the international society for neurovascular disease. j vasc interv radiol 2014;25:178594 e17. 38. rahman mt, sethi sk, utriainen dt, et al. a comparative study of magnetic resonance venography techniques for the evaluation of the internal jugular veins in multiple sclerosis patients. magn reson imaging 2013;31:1668-76. 39. jiang j, kokeny p, ying w, et al. quantifying errors in flow measurement using phase contrast magnetic resonance imaging: comparison of several boundary detection methods. magn reson imaging 2015;33:185-93. 40. doepp f, schreiber sj, von munster t, et al. how does the blood leave the brain? a systematic ultrasound analysis of cerebral venous drainage patterns. neuroradiology 2004;46:565-70. 41. hojnacki d, zamboni p, lopez-soriano a, et al. use of neck magnetic resonance venography, doppler sonography and selective venography for diagnosis of chronic cerebrospinal venous insufficiency: a pilot study in multiple sclerosis patients and healthy controls. int angiol 2010;29:127-39. 42. zaharchuk g, fischbein nj, rosenberg j, et al. comparison of mr and contrast venography of the cervical venous system in multiple sclerosis. ajnr am j neuroradiol 2011;32:1482-9. 43. mctaggart ra, fischbein nj, elkins cj, et al. extracranial venous drainage patterns in patients with multiple sclerosis and healthy controls. ajnr am j neuroradiol 2012;33:1615-20. 44. kramer la, cohen am, hasan km, et al. contrast enhanced mr venography with gadofosveset trisodium: evaluation of the intracranial and extracranial venous system. j magn reson imaging 2014;40:63040. 45. caiazzo a, montecinos g, muller lo, et al. computational haemodynamics in stenotic internal jugular veins. j math biol 2015;70:745-72. 46. habib ca, liu m, bawany n, et al. assessing abnormal iron content in the deep gray matter of patients with multiple sclerosis versus healthy controls. ajnr am j neuroradiol 2012;33:252-8. 47. beggs cb, magnano c, shepherd sj, et al. aqueductal cerebrospinal fluid pulsatility in healthy individuals is affected by impaired cerebral venous outflow. j magn reson imaging 2014;40:1215-22. 48. lagana mm, chaudhary a, balaguru nathan d, et al. cerebrospinal fluid flow dynamics in multiple sclerosis patients through phase contrast magnetic resonance imaging. curr neurovasc res 2014;11:349-58. 49. marshall o, lu h, brisset jc, et al. impaired cerebrovascular reactivity in multiple sclerosis. jama neurol 2014; 71:1275-81. 50. kudo k, terae s, ishii a, et al. physiologic change in flow velocity and direction of dural venous sinuses with respiration: mr venography and flow analysis. ajnr am j neuroradiol 2004;25:551-7. 51. mehta nr, jones l, kraut ma, melhem er. physiologic variations in dural venous sinus flow on phase-contrast mr imaging. ajr am j roentgenol 2000;175:221-5. 52. paksoy y, genc bo, genc e. retrograde flow in the left inferior petrosal sinus and blood steal of the cavernous sinus associated with central vein stenosis: mr angiographic findings. ajnr am j neuroradiol 2003;24:1364-8. 53. jang j, kim bs, kim by, et al. reflux venous flow in dural sinus and internal jugular vein on 3d time-of-flight mr angiography. neuroradiology 2013;55: 1205-11. no n c om me rci al us e o nly hrev_master veins and lymphatics 2013; volume 2:e6 [veins and lymphatics 2013; 2:e6] [page 17] elasticity, hysteresis and stiffness: the magic triangle h.a. martino neumann department of dermatology, erasmus mc university medical center, rotterdam, the netherlands abstract the use of external compression on the human leg is still a cornerstone in the treatment of venous diseases. the most important question to answer is: how will compression perform on the human leg? introduction first of all the applied compression generated by a device as a medical elastic compression stocking (mecs), bandage or whatever is used, exerts its pressure on the surface of the leg, e.g. the skin. normally this is expressed as interface pressure and the shape of the leg pressure differences are depending on laplace low. second step is the transmission of this interface pressure into the tissue as the subcutaneous fat, muscles, and veins. this process depends on pascal law. the third item is the pressure changes during walking depending on the circumference chances of the leg (laplace law) and, fourth, the durability of the pressure in time, which depends on the quality of the device. brief report for a long time research was focused on interface pressure, usually under static conditions and pressure course in time.1 the quality of compression capacity of a given device is depending on the characteristics of the used materials. all used materials for medical compression therapy have three major characteristics: i) elasticity, which is the capacity to return to the original shape and size after the material has been stretched. the pressure/elasticity relation under static condition on the leg is influenced by laplace law; ii) stiffness or elasticity coefficient; this term is defined as the increase in pressure after a certain given elongation. for mecs the centre européenne de normali sation uses the increase of the normal tension at the b1 level with 1 cm expressed in hpa. stiffness is depending on elasticity in static condition; iii) hysteresis, which reflects the inborn resistance of material as result of internal friction hysteresis, can be visualized in a force/elongation curve (figure 1a). by increasing the speed to perform such a fair elongation curve the angle towards the x-axis will move. so hysteresis is influenced by the speed of movements (figure 1b).2 these three characteristics works all together in compression therapy (figure 2). as normally compression is only expressed as interface pressure we are not informed about the contribution of stiffness, hysteresis and changes during walking. in fact we only know the resting pressure which is far away from the reality of a walking patient with a compression device as a mecs. to overcome this problem we defined the dynamic stiffness index (dsi).3 analyzing the differences between static and dynamic compression it turns out that hysteresis is the most important factor. our triangle can be changed from static (figure 2) into dynamic (figure 3) where hysteresis plays the main role. as pressure diminishes in time static compression will become ineffective during the day. however dsi remains in the same time (figure 4).4 for mecs, dsi is independent from compression pressure (class) and manufacturing differences as roundand flat knitted.5 the clinical implication of dsi is that low correspondence: h.a. martino neumann, dermatologie en venereologie, erasmus mc university medical center, rotterdam, the netherlands. e-mail: h.neumann@erasmusmc.nl key words: compression, elasticity, hysteresis, stiffness. conference presentation: part of this paper was presented at the international compression club (icc) meeting on stiffness of compression devices, 2012 may 25, vienna, austria (http:// www.icc-compressionclub.com/). received for publication: 9 october 2012. revision received: 15 november 2012. accepted for publication: 29 november 2012. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright h.a.m. neumann, 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e6 doi:10.4081/vl.2013.e6 figure 1. a) hysteresis curve of an elastic fabric: x-axis represents stretch, y-axis the applied force; b) force elongation curve of elastic knitwear. the elongation increments are progressively made larger. the steepness of the initially small cycle is diminished with the increased amplitude (modified from stolk and salz, 19882 with permission). figure 2. the magic triangle, static. no n c om me rci al us e o nly conference presentation [page 18] [veins and lymphatics 2013; 2:e6] compression and high dsi can be very efficient for ambulatory patients and have the same effect as high compression with low dsi. to combine compression and dsi the physician can prescribe the optimal device, e.g. mecs for the patient. as logical consequence the higher changes of interface pressure during walking will be transferred to the tissue resulting in a high massage effect and by this the effects of laplace and pascal law comes together. conclusions in order to optimize venous function with compression therapy, three key-points should be considered: i) hysteresis, mainly influenced by the type of knitwear determines the efficacy of compression force elongation relation; ii) the quality of compression (laplace law) defined by dsi; iii) the final effect of compression (pascal law) defined by the composition of the subcutaneous tissue. for daily practice: dsi is the most important characteristic of compression. references 1. veraart jcjm, daamen e, neumann ham. short stretch versus elastic bandages: effect of time and walking. phlebology 1997;26:19-24. 2. stolk r, salz p. a quick pressure-determining device for medical stockings based on the determination of the counter-pressure of airfilled leg-segments. swiss med 1988;10:91-6. 3. stolk r, van der wegen-franken cpm, neumann ham. a method for measuring the dynamic behaviour of medical compression hosiery during walking. dermatol surg 2004;30:729-73. 4. van der wegen cpm, tank b, nijsten t, neumann ham. changes in the pressure and the dynamic stiffness index of medical elastic compression stockings after having been worn for eight hours: a pilot study. phlebology 2009;24:31-7. 5. van der wegen-franken cpm, tank b, neumann ham. correlation between the static and dynamic stiffness indices of medical elastic compression stockings. dermatol surg 2008;34:1477-85. figure 3. dynamic relation between pressure, stiffness and hysteresis. figure 4. in spite of decreasing pressure of a stocking, stiffness is maintained (modified from van der wegen et al., 20094 with permission). no n c om me rci al us e o nly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: evaluation of pain in varicose vein surgery under tumescent local anesthesia using sodium bicarbonate as excipient without any intravenous sedation by creton d, re’a b, pittaluga p, chastanet s, allaert fa. phlebology 2011:1-6. stefano ricci abstract the aim of this survey was to study the feasibility of varicose vein surgery under tumescent local anesthesia (tla). a total of 215 patients at two private surgical centers in france were included. all the operations were performed under tla without any intravenous sedation. the tumescent liquid was obtained by diluting lidocaine 1% (20 ml containing 200 mg lidocaine). a solution of 14 ml of 1% lidocaine (with 1:100,000 epinephrine) was diluted in a bottle with 500 ml of 1.4% sodium bicarbonate (lidocaine dilution at approx. 0.028%). injections were performed with 25 gauge needles, with syringes or an electric pump. patients had to arrive in the morning after eating breakfast as usual. surgery was performed in an operating theater without any particular monitoring. the patients’ faces were not covered with sterile operative fields to allow visual and oral communication. operations included either phlebectomies or stripping or thermoablation of truncular segments (table 1). double compression with a class ii elastic stocking was placed for 48 h and then replaced with one single stocking for one week. every patient filled in a questionnaire to evaluate the surgery-related pain on an analog scale ranging from 0 to 10, along with pain duration (from some seconds to some minutes or much longer). patients could return home the day after surgery and they then filled in the same questionnaire again. the patients returned their questionnaire two months later at their postoperative check-up. the majority of the patients were classified c2 while 30 were classified c3, 26 were c4a, 4 were c4b, one was c5 and one was c6. mean vcss score was 1.5+1.4 (1.0-13.0). complete phlebectomies were performed in all patients. mean number of phlebectomies was 24.0+13.0 (3.0-63.0). mean volume of tumescence was 268.1+127.1 ml. mean dilution of lidocaine epinephrine in relation to patient mean weight (65.7+12.0 kg; range 42.0-106.0) was 75.1+35.6 mg of lidocaine and 0.037+0.0178 mg of epinephrine injected. this represents a mean 1.17+0.54 mg of lidocaine per kg bodyweight and 0.58+0.27 mg epinephrine/ kg bodyweight. the different levels of pain sustained during surgery (figure 2) show that mean pain level was 2.7+2.1 (range 0.0-9.0). in 69.3% of cases, the pain was considered light (0–3), in 25.5%, moderate (4–6) and in 5.2% severe (7–10). in 91.9% of the cases, surgery was considered as not very or not at all painful. in 8.1% of the cases, surgery was considered to be rather painful; for 81.2% of these patients, pain lasted for only a few seconds and for 17.4% for some minutes. no patients considered their surgery to be extremely painful. in cases in which more than 30 incisions were performed, patients felt significantly more pain (3.4+2.1) than when 16-30 incisions (2.2+1.9) or less than 16 incisions (2.8+2.2) were performed. when asked whether they would undergo this type of anesthesia again, 97.7% of the patients said they would. mean surgery time between the first tla injection and the last phlebectomy was 32+14 min (8–77 min). in 82.8% of the cases, the patients were dismissed less than 2 h after surgery. mean duration of the postoperative period was one hour and 45 min (range 30 min–7 h). mean length of hospital stay was 4 h and 10 min (2–9 h). this operation with parenteral sedation carried out by an anesthesiologist would have cost 52,839 euros while surgery with tumescent local anesthesia cost 30,788 euros; a saving of 22,051euros. the use of pure sodium bicarbonate 1.4% as tumescent solution, instead of saline solution or ringer’s solution, facilitates surgery by eliminating the onset time dilution. furthermore, in this study, lidocaine dilution was 0.028% and epinephrine dilution was 0.14:1,000,000 while the dilution currently recommended by many authors is respectively 0.05-0.1% and 1:1,000,000. tla without any sedation makes it possible to perform varicose vein surgery in external ambulatory surgical units outside conventional hospital centers, greatly reducing costs. table 1. classification of the operations and different parts of the operations (one operation could incorporate several parts). figure 2. distribution of the pain felt by the patients during surgery evaluated on an analogue scale ranging from 0 = no pain to 10 = extremely painful. comment by stefano ricci this type of local anesthesia increases the possibilities of carrying out surgical interventions in an outpatient setting. this is of particular importance in times in which health services face serious economic difficulties. the reduction in lydocaine and epinephrine dosage when diluted in isotonic sodium bicarbonate is particularly interesting. furthermore, when performing surgery under local anesthesia, it is well known that most of the discomfort for the patient is due to the painful infiltration procedure, presumably due to lidocaine/epinephrine acidity. dilution with pure sodium bicarbonate instead of saline greatly reduces the infiltration pain because of the inherent production of non-ionized lidocaine that passes more easily through the cellular membranes. however, the authors should not forget that outpatient surgery of varices under local infiltration anesthesia (without any sedation or pre-medication) was made popular worldwide during the 1960s by robert muller,1,2 either with ambulatory phlebectomy, or, through the work of his colleague dr. crossetti, with ambulatory saphenectomy. muller’s pupils subseuently published several papers on outpatient varicose vein surgery.3 even a european society of phlebectomy was created. the novel approach outlined above concerning the infiltration solution is just one more step along a road which has already been well defined. unfortunately, this solution is often not taken into consideration, as demonstrated by the absence of any reference to the papers of muller et al. reply by the author (creton) i agree with your two comments. this article aims to demonstrate that it is possible to perform stripping under local anesthesia without intravenous sedation. despite the difficulty i had in finding articles in the literature about this topic, i saw this method being used in an outpatient setting by paolo santoro in 1986! it would have been possible to observe this same procedure even earlier in italy and switzerland. the aim was to show that using 1.4% sodium bicarbonate as excipient at the tumescence definitely makes things easier. we wanted to assess this feasibility in 215 consecutive cases. we did not study the level of pain level of the injections (that are completely painless) since, before using this type of tumescence, our injections for local anesthesia were already painless (lidocaine mixed at 50% with 1.4% sodium bicarbonate). in these solutions, a low concentration of sodium bicarbonate was used to neutralize lidocaîne acidity and make injections painless. it is a highly significant aspect of the procedure that surgeons who do not use lidocaïne alkalinization know nothing about. references 1. muller r. traitement des varices par la phlébectomie ambulatoire. phlébologie 1966;19:277-9.[pubmed] 2. muller r, joubert b. la phlébectomie ambulatoire. paris: les editions médicales innothéra; 1992. 3. ricci s, georgiev m, goldman m. ambulatory phlebectomy a practical guide for treating varicose veins. st. louis: mosby-year book inc.; 1995. [top] hrev_master veins and lymphatics 2015; volume 4:5600 [veins and lymphatics 2015; 4:5600] [page 67] post-thrombotic syndrome in the middle age paolo zamboni vascular diseases center, university of ferrara, italy post-thrombotic syndrome (pts) is a disabling disease, which often leads to chronic venous leg ulceration. it can be treated and/or prevented after deep vein thrombosis (dvt) by the use of elastic stockings, because surgery is a highly selected option. symptoms and complications of pts appear several years after dvt. while varicose veins and ulcerations were extensively described in antique art and literature, the first medical case truly compatible with a pts story was depicted in the manuscript of guillaume de saint-pathus, in the middle age. the manuscript titled la vie et les miracles de saint louis1 tells us that in 1271 raoul, a 20year-old young man, suffered from a monolateral acute edema in the right calf. some days later, the swelling extended up to the thigh (figure 1a). he was a norman shoemaker and underwent to a medical consult. in 1271 raoul’s phlebologist was henri de perche. this confirms us that french physicians were absolute beginners in phlebology. henri suggested him to lie supine, as well as to wait and see. what happened some months later, with big surprise of raoul and his relatives, was the disappearance of the swelling (figure 1b). for some years the leg was slim and he resumed to work. however, some years later raoul again worsened in the right lower limb, and suddenly developed an ulceration at the medial aspect of the right ankle (figure 1c). at that time st. eloi’s shrine was the hub center for venous leg ulceration. raoul underwent to additional unspecified treatment attempts, but everything was unsuccessful. the last hope was to visit the tomb of king saint louis, where raoul spent days after days in praying the saint. finally, he collected the dust found below the stone covering the tomb, and applied it directly to the ulcer. this was not the first description of an advanced dressing for venous leg ulcer. in the bassi library, glauco bassi’s typewritten notes report other previous descriptions, starting from the bible.2 however, the manuscript reports that the wound miraculously healed. we do not know about the big problem of ulcer recurrences in raoul’s rest of the life, as in modern pts happens. however, it has been reported that raoul was still alive 11 years after the saint louis miracle. i came curious to deepen the story of raoul, after reading a monograph on the history of dvt. the story of raoul was also, according to galanaud et al., the first medical report of dvt.3 in ancient greece, neither hippocrates nor oribasius, reported clinical cases resembling dvt; this is also true looking to the art of ancient egypt, persia, and south america. even roman physicians such as galen or caelius, did not report something suggesting a diagnosis of dvt.3 we can conclude that, to the best of our knowledge, raoul’s story is the first medical report on both dvt and pts. references 1. de saint pathus g. la vie et les miracles de saint louis. paris: bibliothèque national de france; 1330-1340. 2. bresadola m. the bassi historical international library of phlebology at the ferrara university hospital. veins and lymphatics 2014;3:4150. 3. galanaud jp, laroche jp, righini m. the history and historical treatments of deep vein thrombosis. thromb haemost 2013;11:402-11. correspondence: paolo zamboni, vascular diseases center, university of ferrara, via aldo moro 8, 44124 cona, ferrara, italy. e-mail: paolozamboni@icloud.com received for publication: 22 october 2015. revision received: 11 december 2015. accepted for publication: 1 february 2016. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright p. zamboni, 2015 licensee pagepress, italy veins and lymphatics 2015; 4:5600 doi:10.4081/vl.2015.5600 figure 1. a) acute lower limb edema in raoul’s lower right extremity; b) edema resolution; c) ulcer development several years later. modified from de saint pathus, 13301340.1 a b c no n c om me rci al us e o nly stefano ricci comment to: strip-tract revascularization as a source of recurrent venous reflux following high saphenous tie and stripping: results at 5-8 years after surgery by ostler ae, holdstock jm, harrison cc, price ba, whiteley ms. phlebology 2014 may 20 [epub ahead of print] stefano ricci abstract this study reports the rate of strip-tract revascularization and reflux (str&r = refluxing veins within the saphenous fascia, running in the line of where the gsv had run before being stripped) 5-8 years after high ligation and stripping (hsl&s). it was previously shown by the same group that 1 year after operation 23% of patients had revascularization of the strip-tract with reflux. dus guided saphenofemoral ligation (using non-absorbable prolene sutures) with closure of the cribriform fascia and inversion stripping was performed in 64 patients (70 legs) between 2003 and 2005. in 2008, 5-8 years after surgery, 35 patients attended the invited dus appointment (39/70 legs of patients) (response rate 55%). five limbs of patients showed full str&r (12.8%), 23 limbs had partial strip-tract revascularization; 7 legs showed no evidence of revascularization of the strip-tract or of neovascularization of the sfj. it has long been held that hsl&s is the gold standard treatment for varicose veins however a high rate of str with reflux is associated with this procedure; 82% of patients showed either full or partial revascularization at between 5 and 8 years. it is interesting to see that some patients have shown an aggressive revascularization whilst other show little or no such reaction to the open surgery. this might be related to the volume of haematoma caused at the time of stripping. there is a progression of str&r over and above that found at 1 year (23 %), suggesting a progressive deterioration (82%); interestingly, it has been observed that following endovenous laser ablation, only 1% of legs of patients showed neovascularization compared with 18% of legs of patients that showed neovascularisation following open surgery. comment by stefano ricci gsv stripping according to babcock (1907), one of the most applied operations of the last 100 years of surgery history is still under debate. strip-tract revascularization and reflux, a frequent finding in our follow-up evaluations, is very well studied and analysed in this interesting paper that leaves, however some questions unsolved: i) no data are given about the origin of the reflux in the strip-tract; when reflux starts high (as when complete), does it comes from a junction recurrence, lymphatic space, pelvic reflux or perforators? when reflux is partial, does it come from a perforator, anterior accessory vein or tributaries? ii) how many patients had duplex recurrence and how many of these clinical recurrence, needing re-operation? in fact, not all the refluxing strip-tracts need to be treated. iii) where did the strip-tract refluxes empty: perforators, varices? iv) what was the original diameter of the gsvs and did it correlate with recurrence? v) what was the saphenous terminal valve and common femoral valve situation? (even if not studied at the beginning these valves could be partly studied at follow-up). vi) is it possible that a partial sub-clinical recanalization of the gsv could be considered as a positive result, allowing the basic drainage of the thigh superficial veins and consequently avoiding subcutaneous varices reappearing (like in some sclerotherapy results)? vii) what treatment is suggested? [top] hrev_master veins and lymphatics 2013; volume 1:e9 [page 26] [veins and lymphatics 2013; 2:e9] relevance of stiffness of compression material on venous hemodynamics and edema giovanni mosti angiology department, clinica md barbantini, lucca, italy abstract elastic and inelastic stockings or bandages may provide the same degree of compression pressure in the resting supine position but inelastic material provides much greater compression pressure in the standing or working position. for elastic compression to have the same effect in the standing or exercising state would require a degree of compression in the resting position that would be intolerable. studies have shown that this applies to reduction of reflux and improved venous pumping although both appear to have a similar effect for reducing edema. introduction stiffness and its importance on venous disease venous reflux, obstruction and reduced venous pumping function from the lower leg during exercise are the main pathophysiological parameters of venous disease.1 compression therapy can improve hemodynamic impairment. in particular compression has been proven effective in reducing venous volume, reflux, venous pumping function, edema and, consequently, ambulatory venous hyperten sion.2-8 compression may be applied to the leg by different materials: elastic stockings, elastic and inelastic bandages, and/or velcro-banddevices. the main differences between these materials are the exerted pressure and the elastic properties which can influence their hemodynamic effects. the resting pressure produced by a stocking rarely exceeds 40 mmhg9 while the resting pressure exerted by a bandage depends mainly on the strength of application. when applied by means of inelastic bandages, which must be applied under full stretch, or of velcro band devices which are completely inelastic and inextensible, the exerted pressure is usually higher than 60 mmhg. nevertheless, the pressure increase when moving from the resting supine to the standing position represents the main difference between elastic and inelastic material, even more important than resting pressure. the pressure increase by standing characterizes the stiffness of the material9 and can be measured in vivo10 just by subtracting supine from standing pressure. this difference has been termed static stiffness index (ssi) and the cut off in distinguishing elastic from inelastic material is 10.11,12 elastic material gives way to the muscle volume increase during muscle contraction achieving a pressure increase in the standing position only slightly higher than supine resting pressure and always lower than 10 (figure 1). inelastic material doesn’t give way to the muscle expansion and the exerted pressure will rise significantly; ssi will always be higher than 10. other parameters of stiffness are the maximal working pressure, the pressure peaks and pressure amplitudes during walking (the difference between systolic and diastolic pressure).13 when inelastic material is correctly applied with full stretch exerting a pressure of 50-60 mmhg in supine position, the significant pressure increase to 70-90 mmhg with standing will produce a significant vein narrowing or occlusion (figure 2). also elastic material could exert this very strong pressure and narrow or occlude the veins but, due to its elastic characteristics, it must be applied with similar strong pressure even at rest which will make the bandage painful and intolerable (figure 3).14 narrowing/ occlusion of veins by external compression devices is a prerequisite for their hemodynamic efficacy and can be observed with phlebography, duplex ultrasound or magnetic resonance imaging. the amount of narrowing depends on the body position and the range of compression pressure. in the supine position a pressure of about 20 mmhg is able to narrow the veins while in the upright position, a pressure range of 70-80 mmhg will be necessary to counteract the standing intravenous pressure and to narrow up to near occlusion of the vein lumen.15,16 similar vein narrowing may occur while walking with inelastic materials that produces pressure peaks which overcome the intravenous pressure with every step and leads to an intermittent narrowing of the veins15 thus restoring a kind of artificial valve mechanism.17 elastic material or elastic stockings cannot achieve similar results because in order for the compression to be tolerable the exerted pressure range can never exceed 50 mmhg. this degree of compression can slightly influence the venous diameter but certainly cannot produce significant vein narrowing.18 relevance of stiffness on reflux and venous pumping function in venous disease effect on reflux reflux has been shown to be abolished both in patients with post-thrombotic syndrome19 and severe superficial venous incompetence20 by using different methods that produce similar results. in the first study,19 the authors used air-plethysmography and were able to show a progressive reduction up to the abolishment of venous reflux by increasing the pressure of compression devices. at every pressure range inelastic material was able to reduce reflux more than elastic material. only with very strong pressure of 60 mmhg does elastic and inelastic material provide similar result. in patients with severe reflux of the great saphenous vein20 similar results could be demonstrated using duplex ultrasound: increasing leg compression led to a progressive reduction of reflux, with inelastic always more effective than elastic material. reflux reduction up to abolition is due to external pressure which progressively reduces the venous reservoir of the lower leg. the superiority of inelastic compared with elastic material can be explained by higher standing pressure exerted by inelastic material starting from the same supine pressure of 20 or 40 mmhg. this produces a more pronounced narrowing of leg veins, a greater reduction of their reservoir capacity leading to a greater decrease of venous reflux. a very high pressure will occlude the leg veins irrespective of the elastic properties of materials used; therefore venous reflux is blocked by both elastic and inelastic devices. nevertheless it is necessary to take into account that elastic material applied with this strong pressure can be used only for the short period of time of a laboratory test but not in clinical practice because such pressure is barely tolerated by patients.14,20 correspondence: giovanni mosti, angiology department, clinica md barbantini, lucca, italy. e-mail: jmosti@tin.it key words: elastic compression, inelastic compression, venous insufficiency, venous reflux, ejection fraction, edema. conference presentation: part of this paper was presented at the international compression club (icc) meeting on stiffness of compression devices, 2012 may 25, vienna, austria (http://www.icc-compressionclub.com/). received for publication: 27 october 2012. revision received: 7 january 2013. accepted for publication: 20 february 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright g. mosti, 2013 licensee pagepress, italy veins and lymphatics 2013; 2:9 doi:10.4081/vl.2013.e9 no nco mm er cia l u se on ly conference presentation [veins and lymphatics 2013; 2:e9] [page 27] in conclusion reflux abolition depends only on the standing pressure necessary to narrow the veins but it is only theoretically independent from the elastic properties of the compression material: elastic material can produce a pressure strong enough to narrow the vein diameter but this pressure will be painful and impossible to use in the clinical practice. effect on venous pumping function effects of compression on venous pumping function maybe demonstrated by different plethysmographic techniques, such as foot volumetry, air plethysmography or strain gauge plethysmography.8,19,21-28 with this method we could demonstrate that the ejection fraction (ef) from the lower leg is reduced in patients with chronic venous insufficiency and that it can be improved by external compression.28 inelastic compression material is able to increase ef from the lower leg and restore normal venous pumping function. the increased ef achieved by inelastic is significantly higher than by elastic material applied with the same pressure. elastic material never restores the normal function even if applied with high stretch producing a very strong pressure higher than 60 mmhg. therefore not only pressure but also elastic properties of the compression devices play an important role in increasing venous pumping function. in particular the difference between systolic and diastolic pressure during walking (the so called massaging effect) seems to play a deciding role squeezing blood from the leg. the significant correlation between ejection fraction and sub-bandage pressure during standing and walking and between ejection fraction, static stiffness index and walking pressure amplitudes confirm the hemodynamic superiority of inelastic material.29 furthermore inelastic material has been shown to be effective even when applied with a low pressure of 20-30 mmhg, (in a range where elastic stocking are unable to increase the ejection fraction) and demonstrated a positive correlation with an increasing application pressure.30 finally inelastic materials are claimed to lose effectiveness as they lose pressure overtime. it was proved that this material is able to maintain its effectiveness over time (one week) even despite significant pressure loss.31 edema edema develops because of a complex interaction that involves the permeability of the capillary wall and the hydrostatic and oncotic pressure gradients that exist between the blood vessels and the tissues.32 as almost all interstitial fluid is removed by the lymphatic circulation,33 edema will form when net capillary filtration exceeds lymphatic drainage capacity. compression counteracts edema formation by increasing the tissue pressure34 and lymphatic drainage in the initial stage of lymphatic damage.35 edema is always reduced by compression and the beneficial effect of compression on edema is so clear that only relatively few studies were performed to investigate this effect. edema is effectively treated by inelastic material applied with very strong pressure and by elastic stockings of moderate pressure (in the range of 23-32 mmhg).36 the inelastic bandage seems to be slightly more effective without statistical significance. if elastic and inelastic materials are equally effective in treating edema we could conclude that, so far, stiffness does not seem to play a role in treating leg edema. figure 1. interface pressure of an elastic compression device applied with 50% stretch and 50% overlapping of each layer. the exerted pressure always (during dorsiflexion in the supine position, standing, walking in place) remains well below the intravenous pressure (red line) which would be necessary to compress or occlude the veins. figure 2. interface pressure of an inelastic compression device applied with full stretch and 50% overlapping of each layer. the exerted pressure always (during dorsiflexion in the supine position, standing, walking in place) overcomes the intravenous pressure (red line) narrowing/occluding the veins thus restoring a kind of valve mechanism. no nco mm er cia l u se on ly conference presentation [page 28] [veins and lymphatics 2013; 2:e9] conclusions there is clear evidence that compression exerted by inelastic materials with high stiffness are able to achieve a very strong pressure starting by low and comfortable pressure at rest. this strong pressure can narrow and even occlude the venous system. this leads to a reduction or even abolition of venous reflux and an improvement or normalization of the venous pumping function. when the supine resting position is resumed the compression pressure is lower and comfortable for the patient, but still effective when ambulation is resumed. elastic materials with low stiffness are unable to get strong pressure during standing and ambulation and are much less effective than inelastic with a statistically significant difference. stiffness plays a deciding role in the hemodynamic effects of compression. the effect of stiffness in reducing leg edema doesn’t seem very relevant so far. references 1. nicolaides a, christopoulos d. quantification of venous reflux and outflow obstruction with air-plethysmography. in: bernstein ef, ed. vascular diagnosis. st louis, mo: mosby; 1993. pp 915-921. 2. partsch h. do we still need compression bandages? haemodynamic effects of compression stockings and bandages. phlebology 2006;21:132-8. 3. partsch b, mayer w, partsch h. improvement of ambulatory venous hypertension by narrowing of the femoral vein in congenital absence of venous valves. phlebology 1992;7:101-4. 4. ibegbuna v, delis kt, nicolaides an, aina o. effect of elastic compression stockings on venous hemodynamics during walking. j vasc surg 2003;37:420-5. 5. oduncu h, clark m. williams rj. effect of compression on blood flow in lower limb wounds. int wound j 2004;1:107-13. 6. partsch h, winiger j, lun b. compression stockings reduce occupational leg swelling. dermatol surg 2004;30:737-43. 7. partsch h. compression therapy in venous leg ulcers. how does it work? j phlebol 2002;2:129-36. 8. van geest aj, veraart jc, nelemans p, neumann ha. the effect of medical elastic compression stockings with different slope values on oedema. measurements underneath three different types of stockings. dermatol surg 2000;26:244-7. 9. european committee for standardization (cen). non-active medical devices. working group 2 env 12718: european pre-standard 'medical compression hosiery.' cen tc 205. brussels: cen; 2001. 10. partsch h, clark m, bassez s, et al. measurement of lower leg compression in vivo: recommendations for the performance of measurements of interface pressure and stiffness. dermatol surg 2006;32:224-33. 11. partsch h. the static stiffness index: a simple method to assess the elastic property of compression material in vivo. dermatol surg 2005;31:625-30. 12. partsch h. the use of pressure change on standing as a surrogate measure of the stiffness of a compression bandage. eur j vasc endovasc surg 2005;30:415-21. 13. van der wegen-franken k, tank b, neumann m. correlation between the static and dynamic stiffness indices of medical elastic compression stockings. dermatol surg 2008;34:1477-85. 14. mosti g, mattaliano v, partsch h. inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous reflux. phlebology 2008;23:287-94. 15. partsch b, partsch h. calf compression pressure required to achieve venous closure from supine to standing positions. j vasc surg 2005;42:734-8. 16. partsch h, mosti g, mosti f. narrowing of leg veins under compression demonstrated by magnetic resonance imaging (mri). int angiol 2010;29:408-10. 17. partsch b, mayer w, partsch h. improvement of ambulatory venous hypertension by narrowing of the femoral vein in congenital absence of venous valves. phlebology 1992;7:101-4. 18. partsch h. improving the venous pumping function in chronic venous insufficiency by compression as dependent on pressure and material. vasa 1984;13:58-64. 19. partsch h, menzinger g, mostbeck a. inelastic leg compression is more effective to reduce deep venous refluxes than elastic bandages. dermatol surg 1999;25:695700. 20. mosti g, partsch h. duplex scanning to evaluate the effect of compression on venous reflux. int angiol 2010;29:416-20. 21. gjöres je, thulesius o. compression treatment in venous insufficiency evaluated with foot volumetry. vasa 1977;6:364-8. 22. norgren l. elastic compression stockings: an evaluation with foot volumetry, straingauge plethysmography and photoplethysmography. acta chir scand 1988;154:5057. 23. partsch h. do we need firm compression stockings exerting high pressure? vasa 1984;13:52-7. 24. christopoulos dg, nicolaides an, szendro g, et al. air-plethysmography and the effect of elastic compression on venous hemodynamics of the leg. j vasc surg 1987; 5:148-59. 25. spence rk, cahall e. inelastic versus elastic leg compression in chronic venous insufficiency: a comparison of limb size and venous hemodynamics. j vasc surg 1996;z24:783-7. 26. ibegbuna v, delis kt, nicolaides an, aina o. effect of elastic compression stockings on venous hemodynamics during walking. j vasc surg 2003;37:420-5. 27. poelkens f, thijssen dh, kersten b, et al. counteracting venous stasis during acute lower leg immobilization. acta physiol (oxf) 2006;186:111-8. 28. mosti g, partsch h. measuring venous pumping function by strain-gauge plethysmography. int angiol 2010;29:421-5. 29. mosti g, mattaliano v, partsch h. inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous reflux. phlebology 2008;23:287-94. 30. mosti g, partsch h. is low compression pressure able to improve venous pumping function in patients with venous insufficiency? phlebology 2010;25:145-50. 31. mosti g, partsch h. inelastic bandages maintain their hemodynamic effectiveness over time despite significant pressure loss. j vasc surg 2010;52:925-31. 32. starling eh. on the absorption of fluids from the connective tissue spaces. j physiol (london) 1896;19:312. 33. levick jr, michel cc. microvascular fluid exchange and the revised starling principle. cardiovasc res 2010;87:198-210. 34. murthy g, ballard re, breit ga, et al. intramuscular pressures beneath elastic and inelastic leggings. ann vasc surg 1994;8:543-8. 35. partsch h, stöberl c, urbanek a, et al. clinical use of indirect lymphography in different forms of leg edema. lymphology 1998;21:152-60. 36. mosti g, picerni p, partsch h. compression stockings with moderate pressure are able to reduce chronic leg oedema. phlebology 2012;27:289-96. nction in chronic venous insufficiency by compression as dependent on pressure and material. vasa 1984;13:58-64. partsch h, menzinger g, mostbeck a. inelastic leg compression is more effective to reduce deep venous refluxes than elastic bandages. dermatol surg 1999;25:695-700. mosti g, partsch h. duplex scanning to evaluate the effect of compression on venous reflux. int angiol 2010;29:416-20. gjöres je, thulesius o. compression treatno nco mm er cia l u se on ly conference presentation [veins and lymphatics 2013; 2:e9] [page 29] ment in venous insufficiency evaluated with foot volumetry. vasa 1977;6:364-8. norgren l. elastic compression stockings: an evaluation with foot volumetry, straingauge plethysmography and photoplethysmography. acta chir scand 1988;154:5057. partsch h. do we need firm compression stockings exerting high pressure? vasa 1984;13:52-7. christopoulos dg, nicolaides an, szendro g, et al. air-plethysmography and the effect of elastic compression on venous hemodynamics of the leg. j vasc surg 1987;5:14859. spence rk, cahall e. inelastic versus elastic leg compression in chronic venous insufficiency: a comparison of limb size and venous hemodynamics. j vasc surg 1996;24:783-7. ibegbuna v, delis kt, nicolaides an, aina o. effect of elastic compression stockings on venous hemodynamics during walking. j vasc surg 2003;37:420-5. poelkens f, thijssen dh, kersten b, et al. counteracting venous stasis during acute lower leg immobilization. acta physiol (oxf) 2006;186:111-8. mosti g, partsch h. measuring venous pumping function by strain-gauge plethysmography. int angiol 2010;29:421-5. mosti g, mattaliano v, partsch h. inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous reflux. phlebology 2008;23:287-94. mosti g, partsch h. is low compression pressure able to improve venous pumping function in patients with venous insufficiency? phlebology 2010;25:145-50. mosti g, partsch h. inelastic bandages maintain their hemodynamic effectiveness over time despite significant pressure loss. j vasc surg 2010;52:925-31. starling eh. on the absorption of fluids from the connective tissue spaces. j physiol (london) 1896;19:312. levick jr, michel cc. microvascular fluid exchange and the revised starling principle. cardiovasc res 2010;87:198-210. murthy g, ballard re, breit ga, et al. intramuscular pressures beneath elastic and inelastic leggings. ann vasc surg 1994;8:543-8. partsch h, stöberl c, urbanek a, et al. clinical use of indirect lymphography in different forms of leg edema. lymphology 1998;21: 152-60. mosti g, picerni p, partsch h. compression stockings with moderate pressure are able to reduce chronic leg oedema. phlebology 2012;27:289-96. no nco mm er cia l u se on ly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: duplex ultrasound investigation of the veins of the lower limbs after treatment for varicose veins – uip consensus document by de maeseneer m, pichot o, cavezzi a, earnshaw j, van rij a, lurie f, smith pc; union internationale de phlebologie. eur j vasc endovasc surg 2011;42:89-102. stefano ricci abstract (extended summary by s. ricci) the aim of this paper is to summarize the best practice for venous duplex ultrasound investigation (dus) examination of the lower limbs after treatment. parts of this paper have been taken from the limited evidence available in the literature and was agreed upon by a group of experts who regularly use this technology. dus evaluation after treatment must take into consideration the pre-treatment assessment. patients have different profiles of anatomic and hemodynamic superficial venous insufficiency. clear documentation of pre-treatment clinical features and dus findings is, therefore, essential as these may influence the interpretation of post treatment results and expectations the minimum requirements for pre-treatment dus assessment are described in table 1. when assessing superficial veins, patients should be examined, where possible, in a standing position in order to standardize measurement of the venous diameter and reflux. if obesity or other cardio-respiratory conditions make this impractical, it is vital that the position used is adopted for any follow-up imaging. the diameter should be measured in transverse view 3 cm below the saphenofemoral junction (sfj), at mid-thigh level, at the knee and also at mid-calf level; the outer diameter should also be measured (including the vein wall) for comparison with the postoperative diameter after endovenous ablation (eva). similarly, these modalities should be used for the anterior accessory saphenous vein (aasv) and for the small saphenous vein (ssv). to detect the presence of reflux, a pressure gradient in the venous system by a valsalva maneuver (high pressure in the venous system) is required, or this should be achieved by a compression /release maneuver (low pressure in the distal venous system during release). at the level of the sfj, the combination of these two maneuvers is essential to assess the state of the terminal valve (tv) of the great saphenous vein (gsv). tv and ptv hemodynamics are best assessed through the combined use of color flow and doppler, with the sample volume placed above each valve to test for the presence or absence of reflux. the inguinal lymph node area should be studied, particularly in patients with recurrent varicose veins and also for veins that are part of the abdominal/pelvic venous network. any treatment should be recorded in sufficient detail as to allow an informed dus follow up. the timing of outcome assessment should be classified as immediate (1-4 weeks), short-term (1 year), midterm (2-3 years) and long-term (5 years or more). following surgical treatment, dus imaging should focus on the saphenous junctions (sfj and spj) and keep track of the stripped saphenous trunk (gsv, aasv or ssv). in recurrences, all escape points should be documented to highlight either reflux following a valsalva, which indicates that there is a change of compartment or escape points (connection with the deep veins) or that a reflux which is generated only by a compression/release maneuver (not by valsalva) is not linked to an escape points but takes place only in the superficial network. neovascularization is defined as the presence of multiple new, small tortuous veins in anatomic proximity to a previous venous intervention. neovascular veins may show reflux with a valsalva maneuver (escape points usually in the sfj area) and/or during release after calf compression (filling from the subcutaneous abdominal venous network). if they are seen to be associated with a lymph node, they are described as a lymph node vein network. the largest diameter of the vein(s) of the vascular network in the groin should be measured. if gsv ligation has been performed at a distance from the cfv (low ligation) instead of flush to the sfj level, a residual stump may be seen. reflux from the residual stump can connect with a residual aasv or other varices and should be assessed on dus. when the terminal valve is competent, the stump receives inflow from its tributaries that normally drain into the sfj. this may be found after selective stripping of the gsv trunk without a flush ligation, preserving the saphenofemoral confluence. in patients who have had surgical stripping, revascularization of the strip-track (the presence of multiple convoluted channels in the track of the previously stripped gsv) may be found. the aasv should be examined along its course as it is often involved in recurrence after gsv stripping. after ssv surgery at the level of the spj, dus findings are comparable to those at the sfj after gsv surgery. anatomy and hemodynamics of the popliteal fossa complex vary in spj. it is, therefore, particularly important to have details about the pre-operative anatomic and hemodynamic situation, as well as of the procedure performed. similar to the groin, the neovascular veins may connect directly to the popliteal vein, or they may connect with incompetent veins in the posterior thigh. an incompetent residual stump with or without reflux is frequently seen after ssv surgery. this may be due to the great variation in spj level. in primary venous insufficiency, perforators that transmit part or all the reflux from the superficial into the deep venous system are described as re-entry perforators. after saphenous stripping and phlebectomy, they mainly show normal inward flow and a diameter reduction at shortand mid-term follow up. conversely, many cases of recurrent varices can be related to more or less underdiagnosed incompetent perforators. on the back of the thigh, varicose veins may receive reflux from a gluteal plexus or vulvar/perineal veins, and are often related to pelvic vein incompetence. by carefully tracing these veins upwards while eliciting reflux with a distal compression/release maneuver, it is possible to detect their origin. after endovenous treatment of the gsv with laser, rfa or foam, the terminal part of the gsv usually remains open allowing one or more tributaries of the sfj to drain; under 3 cm in length is considered to be within normal limits. protrusion of a thrombus into the lumen of the cfv is very unusual (table 4) that allows a precise analysis of the results after eva in order to compare different techniques and introduce a standard dus assessment of outcomes following any eva procedure. using a single grading system for clinical outcome that combines symptom scores, clinical findings and dus findings to define the global outcome will not produce a coherent classification system, as the relative importance of individual variables may differ. it is, therefore, appropriate to report separately on clinical outcome parameters and dus findings in all patients included in prospective studies.   table 1. preoperative duplex imaging. table 4. proposed classification of duplex findings at the junction (j) and at the treated trunk (t) after endovenous ablation. comment it is particularly difficult to summarize a consensus paper in which nearly every sentence is important and content has already been synthesized. i have tried to report the most important aspects of the paper but it should be read in full in order to appreciate the consensus recommendations in detail. first of all, the authors have to be congratulated for their achievement in trying to fill the gaps and put in order the missing information on traditions, common language and methodology. a comment on this paper has been already issued in phlebology forum (nov. dec. 2011) by a. pieri: as to the possible speculations a reader could do, the qualitative reflux assessment deserves some attention; reflux is usually defined as retrograde flow lasting more than 0.5 s but... how to perform this time measure? standing? supine?. in fact real reflux lasts all the time of valsalva (in supine position) or till the achievement of pressure equilibrium between superficial and deep veins during compression-release manoeuvres (standing or sitting). standing valsalva may be confusing because pressure equilibrium is already reached and the refluxing time is obviously shorter. parana’s manoeuvre (described by claude franceschi) is perhaps the best standing method to evaluate reflux. i personally think that some other points could be discussed. 1. the study (us machine regulations) and follow up of small vessels inside closed trunks. 2. terminal valve incompetence classification and relation with gsv calibre. what about initial early incompetence (commissural reflux)? 3. diameter measurement should be performed in transverse view and the outer diameter should be measured (including the vein wall) to compare this with the postoperative diameter after endovenous ablation. this statement is not clear; measuring the inner diameter is the traditional method commonly used. 4. detection of isolated dilatations in the saphenous stem. 5. disappearance of reflux in gsvs after treatment of distal varicose vein disconnection/avulsion/closure (chiva, phlebectomy, sclerotherapy) in gsv conservative treatments. what is the hemodynamic significance and pathophysiology? 6. deep system incompetence in venous segments which are connected to refluxing superficial stems: hemodynamic significance. is it a true deep system incompetence? 7. very long reflux with very low velocity; very short reflux with very high velocity. how to interpret them? 8. due to the great variability in the spj, the exact level and shape of the junction should be defined before treatment. junctions may have variable terminations (full channel, funnel shape, tortuous, double) placed in a variable position in the popliteal vein section, at a variable level, with a variable relationship with the gastrocnemious veins and thigh extension vein. both the pre-operative situation and post-operative findings need to be clearly understood. 9. gsv hypoplasia is a well known and frequent finding. it should be properly described at first assessment to evaluate its possible role in post-treatment recurrence. 10. great importance should be given to the giacomini vein (in particular) and the presence of aasv, and their calibre and flow should be registered as a possible (probable) origin of recurrence after gsv stripping or closure. [top] hrev_master veins and lymphatics 2012; volume 1:e8 [veins and lymphatics 2012; 1:e8] [page 31] familial hyperhomocysteinemia, age and peripheral vascular diseases an italian study sandro michelini,1 marco cardone,1 adriano micci,1 francesco cappellino,1 alessandro fiorentino,1 vincenzo sainato,1 maria mora,1 rachele todisco,1 maddalena todini,1 serena michelini,2 guido valle3 1hospital san giovanni battista – acismom, rome; 2la sapienza university, 2nd school of medicine, rome; 3nuclear medicine unit, scientific institute “casa sollievo della sofferenza”, san giovanni rotondo (fg), italy abstract hyperhomocysteinemia is a widely recognized, although not yet entirely understood, risk factor for cardiovascular disease. particularly, the complex relationships between age, hyperhomocysteinemia, predisposing genetic factors and peripheral vascular diseases have not been fully evaluated. our contribution to this issue is a retrospective analysis of a large series of patients with peripheral arterial, venous and lymphatic disease, and of their blood relatives, with special reference to homocysteine plasma levels, age and methylenetetrahydrofolate reductase (mthfr) polymorphisms. serum homocysteine was measured in 477 patients (286 males, 191 females, age range 19-78 years) with various vascular clinical conditions: postphlebitic syndrome (46) recurrent venous ulcers (78), arterial diseases (101) primary lymphoedema (87), secondary lymphoedema (161) and outlet thoracic syndrome (4), and in 50 normal controls. a mthfr study for polymorphisms was carried on in the subjects with homocysteine values exceeding 15 �mol/l. serum homocysteine determination and mthfr polymorphism studies were performed also in 1430 healthy blood related relatives (mainly siblings, descendents and sibling descendents) of the subjects with hyperhomocysteinemia and mthfr polymorphisms. we found mthfr polymorphisms in 20% of controls and in 69.3%, 69.5% and 53.8% of hyperhomocysteinemic subjects with arterial diseases, postphlebitic syndrome and venous ulcers, respectively. as expected, the percentage of hyperhomocysteinemia in patients with secondary lymphoedema and with thoracic outlet syndrome did not show significant differences compared to the control group. a mthfr polymorphism was found in 116 out of the 214 hyperhomocysteinemic patients, i.e., in the 54% of the overall patient population with hyperhomocysteinemia (214 patients). interestingly 750 (52%) out of the 1430 blood relatives of the 116 patients with hyperhomocysteinemia and mthfr polymorphisms showed at least one polymorphism in mthfr gene. in this latter group of 750 healthy blood-related relatives bearing a mthfr polymorphism the finding of hyperhomocysteinemia increased according to the age class from 1.6% in the age range <40 years up to 54.9% in the age range >60 years. the present study demonstrate that patients with peripheral arterial disease, post-phlebitic syndrome, venous ulcers and primary lymphoedema show a significantly higher incidence of hyperhomocysteinemia compared to controls, and adds further evidence to the causative role of hyperhomocysteinemia in the development of both arterial and venous disease. moreover our data indicate a possible causative role of hyperhomocysteinemia in primary lymphoedema. in more than 50% of our hyperhomocysteinemic patients a polymorphism of mthfr (c677t and/or a1298c) was detected. in subjects with these polymorphisms the frequency of hyperhomocysteinemia increases with age. we observed a quite similar frequency of the two polymorphisms in the studied population and therefore claim for the need to study both c677t and a1298c mutations in hyperhomocysteinemic patients. introduction the possible role of homocysteine high levels as a risk factor for vascular disease was described for the first time more than forty years ago,1,2 and in the following decades a large amount of evidence has demonstrated that even mild increases in homocysteinemia are associated with an increased risk of cardiovascular diseases3,4 including venous thromboembolic disease.5 hyperhomocysteinemia is frequently associated with mthfr polymorphisms c677t and a1298c. mthfr catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. figure 1 summarizes homocysteine metabolism.6-13 figure 2 shows the pathophysiologic mechanism(s) of hyperhomocysteinemia-induced vascular damage.14-18 in the last few years, however, the causative role of hyperhomocysteinemia in cardiovascular disease has been questioned mainly based on the reports that failed to demonstrate a clinical benefit after lowering homocysteinemia levels with vitamins b6, b12 and folate.19-21 particularly, it has been pointed out that treatment with homocysteine lowering agents, i.e. folic acid and b6 and b12 vitamins, over prolonged times, does not reduce the incidence of cardiovascular adverse effects,19 although it has been reported that folate, vitamin b12 intake is associated with a reduction of the risk of ischemic stroke.22,23 therefore further studies have been advocated to address this issue.24 in order to understand the relationships between homocysteinemia and vascular disease we made a retrospective analysis of the patients who were referred to vascular disease rehabilitation program of our institute for peripheral arterial, venous and lymphatic disorders, paying special attention to homocysteine blood levels, mthfr polymorphisms and age. the influence of mthfr polymorphisms on homocysteine blood levels was also studied in the available healthy blood related relatives of hyperhomocysteinemic subjects with mthfr polymorphisms. materials and methods a general description of the study is reported in figure 3. briefly, serum concentration of homocysteine was measured in 477 consecutive patients (286 males, 191 females, mean age 56.5 years, age range 19-78 years) with various vascular clinical conditions: post-phlebitic syndrome (46) recurrent venous ulcers (78), peripheral arterial diseases (101) primary lymphoedema (87), secondary lymphoedema (161) outlet thoracic syndrome (4) admitted to the rehabilitation program of our hospital. serum homocysteine determination was also performed in 50 normal control subjects (29 males and 21 females, mean age 55 years). the quantitative determination of the correspondence: sandro michelini, hospital “san giovanni battista” acismom, via luigi ercole morselli 13, 00148 rome, italy. tel. +393358410881. e-mail: sandro.michelini@fastwebnet.it key words: homocysteine, methylenetetrahydrofolate reductase, thrombosis risk factor. acknowledgments: the authors gratefully thank prof. rossella antonelli (endocrinology unit, asl rm/c, hospital sant’eugenio, rome) for her kind suggestions and comments on the text. received for publication: 22 september 2012. revision received: 5 december 2012. accepted for publication: 6 december 2012. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s michelini et al., 2012 licensee pagepress, italy veins and lymphatics 2012; 1:e8 doi:10.4081/vl.2012.e8 no nco mm er cia l u se on ly article [page 32] [veins and lymphatics 2012; 1:e8] homocysteine serum levels was performed with an automated latex enhanced immunoassay (hemosil, homocysteine 0020007800, instrumental laboratory spa, milano, italy). when the plasma homocysteine values exceeded 15 �mol/l patients underwent mthfr study for c677t and/or a1298c polymorphisms. mthfr polymorphism analysis was performed after genetic amplification on venous blood edta treated samples by molecular genetic real time techniques in an associated laboratory (bios, rome, italy). homocysteine plasma determination and mthfr polymorphism studies were performed also on 1430 healthy blood related relatives (mainly, siblings, descendents and sibling descendents) of the subjects with hyperhomocysteinemia and mthfr polymorphisms. results patients hyperhomocysteinemia was found in 20% of controls and in 69.3%, 69.5% and 53.8 % of subjects with arterial diseases, postphlebitic syndrome and venous ulcers, respectively (table 1). as expected, the percentage of hyperhomocysteinemia in patients with secondary lymphoedema and with thoracic outlet syndrome did not show significant differences compared to the control group (table 1). at least one mthfr polymorphism was found in 116 out of the 214 hyperhomocysteinemic patients i.e. in the 54% of the overall patient population with hyperhomocysteinemia (table 2). blood related relatives of hyperhomocysteinemic patients bearing a methylenetetrahydrofolate reductase polymorphism in 750 (52%) out of the 1430 blood relatives of the 116 patients with hyperhomocysteinemia and mthfr polymorphisms at least one polymorphism in mthfr gene was found. in this group of 750 asymptomatic subjects bearing a mthfr polymorphism the frequency of the finding of hyperhomocysteinemia increased according to the age class from 1.6% in the age range <40 years up to 54.9% in the age range >60 years (table 3). c677t polymorphism-associated hyperhomocysteinemia did not significantly differ from a1298c-induced hyperhomocysteinemia either in frequency or in hyperhomocysfigure 1. homocysteine metabolism. homocysteine is a sulphydryl amino acid derived from the intracellular demethylation of methionine. homocysteine, when activated, yields a methyl group to different receivers (including creatine, steroid hormones, purine bases of dna and rna) and then it can be converted into homocysteine. homocysteine may be, in turn, transformed irreversibly into cystathionine and then cysteine, or, in the absence of dietary methionine, remethylated to methionine. a series of enzymes and cofactors regulate these pathways. homocysteine is produced through two possible pathways: remethylation or trans-sulphuration. the remethylation process converts back homocysteine to methionine (utilizing folate, vitamin b12 or trimethylglycine). the trans-sulphuration process utilizes vitamin b6, pyridoxal-5-phosphate, and catabolizes the homocysteine excess into metabolites that can be excreted from the organism. a mildly failure of the remethylation pathway (often due to reduced levels of folate, vitamin b12 or genetic defects) can increase significantly the homocysteine plasma levels. a mild failure in the trans-sulphuration pathway (caused by genetic defect or indadeguate levels of vitamin b6) can only increase slightly the homocysteine plasma concentration. there are several causes of hyperhomocysteinemia, some create a deficiency of the enzyme co-factors, and others reduce the activity of enzymes, involved in its metabolism. the deficiencies of vitamin b12, b6 or folic acid may be due to an inadequate diet, intake of drugs like methotrexate, nitroxide and levodopa or conditions involving hormonal changes like pregnancy and hypothyroidism. no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e8] [page 33] figure 2. hyperhomocysteinemia mechanisms of endothelial damage and thrombosis. hyperhomocysteinemia induces an oxidative stress through both direct and indirect effects. particularly important are the inhibition of glutathione peroxidase, the reduction of cysteine blood concentration, which results in depressed glutathione levels, the overexpression of nadph and the reduced availability of nitric oxide. in its turn the depression of nitric oxide activity activates mmp-2 and mmp-9 with consequent increased aggregation of platelets and increased interaction between platelets and endothelium. moreover mmp activation increases the production of endostatin from collagen and of angiostatin from plasminogen with consequent vascular damage. thrombophilia is also sustained by the hyperhomocysteinemia-enhaced activation of tf, of tafi and of factor xiii. all these data explain why abnormally elevated homocysteine blood levels result in endothelial damage and in a consequent increase of the risk of both arterial and venous thrombosis. tf, tissue factor; tafi, thrombin activable fibrinolysis inhibitor; mmp-2, matrix metalloproteinase 2; mmp-9, matrix metalloproteinase 9. no nco mm er cia l u se on ly article [page 34] [veins and lymphatics 2012; 1:e8] teine induced levels (table 4). moreover, the association of the two polymorphisms in the same subject did not result either in an earlier appearance of hyperhomocysteinemia or in higher homocysteinemia levels. from a clinical point of view our findings indicate a quite similar frequency of the two polymorphisms in the studied population and therefore the need to study both c677t and a1298c mutations in hyperhomocysteinemic patients (table 4). discussion and conclusions despite some uncertainity due to the limited number of control subjects the present study shows a far higher incidence of hyperhomocysteinemia in patients with peripheral artery disease, post-phlebitic syndrome, venous ulcers and primary lymphoedema compared to controls, therefore adding further evidence to the causative role of hyperhomocysteinemia in the development of both peripheral thrombotic arterial and venous disease and of primary lymphoedema. the patients with primary lymphoedema recruited in the present study had no evidence of other vascular disease. in more than 50% of our hyperhomocysteinemic patients a polymorphism of mthfr (c677t and/or a1298c) was detected. it has been also observed that in subjects with mthfr c677t and/or a1298c polymorphism the frequency of hyperhomocysteinemia increases with age. this latter finding is especially unexpected taking into account that genetic disorders usually, although not always, produce clinically evident disorders in the first decades of life. this could possibly be explained by an age related reduction of the defences against oxidative stress. another interesting observation is that c677t polymorphism-associated hyperhomocysteinemia did not significantly differ from a1298c-induced hyperhomocysteinemia either in frequency or in severity. moreover, surprisingly, the association of the two polymorphisms in the same subject is not associated either with an earlier appearance of hyperhomocysteinemia or with higher homocysteinemia levels. the very similar frequency of the c677t and a1298c polymorphisms in the patient population implies the need to study both c677t and a1298c mutations in hyperhomocysteinemic patients. particularly, it is known that in southern europe, and especially in italy, the prevalence of c677t homozygous polymorphism is quite higher compared with northern and central europe.25 finally, at authors’ knowledge this is the first report indicating a possible causative role of hyperhomocysteinemia in primary lymphoedema. table 1. homocysteine plasmatic values according to the underlying disease (data on 477 patients) and in the control group (50 subjects). test results groups arterial post-phlebitic venous leg primary secondary thoracic outlet control diseases syndrome ulcers lymphoedema lymphoedema syndrome subjects 101 46 78 87 161 4 50 5 to 15 mmol/l normal levels 31 14 36 61 117 4 40 15 to 30 mmol/l moderate 44 17 30 19 28 0 9 hyperhomocysteinemia 30 to 100 mmol/l intermediate 17 10 9 7 15 0 1 hyperhomocysteinemia >100 mmol/l severe 9 5 3 0 1 0 0 hyperhomocysteinemia hyperhomocysteinemic 69.3 69.5 53.8 29.9 27.3 0 20 subjects (%) hyperhomocysteinemic subjects were significantly (p<0.001 at chi-square test) more frequent in the groups of subjects with arterial diseases, postphlebitic syndrome, venous ulcers and primary lymphoedema compared to controls. table 2. patients bearing a1298c and/or c677t polymorphisms (n=116), methylenetetrahydrofolate reductase polymorphism, homocysteinemia level and associated clinical disorders. mutation moderate intermediate severe arteriopathy thrombo-phlebitis venous hyperhomohyperhomohyperhomoleg ulcers cysteinemia cysteinemia cysteinemia c677t eterozygous 18 subjects 15 3 1 11 3 4 c677t homozygous 16 subjects 2 6 4 8 2 6 a1298c homozygous 28 subjects 17 10 1 19 5 4 a1298c homozygous 16 subjects 6 11 2 7 3 6 c677t eterozygous a1298c eterozygous 9 6 4 8 6 5 5 subjects c677t eterozygous+a1298c homozygous 6 3 3 5 5 2 19 subjects c677t homozygous+a1298c eterozygous 0 0 2 1 1 0 12 subjects c677t homozygous+a1298c homozygous 2 2 1 1 3 1 2 subjects the first three columns refer to the degree of hyperhomocysteinemia. the last three columns illustrate the associated vascular disease. no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e8] [page 35] table 3. age related finding of hyperhomocysteinemia in asymptomatic methylenetetrahydrofolate reductase polymorphism bearers. age no. subjects c677t c677t a1298c a1298c no. subjects with % subjects with (years) eterozygotic homozygotic eterozygotic homozygotic hyperhomohyperhomomutation mutation mutation mutation cysteinemia cysteinemia ≤39 83 24 16 28 19 2 1.66 40-49 254 66 48 89 55 34 13.4 50-59 211 56 45 61 56 79 37.4 ≥60 202 53 42 63 55 111 54.9 the frequency of hyperhomocysteinemic subjects among age groups resulted always highly significant (p<0.001 at chi-square test). notice that in 38 cases a double polymorphism was found. table 4. incidence of methylenetetrahydrofolate reductase (mthfr) polymorphisms in the 750 blood relatives of the patients with mthfr mutation and relative incidence and level of related hyperhomocysteinemia. mutation moderate hyperhomocysteinemia intermediate hyperhomocysteinemia severe hyperhomocysteinemia c677t eterozygotic 199 subjects 20 23 8 c677t homozygotic 151 subjects 22 27 9 a1298c eterozygotic 241 subjects 23 25 9 a1298c homozygotic 185 subjects 28 26 6 notice that 95 out of 226 (42%) bearers of a mthfr polymorphism presented, at a carefully made clinical interview, a history for peripheral vascular disease. figure 3. study design, patients and subjects. mthfr, methylenetetrahydrofolate reductase. no nco mm er cia l u se on ly article [page 36] [veins and lymphatics 2012; 1:e8] references 1. gibson jb, carson naj, neill dw. pathological findings in homocystinuria. j clin path 1964;17:427-37. 2. mccully ks. vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. am j pathol 1969;56:111-28. 3. graham im, o’callaghan p. vitamins, homocysteine and cardiovascular risk. cardiovasc drugs ther 2002;16:383-9. 4. de ruijter w, westendorp rg, assendelft wj, et al. use of framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study. br med j 2009;338:a3083. 5. ray jg. meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. arch int med 1998;158: 2101-6. 6. swift me, schultz dt. relationship of vitamins b6 and b12 to homocysteine levels: risk for coronary heart disease. nutr rep int 1986;34:1-14. 7. selhub j, miller jw. the pathogenesis of homocyst(e)inemia: interruption of the coordinate regulation by s-adenosylmethionine of remethylation and transsulfuration of homocysteine. am j clin nutr 1991;55:131-8. 8. miller jw, ribaya-mercado jd, russell rm, et al. total homocysteine in fasting plasma is not a good indicator of b6 deficiency, am j clin nutr 1992;55:1154-560. 9. miller jw, nadeau mr, smith d, selhub j. vitamin b6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats. am j clin nutr 1994;59: 1033-9. 10. haagsma cj, blom hj, van riel pl, et al. influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with reumathoid arthritis, ann rheum dis 1999;58:79-84. 11. müller t, werne b, fowler b, kuhn w. nigral endothelial dysfunction, homocysteine, and parkinson’s disease. lancet 1999;354:126. 12. sorensen tk, malinow mr, williams ma, et al. elevated second-trimester serum homocyst(e)ine levels and subsequent risk of preeclampsia. gynecol obstet invest 1999;48:98-103. 13. catargi b, parrot-rouland f, cochet c, et al. homocysteine, hypothyroidism, and the effect of thyroid hormone replacement. thyroid 1999;9:1163-6. 14. handy de, zhang y, loscalzo j. homocysteine down-regulates cellular glutathione peroxidise (gpx1) by decreasing translation, j biol chem 2005;280:15518-25. 15. ungvari z, csiszar a, edwards jg, et al. increased superoxide production in coronary arteries in hyperhomocysteinemia: role of tumor necrosis factor-�, nad(p)h oxidase and inducible nitric oxide synthase. arterioscler thromb vasc biol 2003; 23:418-24. 16. topal g, brunet a, millanvoye e, et al., homocysteine induces oxidative stress by uncoupling of no synthase activity through reduction of tetrahydrobiopterin. free radic biol med 2004;36:1532-41. 17. fernandez-patron c, martinez-cuesta ma, salas e, et al. differential regulation of platelet aggregation by matrix metalloproteinases-9 and -2. thromb haemost 1999; 82:1730-5. 18. loscalzo j. homocysteine-mediated thrombosis and angiostasis in vascular pathobiology. j clin invest 2009;119:3203-5. 19. abraham jm, cho l. the homocysteine hypothesis: still relevant to the prevention and treatment of cardiovascular disease? cleveland clinic j med 2010;77:911-8. 20. marcus j, sarnak mj, menon v. homocysteine lowering and cardiovascular risk: lost in translation. can j cardiol 2007;23:707-10. 21. ray jg, kearon c, yi q, et al. homocysteine lowering therapy and risk for venous thromboembolism: a randomized trial. ann intern med 2007;146:761-7. 22. he k, merchant a, rimm eb, et al. folate, vitamin b6 and b12 intakes in relation to risk of stroke among men. stroke 2004;35: 169-74. 23. saposnik g, ray jg, sheridan p, et al. homocysteine-lowering therapy and stroke risk severity, and disability: additional findings from the hope 2 trial. stroke 2009;40: 1365-72. 24. smulders ym, blom hj. the homocysteine controversy. j inherit metab dis 2011;34: 93-9. 25. wilcken b, bamforth f, li z, et al. geographical and ethnic variation of the 677c>t allele of 5,10 methylenetetrahydrofolate reductase (mthfr): findings from over 7000 newborns from 16 areas worldwide. j med genet 2003;40:619-25. no nco mm er cia l u se on ly stefano ricci part iii: local anesthesia in phlebology practice stefano ricci although, according to trendelemburgh1 in 1890: scarsely anything needs to be said on the technic of operation. the vein is exposed through a skin incision about 3 cm long and isolated with the handle of the scalpel. then a catgut suture is passed around above and below by means of an aneurysm needle, ... the vein doubly ligated and severed between the legatures, whereupon the skin incision is closed by suturing. the operation can be completed in a few minutes and is not painful enough that narcosis is indispensably necessary, in 1896 w. moore published:2 the next four cases were treated in the outpatient room: they were operated on under chloroform, and were allowed to go home in an hour or two. more recently i have employed cocaine (... a very weak solution is injected into and underneath the skin...), and the patient goes home at once. w. thelwell thomas3 writes in 1896 about... ligature and division of the internal saphena vein at the saphenous opening: anaesthetics firstly, and then antiseptic surgery, reopened the question, by relieving pain and allowing careful dissection by the surgeon, and doing away the desperate complications of septic phlebitis and pyemia, and in the literature of the subject one finds that only after 1870 did operative proceedings become general. and more: cocaine may be used as local anesthetic if desired, reclus, schwartz, woltt, and schleich do so. in 1895 g. perthes4 (trendelembugh’s pupil) reported data from 63 patients 87 operations done since 1884, referring that: in our cases the operation was performed almost exclusively under narcosis. but experience showed that narcosis could be omitted. in one case, local anesthesia (schleich) was used and it proved to be extremely suitable for this operation. in 1907 w. w. babcok,5 announcing to the community the method that will become universally employed for the next 100 years reported: spinal anesthesia by means of stovaine or tropocaine hydroclorate has been employed in nearly all of our cases. b. schassi6 in 1909 (the medical press 1909) made saphenous ligature in local anesthesia and injected distally an iodine solution with very striking results. interestingly, the beginning of gsv surgery, represented mostly by gsv ligature and division, experienced local anesthesia, and even spinal anesthesia, when cocaine could be dismissed. however during the first half of the xx century general anesthesia prevailed in gsv surgery as a consequence of its progressive safety, of more demanding operations, of more generalized patients request and of standardization of the treating method (stripping + varicectomies). in fact, in 1954 tom mayer7 published the paper on varicose veins surgery that will be nearly universally considered the gold standard for many years on (not forgotten still nowadays). this surgery ought to be accurate and complete: junction dissection and ligation of the gsv flush to the femoral vein; ligation and section of all the tributaries; ligation and section of the perforators; varicosities multiple ligation. the surgical time was long and tedious, often hemorrhagic, needing a transfusion at times.8 general anesthesia became obviously the preferred method by surgeons and patients, while postoperative bed rest was measured in weeks more than in days. this being the general trend, still some surgeons preferred to perform their veins surgery by local anesthesia,9 mostly considered as extravagance or originality. in a survey made by the french society of phlebology published in 196210 with the purpose of stating at that date the current treatment of varicose disease, over the 146 phlebologists answering (93 french, 53 from other countries for a total of 87,685 patients), the great majority was operating in general anesthesia. as an exception, 7 surgeons preferred local anesthesia, however with an experience of about 12,000 patients. curiously, when asked, all declared that la was possible in many cases but the impression is of a diplomatic sentence. starting from the 60s of last century finally a technique of varices ablation suggested by r. muller11 started to rise attention (not without scepticism), which was less aggressive, performed in an office setting and under la (infiltration of 0.5 % lidocaine + adrenaline), treating each patient in a custom way, avoiding a standard procedure. varices were eliminated by what was called ambulatory phlebectomy, while the gsv, when needed, was stripped according to mayo,12 always by la. ambulatory phlebectomy spread slowly but constantly with a progressive number of followers and imitators13, 14 even with the creation of a specific society (societé européenne de phlebectomie ambulatoire). the diffusion of duplex facilities in the last 20 years of last century progressively induced to a better knowledge of the disease and, consequently, a less aggressive surgery;15 in the same time, sparing requests from the public health systems became insistent, while patients expectation called for simpler/cosmetic methods. this complex of conditions gave rise to several (revolutionary) changes in the varicose veins treatment during the last 10 years of the century all in the direction of la adoption. in 1988, franceschi16 described an office-based procedure for the treatment of cvi with preservation of the superficial venous system. franceschi called this procedure ambulatory conservative hemodynamic correction of venous insufficiency (chiva: cure conservatrice hémodynamique de l’insuffisance veineuse en ambulatoire). the chiva method is a minimally invasive surgery procedure, performed under local anesthesia, based on a careful duplex analysis of the hemodynamic superficial venous network. conservation of most of the dilated veins is obtained through precise venous ligation/sections (saphenofemoral ligation, disconnection from the great saphenous vein of the varicose tributaries and their avulsion through cosmetic incisions), achieving disconnection at the escape points, fractionation of the blood column, respect of the disconnected varicose veins physiological draining flow by preservation of the re-entry perforators. gsv endovascular thermal obliteration techniques appear at the very end of 2000, based on radiofrequency in 199817 and laser in 1999.18 these techniques do not need groin dissection, hospitalization, and are easily (even if not universally) performed in local anesthesia. moreover, local infiltration anesthesia is a fundamental part of the procedure: used with a high dilution (tumescence) all along the gsv tract to be treated, it avoids skin burns by separating it from the vein. tumescent local anesthesia in 1988 j. klein19 introduces the principle of high dilution of the local anesthetic (1000 ml nacl serum + 500 mg lidocaine + 1 mg adrenaline + 12.5 meq lidocaine) for liposuction. this technique, historically referring to the hard infiltration suggested by a. vishniewsky20 became the gold standard for liposuction after american society of dermatologic surgery (asds) tumescent liposuction survey publication in 1995,21 reporting 15,336 patients treated by 66 dermatologists, without complications. in 1995 cohn, seiger and goldman22 suggested it for phlebectomy procedures, and from that date several authors followed this way20 for the gsv stripping. it was adopted from the beginning by heat endovascular gsv operators with few exceptions. in reality the limit of tumescence is not precise, as local anesthesia may be submitted with different dilutions and volumes, according to the hydrodissection needed (high for endovascular heat procedure and lower for phlebectomy). the writer, for example, uses since 1980 a dilution of 0.4% for all the phlebologic procedures (phlebectomy, saphenectomy).23 at the beginning of the new century all the phlebologic surgery can potentially be performed in local infiltration anesthesia. references trendelemburg f. ueber die unterbindung der vena saphena magna bei unterschenkelvaricen). beitrage zur klinischen chirurgie 1890;7:195. moore w. the operative treatment of varicose veins, with special reference to a modification of trendelemburg’s operation. intercol med j australas 1896;1:393. thelwall thomas w. operative treatment of varicose veins of the lower extremity by ligature and division of the internal saphena vein at the saphenous opening. liverpool med-chir j 1896;16:278. perthes g. ueber die operation der unterschenkelvaricen nach trendelemburg. deutsche medicinische wochenschrift 1895;16:253. babcock ww. a new operation for extirpation of varicose veins of the leg. new york med j 1907;86:153. schassi b. la cure des varices du membre inférieur par l’injection intraveineuse d’une solution d’iode. sem méd (paris) 1908;28:601-2. myers tt, cooley jj. varicose vein surgery in the menagement of the postephlebitic limb. surg gynecol obstet 1954;99:733-44. rose ss. historical development of varicose vein surgery. chapter 8. in: bergan jj, goldman mp, eds. varicose veins and telangectasias. st. louis, mo: qmp; 1993. van der stricht j. saphenéctomie par invagination sur fil. presse med 1963;71:1081. société française de phlébologie. crossectomie et stripping de la saphéne interne dans le traitement des varices essentielles. paris: l’expansion scientifique francaise; 1964. muller r. traitement des varices par la phlebectomie ambulatoire. phlébologie 1966;19:277-9. ricci s. saphénectomie par stripper externe. phlébologie 1999;52:61-8. muller r, joubert b. la phlébolgie ambulatoire. de l’anatomie au geste. paris: les editions médicales innothéra; 1992. varady z. mikrochirurgische phlebextraktion nach varady in der varizenchirurgie. intern. diskussionsblatt 1988;1:8-9. negus d. should the incompetent saphenous vein be stripped to the ankle? phlebology 1986;1:33-6. franceschi c. théorie et pratique de la cure conservatrice de l’insuffisance veineuse en ambulatoire. précy-sous-thil: editions de l’armançon; 1988. weiss ra, feied cf, weiss ma. a comprehensive approach rf mediated endovenous occlusion. chapter 20: vein diagnosis and treatment. paris: mc grew-hill; 2000. pp 211-222. boné c. tratamiento endoluminal de las varices con laser de diodo. rev patol vasc 1999;5:35-46. klein ja. anesthesia for liposuction. jdso 1988;14:1124-32. garde c. l’anesthésie tumescente en chirurgie veineuse superficielle. phlébologie 2014;67:64-71. hanke cw, bernstein g, bullock s. safety of tumescent liposuction in 15,336 patients. dermatol surg 1995;21:459-62. cohn ms, seiger e, goldman s. ambulatory phlebectomy using the tumescent technique for local anesthesia. jdso 1995;21:315-8. ricci s, georgiev m, goldman mp. ambulatory phlebectomy. boca raton: taylor & francis; 2005. [top] hrev_master veins and lymphatics 2017; volume 6:6621 [veins and lymphatics 2017; 6:6621] [page 1] hysteresis and medical compression bandage and stockings andré cornu-thenard,1 pascal jollivet2 1st. antoine hospital, paris; 2p-f medical devices, toulouse, france introduction the word hysteresis comes from the greek husteros, which means lagging behind. we can observe it in natural phenomena like electricity and magnetism. hysteresis is a well-understood phenomenon in relation to medical compression bandages (mcb), but remains poorly studied regarding medical compression stockings (mcs). materials and methods two different mcb (long-stretch and short-stretch) and three mcs were used for this in vitro experiment. compression measurements were taken using a french dynamometer. therefore this enabled comparison of the hysteresis curves to be studied. results as it is known short-stretch bandage produces a concave curve. as it is not very well-known long-stretch bandage produces a convex curve. the curve obtained with the mcs is also convex, relatively similar to that obtained with the long-stretch bandage. as stretching starts the pressure increases very fast. then the pressure decreases for becoming nearly horizontal. pressure and resistance (the in vitro stiffness) can be obtained at any point on this curve. discussion and conclusions for mcb, more precise studies should be performed taking into account the number of turns applied. however theses results support previous studies by demonstrating the convex hysteresis curve contour for long-stretch bandages recently described in the literature. for mcs, hysteresis curves give the relationship between the size of mcs (or patient ankle perimeter in cm) and pressure delivered, i.e. the correct dosage for a given situation.1-3 so: i) correct prescription of stockings would be facilitated if manufacturers would provide the hysteresis curves for each of their stocking’s model; ii) such measures would also help avoid the use of compression class systems, which vary significantly from country to country. references 1. van geest aj, veraart jc, et al. the effect of mcs with different slope values on edema. dermatol surg 2000;26:244-7. 2. partsch h, clark m, et al. measurements of lower leg compression in vivo. dermatol surg 2006;32:229-38. 3. cornu-thenard a, benigni jp, uhl jf. terminology: resistance or stiffness for mcs. veins and lymphatics 2013;2:e4. correspondence: andré cornu-thenard, st. antoine hospital, paris, france; pascal jollivet, p-f medical devices, toulouse, france. e-mail: andre.cornuthenard@wanadoo.fr; pascal.jollivet@pierre-fabre.com this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright a. cornu-thenard and p. jollivet et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6621 doi:10.4081/vl.2017.6621 no n c om me rci al us e o nly stefano ricci comment to: selective high ligation of the saphenofemoral junction decreases the neovascularization and the recurrent varicose veins in the operated groin by mariani f, mancini s, bucalossi m, allegra c. int angiol 2014 jul 16 [epub ahead of print] stefano ricci abstract the classical radical high ligation (rhl) performed with the babcock technique is defined as the traditional gold standard technique: superficial tributaries dissection, followed, when possible, back to the secondary branch points, division and ligation; gsv ligation flush to the junction. in the present study the authors analyze, as an alternative, the selective high ligation (shl) of the junction with 5/12 years follow-up. the rationale is that sfj tributary veins coming from the abdominal wall have an important role in draining the venous flow to the deep veins or to the opposite vein network, particularly when the venous abdominal flow is modified for physiological condition (i.e. pregnancy) or external compression or obstruction (i.e. deep venous thrombosis). in shl the veins coming from the abdominal wall, as the superior epigastric vein (sev) or the superior iliac circumflex vein (sicv), are spared, while the superior external pudendal vein (sepv) and the others tributaries which have an acute angle with the saphenic axis or a t branch from the thigh, are carefully isolated and ligated with 2/0 or 3/0 non absorbable thread; the gsv is ligated and dissected flush the confluence of the spared tributary veins, usually about 1 cm from the sfj, to maintain its drainage into the gsv stump. the study included a homogenous cohort of 360 patients (mean aged 51.9 years range 18 to 75 years ceap c2s ep), that underwent unilateral varicose vein surgery from january 2001 to december 2008. the neovascularization and the recurrences in the groin were found in seven patients (1.9%) of the total cases: 3 patients were symptomatic, 4 asymptomatic. the recurrences were due to inadequate groin surgery: the anterior lateral thigh vein, the posterior medial thigh or a t branch of tributaries left, a gsv stump exceeding 1 cm. the gsv stumps and the spared tributaries were open to venous flow; no venous reflux in the groin at valsalva in standing position was present; the compression ultrasonography of the gsv stump was negative in all the patients. during the past 10 years minimal invasive surgery or endovascular approaches with radiofrequency and endolaser ablation have developed. these techniques leave all or nearly all tributaries of the sfj and the results in terms of recurrences from the saphenous stump seem to be better than the babcock’s rhl. the selective high ligation is a reliable technique, decreasing the incidence of neovascularization and recurrent varicose veins in the operated groin. comment by stefano ricci papers about groin recurrence are always interesting: in fact gsv interruption at the groin is constantly debated due to recurrence high frequency (20-25% with more than 1/3 requiring reoperation);1 in fact, ultrasound facilities have demonstrated early recurrences even when new varices are still silent. the authors sponsor a selective high ligation showing a very favorable (1.9%) rate of recurrence at long term follow-up (5-12 years), apparently explained by the maintenance of the high tributaries drainage. this surgical variation seems simple and easy to perform. however some questions arise: every patient was studied before and after the operation (7-15-30 days + every year). this means a huge amount of exams per year (360) since at least 5 years, only for controls, plus 4 inital exams for every case (1440). how did you organize (time, costs, operators) this part of the study? were the patients informed about the surgical variant and how and when was the ethical committee consensus obtained? no mention is done about the duplex scanning protocol. in particular, no data are given about how the terminal valve, and particularly the femoral valves were studied; about gsv diameters (as an indication of the reflux volume); about the anatomical variations (anterior accessory saphenous vein joining as the highest vessel to the gsv, common trunks for tributaries, etc.); neovascularization is identified with cavernoma, which is not the most modern definition. neovascularization is better defined how tiny vessels arising from the operated vein wall. cavernoma has possibly a relation with the vessels of the lamina lymphatica laying around the junction that has been not considered; it is not clear what a t branch is. the rational of this surgical variant is not completely clear: if a less aggressive manipulation is the matter, the groin surgical dissection is not very different from the traditional one; if the tributary drainage is concerned, pregnancies, dvt and hepatopathies (cited in the paper) don’t seem to be present in the patients observed. in other words, why shl gives less recurrence? references fischer r, chandler jg, de maeseneer mg, et al. the unresolved problem of recurrent saphenofemoral reflux. j am coll surg 2002;195:80-94. [crossref] [pubmed] author’s reply (mariani f.) the organization is the same for all operated patients, we ask all operated patients to undergo checks at the times of 7-15-30 days + every year. two operators (m. bucalossi, s. mancini) studied and check the patients, the surgical interventions were performed by f. mariani (first surgeon), c. allegra is the author of the design of the study, and he revised the casuistry, the statistical analysis and the paper. in the section material and methods of the paper is specified that patients signed informed consent; it isn’t mandatory to consult the ethical committee because the wma declaration of helsinki ethical principles for medical research involving human subjects is respected, however the informed consent was approved by the internal ethical committee of the hospital. in the section material and methods is specified that: all patients had a venous reflux from terminal valve of sfj and the femoral valves were continent; the diameters of the gsv were from 7 mm to 12 mm, the anatomical variations of the sfj are not described because the casuistry is a standard casuistry of operated patients for gsv insufficiency, obviously not all the patients can be submitted to a selective ligation for some reasons, i.e.: i) if the sfj greatest diameter is >12-13 mm it is usually very difficult to maintain the tributaries and in the same time to make a good ligation-dissection of the dilated (or in some cases even aneurismatic) sfj; ii) the more complex anatomical variations of the sfj that impede to distinguish clearly the superior and inferior tributaries, or when some common trunks of tributaries are detected. after the preoperative duplex examination the final decision to perform selective high ligation it is usually taken during the surgical intervention, when we can see clearly the anatomy of the sfj. for this reason the sfj is prepared surgically in a meticulous manner, as when we performed a radical high ligation of the sfj. your observation is right, the term of neovascularization is more adequate, but the term cavernoma is always widespread in literature and for this reason we have used it. the t branch is a branch of a tributary that may be a site of reflux as coming from the bottom of the sfj, sometimes the pudendal or circumflex veins can have this anatomical variation. i answer you with the doubts expressed by jg chandler et al. (jvs 2006) and jj bergan (the vein book 2007): ...frustrated abdominal and pudendal superficial drainage consequent to sfj-tributary ligation might be a principal trigger for recurrences and neovascularization at the operated sfj..., it might be a surgical caused obstructive syndrome to drainage? the histological characteristics of neovascularization (b geier et al., jvs 2006) seem to confirm this hypothesis. on the other hand it is clear that some recurrences are due to inadequate groin surgery, while it seems that dissection techniques in the groin did not influence the clinical and sonographic result at 3 months and at 7 years after redo surgery for recurrent varicose veins (wg mouton, mg de maeseneer et al., vasa 2011). bc disselhof et al. (eur j vasc endovasc surg 2011) evaluate whether ligation of the saphenofemoral junction (sfl) improves the results of endovenous laser ablation (evla) of the great saphenous vein (gsv) in a 5-year randomized clinical trial (rct). the results were: the rate of varicose vein recurrence was similar in both study groups, but it is very interesting to observe that there was less neovascularization in the evla without sfl group (0% vs 33%), but more incompetent tributaries (as an inadequate groin surgery!) and early recanalization at 5-year follow-up than in the evla with sfl group. the problem of the recurrences in the operated groin is very important and unresolved, also for the endovenous ablation techniques, but our surgical experience shows that probably it is a good choice to maintain some tributaries of sfj, if these tributaries are chosen carefully and they cannot cause reflux in the postoperative period. [top] hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: prospective, randomized, controlled trial comparing the effectiveness of adjustable compression velcro wraps versus inelastic multicomponent compression bandages in the initial treatment of leg lymphedema by damstra rj, partsch h. j vasc surg 2013;1:13-9. stefano ricci abstract this study was conducted as a prospective, randomized, controlled trial at the lymphedema department at nij smellinghe hospital in drachten, the netherlands, from january 2010 to august 2011. the study enrolled 30 patients hospitalized for non-operative treatment of moderate to severe lymphedema of the leg, not responsive to ambulatory lymphedema treatment with compression and manual lymph drainage for at least 6 weeks. the participants were randomized into two groups. group a was treated with the juxta-fit acw (circaid medical products, san diego, ca, usa), consisting of an initial protective cotton tube liner covered by an adjustable inelastic compression wrap. the adjustable compression velcro (acv) wrap devices were individually tailored to patient legs. group b was treated by means of a three-component trico imc system (bsn medical gmbh, hamburg, germany) consisting of an initial protective layer (tricofix; bsn medical gmbh) and covered with two layers of synthetic cast wadding (delta-rol s; bsn medical gmbh). two layers of trico (12 cm x 4 m) bandaging material were applied over the synthetic cast wadding. in both groups, the initial systems were removed after 2 h. after the initial application, the patients in group a reapplied acvs in co-operation with the hospital staff, and they were further instructed as to how readjust the straps for the remainder of the study. in group b, the staff applied new bandages during the following 24 h. after application of both compression systems, all patients were encouraged to move as much as possible. no other therapeutic intervention was performed before or during the study period. leg volumetry was performed on both groups before bandage application, after removal of the initial bandages (i.e. 2 h later), and after the second removal (i.e. 24 h later). interface pressures were sampled in both groups by a picopress pressure transducer (microlab elettronica, roncaglia di ponte san nicolò, italy). the median lymphedema leg volume before bandaging was 3570 ml for the acv group, and 3268 ml for the inelastic multicomponent compression (imc) bandages group. after 2 h, a median volume reduction of 3.1% was measured in the acv group compared with 2.4% in the imc group, which was not significant. after 24 h, the median volume reduction was 339 ml in the acv group and 190 ml in the imc group (p the median initial interface pressures were 53 mmhg for acv and 49 mmhg for imc bandages. in the next 2 h, interface pressures dropped significantly: by 26.1% under acv, and 50% under imc (both p in the present study, there was significantly greater edema reduction by acv after 24 h than with the imc bandaging system, despite the same initial compression pressure. patients were allowed to tighten acvs when they felt them loose. this also led to an increase of the working pressure, producing a stronger massaging effect during walking. the acv system was less bulky compared with imc; therefore, it was easier for patients to wear shoes and to walk. so far, acv has been mainly used in the maintenance phase of lymphedema treatment. patients’ involvement in their own treatment is a part of self-management and is becoming more and more common in chronic disease management. in principle, patients who are able to put on their shoes should also be able to apply the acv system. in cases where self-application is a problem, such as extreme obesity, relatives may be able to take over home-therapy. stiff material generally exerts a stronger massaging effect during walking, but leads to an immediate pressure loss due to edema reduction. this disadvantage of pressure loss is compensated by the readjustment of the straps by the patients. cost effectiveness aspect was not included in the study deliberately, although acv is much more expensive than a traditional imc. comment by stefano ricci many lymphedema patients hate bandages when they must be worn for several days, particularly if they must be changed frequently by hospital staff. also, it is tedious to apply and to learn how to apply bandaging; patients often get tired of the bandaging methods and tend to progressively reduce the degree of compression. justa fix acv seems able to overcome these difficulties as patients easily learn how to apply it, it is quickly adjustable and less bulky. this study demonstrates the evident concept that a stiff compression is more effective in lymphedema reduction if it can be adjusted frequently than when remaining fix for a long time; interestingly, this aspect is more important than the pressure produced at application. the cost of this system, was deliberately omitted by the authors; however, it deserves particular attention in the present financial public and private shortage. in fact, the same positive effect of acv may be often achieved by using a two-layer-bandage with an (although reduced) elastic component at a reduced cost. the patient holds the deep layer fixed while the outer layer is applied by the same patient as soon as its pressure is reduced, similarly to what is suggested for the acv device. i agree with the fact that it is difficult to teach how to use a bandage. still, if this is partially elastic, it will not be a problem. in fact, it may have the advantage of positively involving the patient in its own treatment for the future. [top] hrev_master veins and lymphatics 2012; volume 1:e1 [veins and lymphatics 2012; 1:e1] [page 1] veins and lymphatics is taking its first steps stefano ricci ambulatorio flebologico "ricci", rome, italy veins represent an important field of medicine. they are frequently involved in several diseases with a very wide range of severity. at one end of the spectrum, we have thrombosis and post-thrombotic syndrome, while at the other we have telangectasias, and a vast number of other conditions lie between these two extremes. varicose veins are not always severe, but they affect an enormous number of people, with a consequent social and economic burden to society. lymphology is also an important subject. lymphatics play a role in many human diseases but lymphedema is a sort of cinderella disease, neglected by patients, doctors and health care administrators. the name itself shows how little we know; a description of the clinical manifestation has been transformed into the name of the disease. lymphedema is usually considered to be an inevitable event, be it congenital or secondary. its incidence is thought to be growing each year, especially in poorer countries and in the field of oncology. lymphedema treatment is mostly unsatisfactory and costs are high, while patient adherence to treatment is low. few journals specialize in phlebology and not all of them have a worldwide distribution. today, publication in print, although universally accepted, has many limitations compared to the global communication opportunities of the internet, where the exchange of information is almost in real time. other prestigious journals include phlebology as a niche subject and the importance of this must be recognized given the growing interest in veins. however, as this specialization becomes increasingly refined and socially important it demands a more independent voice. there are even fewer journals specializing in lymphology partly because of the problems already set out above but also not least because of the limited funds available. so i strongly believe that there is definitely space for not just one more journal, but for a forum in which we can develop our common scientific interests. it may take some time before v&l takes its proper place beside those more established and internationally recognized reference journals. however, we believe there is still space for a cultural initiative such as the launch of a new journal, while taking advantage of an extremely powerful technological tool, the internet, and the attraction of a new format. naturally, it is up to us to do our job properly with rigor and determination. but we also need to keep our eyes open for new ideas. our editorial board is made up of many of the top phlebologists and lymphologists in the field, and they will supervise the project and guarantee the highest scientific standards. we have chosen to free ourselves from the restraints of traditional publishing and have chosen an online open access only format, a format that in the scientific world offers many important advantages: • peer review • immediate publication • free access • worldwide distribution and availability • the possibility of using color figures, videos, information linkage procedures. we welcome original articles, editorials, reviews, short reports and case reports, as well as invited commentaries. debate and discussion will be encouraged in a correspondence section. in fact, sometimes letters are better able to focus on conflicting aspects of a specific argument, especially when the internet can offer a simple and rapid exchange of ideas. however, open access has a cost. in fact, the advantage of complete and free availability of ideas and experiences is only sustainable through the authors’ participation in covering the costs of processing and publishing their articles. we intend to try to overcome this problem with the help of sponsors willing to support this project. we are optimistic that, once we have a sufficiently high number of articles being presented for publication, the journal can stand on its own feet. at present, we are driven forward by optimism, enthusiasm and confidence in the participation and contribution of our many friends and colleagues around the world. we firmly believe this is a golden opportunity to spread and share our experiences in the field of phlebolymphology through an open access journal. it will not be easy but we believe it is time to rise to the challenge! we warmly invite you to submit one or more papers, taking also advantage of this unique opportunity to share rapidly your work worldwide and last but not the least! currently at no cost. correspondence: stefano ricci, ambulatorio flebologico "ricci", corso trieste, 123 roma, italy. e-mail: vandl@tiscali.it this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s. ricci, 2012 licensee pagepress, italy veins and lymphatics 2012; 1:e1 doi:10.4081/vl.2012.e1 no nco mm er cia l u se on ly hrev_master veins and lymphatics 2013; volume 2:e11 [veins and lymphatics 2013; 2:e11] [page 33] alginate hydrocolloid impregnated zinc paste bandages-an alternative in the management of lymphoedema? franz-josef schingale,1 hugo partsch2 1lympho-opt, clinic for lymphology, pommelsbrunn, germany; 2private practice, vienna, austria abstract several studies have shown an impressive reduction in swelling as a result of compression, and inelastic bandages have become widely accepted as a part of lymphatic decongestive therapy for managing lymphoedema. lymphoedema bandaging is indicated to reduce swelling, improve limb shape, skinand tissue-condition and to ameliorate symptoms such as discomfort. compression therapy for lymphoedema is based mainly on the use of inelastic, short-stretch bandages with high compression, usually protecting the skin with polyurethane foam bandages. in this preliminary report it is shown that completely rigid material like zinc paste applied without padding provides a good level of efficacy. introduction in the management of lymphoedema bandages with high stiffness are traditionally preferred. theoretical reasons for this choice are: i) in contrast to venous diseases in which the hydrostatic problem in the upright position has to be tackled and which need compression mainly during daily activities, lymphatic pathology needs 24 h compression,1-3 at least during the initial treatment phase. therefore our compression pressure should be well tolerated in the lying position and at the same time strong in the upright position, prerequisites that are typically fulfilled by stiff materials; ii) the high massaging effect with movement will stimulate lymphatic drainage by opening initial lymphatics due to the intermittent increase of tissue pressure, by propulsion of tissue fluid into the initial lymphatics and by enhancing the spontaneous rhythmic contractions of lymph collectors.4,5 this effect is certainly much stronger with stiff compression than with a yielding elastic device. due to pascal’s law the energy created by muscle contractions will be transmitted into all directions in a closed container while it would partly be lost if the extremity is encircled by elastic material giving way to each muscle contraction (figures 1 and 2). among the available compression materials zinc paste bandages are certainly the products providing minimal stretch and highest stiffness. up to now reports concerning their use in lymphoedema patients are lacking. in this preliminary report we would like to discuss the potential role of zinc paste bandages in the initial treatment phase of lymphoedema of the lower extremities. based on a case series in which we concentrated on clinical aspects only, advantages and disadvantages of this alternative treatment will be considered. materials and methods in 2009 the alegro® (alegro medical hamburg, germany) alginate zinc bandage (azb) was introduced for treating arm lymphoedema.6 it is a semi-rigid zinc bandage drenched with calcium alginate and hydrocolloid that becomes stiff and inelastic by time. twenty patients (2 males and 18 females) with primary and secondary lymphoedema (stage iicorrespondence: franz-josef schingale, lymphoopt klinik, happurgerstr. 15, 91224 pommelsbrunn, germany. tel.+49.9154.911.200. e-mail: schingale@lympho-opt.de key words: lymph bandages, stiffness, zinc paste, lymphoedema. conference presentation: part of this paper was presented at the international compression club (icc) meeting on stiffness of compression devices, 2012 may 25, vienna, austria (http://www.icc-compressionclub.com/). conflict of interests: the authors declare no potential conflict of interests. received for publication: 31 october 2012. revision received: not required. accepted for publication: 22 january 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright f-j.f schingale and h. partsch., 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e11 doi:10.4081/vl.2013.e11 figure 1. typical tracing of the pressure exerted by a zinc paste bandage in the lying position and during walking on spot immediately after application in a patient with lymphoedema of the leg. supine pressure is 55 mmhg, static stiffness index 10 mmhg. figure 2. pressure curve after wearing a zinc paste bandage for 24 h in a patient with lymphoedema of the leg. lying pressure drops down to 20 mmhg but rises to more than 40 mmhg by standing up. the static stiffness index is more than 20 mmhg. the high pressure amplitudes during walking exert a strong massaging effect. no nco mm er cia l u se on ly conference presentation [page 34] [veins and lymphatics 2013; 2:e11] iii as to international society of lymphology classification) of the upper (n=3) and lower limbs (n=17) received such bandages. the range of age was 28-73 years. azb was used on patients with hard and indurate edema, where conventional multilayer low stretch bandaging had poor results, reducing the circumference of the limb by less than 2 cm in one week. no padding was added. the bandage was applied directly to the skin on the lower leg and forearm. an overlying short stretch bandage without additional compression was applied as the most superficial layer, in order to protect clothes. azb material stuck directly to the skin, without any slippage and was kept in situ for 24-48 h. when the pressure dropped to less than 30 mmhg, the bandage was changed. in 16 cases this happened after 24 h. in 4 cases the edema was so hard, that pressure reduction due to a decrease of edema occurred only after 48 h. sub-bandage pressure was measured on the distal medial leg (b1 point) using picopress® [(microlab elettronica sas, roncaglia di ponte san nicolò (pd), italy)] transducers while volume and circumference of the limb before and after treatment was evaluated by an optoelectronic device (perometer®, pero-system messgeraete gmbh, wuppertal, germany). the zinc paste bandage was only applied on the lower leg. results the reduction of volume depended on the volume of the extremity. in two patients we started the treatment from the first day with zinc bandage, because they were suffering from elephantiasis in primary lymphoedema.7 the residual patients received the zinc bandages 1-3 weeks after initial treatment with conventional bandaging. an example is shown in figure 3. table 1 summarizes the volume reduction obtained with azb after one week. two examples illustrating our experience with zinc paste bandages in patients with severe lymphoedema are presented. he first patient was a 38-year old woman with primary lymphoedema, papillomatosis cutis lymphostatica, lymphcysts and lymphorrhoea with inflammation of the skin (figure 4a). the patient was bandaged with alegro®zinc on the lower leg and long stretch rosidal d (alegro germany) for the thigh. after 11 days papillomatosis was reduced, lymphcysts, lymphorrhoea and inflammation had disappeared (figure 4b). the reduction of circumference was 30 cm in the lower leg and 15 cm in the thigh in only 11 days (figure 5). the volume reduction of the whole leg was 12.810 ml. the second patient, a 23-year old man suffering from primary lymphoedema of both legs was treated with azb on the right lower limb and a conventional lymphological bandage (inelastic, multilayer and multi component bandage)8 on the left lower limb. the results showed a reduction of 3.147 ml (40.1%) in 14 days (figure 6a) with azb and of 1.647 ml (31.3%) by usual bandaging8 (figure 6b). the volume reduction in the first 3 days was much faster on the leg treated with azb. in the patients primarily treated with conventional multicomponent lymph bandages a clear improvement was observed when switching to azb, as demonstrated in the following example. a 65-year old patient suffering from secondary lymphoedema, showed a volume reduction of 618 ml in 19 days (33 ml per day) with conventional bandage. after switching to azb a volume reduction of 275 ml in 3 days (92 ml per day) was recorded (figure 3). this finding is in contrast to the usual volume reduction, which is mostly more pronounced in the initial phase of compression treatment (figure 6). only after azb employment a more pronounced tissue softening took place and the pressure under the bandage showed a dramatic drop (57 mmhg after bandaging and 32 mmhg after 24 h) this reduction was higher than with conventional bandages corresponding to a more pronounced volume reduction (figure 3). with azb inflammation and dermatitis disappeared after 3-5 days, lymphorrhoea stopped after the first bandage and cysts were not visible any more after 7 days of compression. discussion zinc paste bandages with gelatin glue, as previously used, were semi-rigid, unyielding and became totally dry after one day. we used this material for treating venous diseases, but due to the dry material skin irritations occurred sometimes. therefore we changed to bandages with cellulose glue, but their hardening was a limitation again. as any skin injury may lead to dermato-lymphangio-adenitis (cellulites, erysipelas, lymphangitis), clinicians used pure zinc-oxide bandages very seldom in lymphoedema. as alegro® (alegro germany) alginate zinc bandage has a more durable moisture level, the present authors introduced azb also in lymphoedema patients. so far one single study reported about efficacy of azb vs conventional bandaging6 in lymphedema. more comparative data are needed to corroborate the results of our preliminary observational study which confirmed that the stiff material results in better and faster edema and fibrosis reduction than the traditional multilayer bandaging. in venous diseases different studies demonstrated that zinc oxide bandages are well tolerated and very effective. table 2 summarizes some general advantable 2. advantages and disadvantages of zinc paste. advantages of zinc paste good tolerance, no skin irritations observed easy to apply, the patient can move better than with conventional lymphological bandage better and faster results skin care and anti-inflammatory properties increased stiffness, which better supports the muscle pump, which partly explains better edema reduction bandage slippage is of limited relevance, which helps in the maintenance phase and for the swift to medical compression stockings/sleeves disadvantages of zinc paste necessity to re-bandage every 24-48 h in the initial treatment phase, due to fast edema reduction single usage of this kind of bandage makes this treatment quite expensive (the usual lymphological bandages can be washed and re-used several times) table 1. volume (ml) before and 1 week after azb (perometer®, pero-system messgeraete gmbh) treatment (mean+standard deviation) in 20 patients. limb (patience no.) before after difference after one week left leg (n=7) 12,874 ml (±4187 ml) 11,949 ml (±3617 ml) 789 ml (±1224 ml) right leg (n=10) 13,067 ml (±976 ml) 11,955 ml (±3578 ml) 976 ml (±1872 ml) right arm (n=3) 3282 ml (±944 ml) 3090 ml(±929 ml) 192 ml (±127 ml)no nco mm er cia l u se on ly articleconference presentation figure 4. a) before and b) eleven days after treatment. figure 3. slow volume reduction by conventional lymph bandages applied for 19 days, followed by a more intensive effect for the last 3 days when azb (perometer®, pero-system messgeraete gmbh) were applied. figure 5. top: longitudinal profile of leg circumferences (perometer®, pero-system messgeraete gmbh) before (green line) and 11 days after compression therapy. bottom: girth-reduction (40 cm on x-axis corresponds to the height of the knee level). a more pronounced reduction of circumference on the lower leg (azb) than on the thigh (elastic bandage) is clearly visible. figure 6. a) volume reduction achieved by azb (perometer®, perosystem messgeraete gmbh) on the right lower limb; b) volume reduction achieved by conventional lymph bandages (perometer®, pero-system messgeraete gmbh) on the left lower limb. [veins and lymphatics 2013; 2:e11] [page 35] a b a b no nco mm er cia l u se on ly conference presentation [page 36] [veins and lymphatics 2013; 2:e11] tages and disadvantages of zinc paste, which have been highlighted in our clinical practice and in the pertinent literature. conclusions our preliminary results demonstrate that azb (pero-system messgeraete gmbh) seem to be more effective than conventional multicomponent lymph bandages (which include a lot of padding material) in reducing oedema in the initial treatment phase of patients with severe lymphoedema of the extremities. it is hypothesized that this is due to the very high stiffness of the alginate/zinc coated bandage, which is applied directly to the skin without padding. references 1. bates do, stanton awb, levick jr, mortimer ps. the effect of hosiery on interstitial fluid pressure and arm volume fluctuations in breast cancer related arm oedema. phlebology 1995;10:46-50. 2. ko dsc, lerner r, klose g, cosimi ab. effective treatment of lymphedema of the extremities. arch surg 1998;133:452-8. 3. badger cma, peacock jl, mortimer ps. a randomised controlled parallelgroup clinical trial comparing multi-layer bandaging followed by hosiery versus hosiery alone in the treatment of patients with lymphoedema of the limb. cancer 2000;88:2832-7. 4. franzeck uk, spiegel i, fischer m, et al. combined physical therapy for lymphedema evaluated by fluorescence microlymphography and lymph capillary pressure measurements. j vasc res 1997;34:306-11. 5. olszewski wl. contractility patterns of human leg lymphatics in various stages of obstructive lymphedema. ann n y acad sci 2008;1131:110-8. 6. kasseroler r, brenner e. a prospective randomised study of alginatedrenched low stretch bandages as an alternative to conventional lymphological bandaging. support care cancer 2010;18:343-50. 7. international society of lymphology. the diagnosis and treatment of peripheral lymphedema. 2009 consensus document of the international society of lymphology. lymphology2009;42:51-60. 8. wound management association (ewma). focus document: lymphoedema bandaging in practice. london: mep ltd.; 2005. no nco mm er cia l u se on ly hocaoglu c. clozapine-induced rabbit syndrome: a case report definition of the venous hemodynamics parameters and concepts claude franceschi abstract a clear understanding of the physical concepts of the venous hemodynamics improves the knowledge, diagnosis and treatment of the venous insufficiency. for this reason they will be presented, defined and weighted according to their physiologic and pathologic incidence. pressure and energy are central concepts of the fluid mechanics thus to the venous hemodynamics. unfortunately, these concepts are frequently misused because of their confused definitions. force represented by a vector, the force is the magnitude, direction and acceleration of the interaction between two physical bodies. this interaction can be attractive or repulsive. it increases with the rate of change of velocity (v) called acceleration (a), and with the quantity of inertia of the object called mass (m). f=ma acceleration unit (a) is m/s2 (meters per second squared). force unit is the newton (n), i.e. the force that applied to a mass of 1 kg produces an acceleration of 1 m/s2. in addition and in an operative manner, force can be also defined as an entity, which can be measured by a dynamometer. the two definitions are equivalent. energy mechanical energy is the capacity of a physical system to perform work, i.e. the integral of the force over a distance of displacement (newton × meter or joule). it can be expressed in several forms such as heat, electricity, light, mechanical energy, potential energy, kinetic energy, etc. the principle of conservation of energy states that energy is neither created nor destroyed but can only be transformed from one form to another in an isolated system. in venous hemodynamics, the energy is mainly expressed or converted into the forms of potential and kinetic energy. it is called potential energy (p.e.) or stored energy when it refers to the ability of a system to do work due to its position such as gravitational potential energy (g.p.e) stored along the vertical vector of the gravitational acceleration (height) or in internal structure such as elastic potential energy is energy stored in a spring. it is called kinetic energy (k.e.) when it represents the energy of a mass (m) in motion velocity (v). it is a scalar quantity therefore always positive with the same work units such as joules (j) newton × m. k.e.=(1/2) mv2 according to the principle of conservation of energy, p.e. and k.e. being two expressions of the same energy they can be converted between each other while the value of the total energy (t.e.) remains constant. te=p.e+k.e=konst pressures the venous pressure of the lower limbs is made of three main components that vary independently: the gravitational hydrostatic pressure, the residual pressure and the muscular and respiratory pressure, which result from the energy of gravity and pumps (cardiac, respiratory and muscular). definition pressure (p) is force (f) exerted per unit area (s): p=f/s. the international unit is the pascal (pa), which is 1 n/m2 1 torr=133.3224 pa=1 mmhg=1.35 cm h2o. in fluid mechanics, pressure is expressed according to the form of energy, the direction and rate of force, the physical features of the fluid and the solid structures that interact. due to the complexity of the fluid mechanics many equations and laws are described. the main ones are newton, pascal, bernouilli, poiseuille, reynolds, navier-stokes equations. each one relates to a particular aspect of the issue and limited to few and strict initial conditions therefore none of them can measure very accurately the pressure and its various expressions. in practice their approximate values are most of the time sufficient for the understanding and the assessment of hemodynamics, provided they are confirmed by experiment. bernouilli equation initial conditions: i) points 1 (up-stream) and 2 (down-stream) lie on the stream line; ii) the fluid has constant density; iii) the flow is steady; iv) there is no friction. although these restrictions sound severe, the bernoulli equation is very useful partly because of its simplicity to use and partly because it can give great insight into the balance between pressure, velocity and elevation (http://www.princeton.edu/~asmits/bicycle_web/bernoulli.html). total pressure=½+ρv2+ρgh+p=constant v is the flow velocity, ρ is the fluid density (mass per unit of volume) and h is the elevation. ½ ρv2 is called the dynamic pressure (dp) because it arises from the motion of the fluid and relates to the kinetic energy. p is the static pressure (sp) because it increases with the slowing of the flow velocity and relates to part of the dynamic energy stored (converted) into potential energy according to the law of conservation of the energy. notice that the energy dp+sp=konst sometimes called stagnation pressure can be supplied by one or more sources (gravity, the cardiac, respiratory and muscular pumps). gh is the hydrostatic gravitational pressure (hgp) that relates to potential energy of the fluid’s position, ρ density, h height is submitted to the gravitational acceleration g. notice that hgp is not influenced by the flow velocity v. in the venous system, hgp is the most variable component of the venous pressure because it varies with the height of the blood column, particularly at the lower limbs extremities where the pressure changes at the ankle from negative when legs are elevated to 90 mmhg in a still upright position and around 20 mmhg when lying horizontally. this is the reason for the predominance of the venous insufficiency below the knee when this excessive hgp cannot be reduced in upright position. fortunately, the muscular activity (moving, walking, running, etc.) lessens it from 90 mmhg down to 30 mmhg thanks to the venous valves competence that fractionates the pressure column during the muscular contraction (systole) and relaxation (diastole) called dynamic fractioning of the hgp (dfhp). the dfhp impairment is the most frequent cause of the lower limbs venous insufficiency. lateral pressure the pressure exerted by the fluid against the wall of the conduits is called lateral pressure (lp) or parietal pressure. flow regime and pressure lp=sp+hgp when the flow is laminar, i.e. made of parallel layers without disruption. when a critical reynolds number (re) is exceeded the laminar flow changes into a turbulent one. when the flow is turbulent, layers are disrupted; the speed of the fluid at a given point is continuously undergoing changes in static pressure, magnitude and direction. therefore turbulences are responsible for the pressure loss (driving pressure reduction) and for the corresponding converted energy into wall caloric/mechanical stress that could explain part of the wall changes (enlargement, thickening, varices, etc.) when veins are submitted to an excess of flow velocity. reynolds number: v=velocity, d=vessel diameter, ρ=blood density, η=blood viscosity. driving pressure regarding the hemodynamics, the driving pressure (dp) is generally the pressure difference (δp) between the arterial pressure (pa) and the venous pressure (pv) referring to any point along the arterial flow and any other point along the venous flow. it can also be called perfusion pressure or pressure gradient. flow (f) varies according to the resistance (r) between the two chosen points. resistance to the flow the resistance (r) in a conduit roughly obeys to the poiseuille law where the radius (r) variation is greatly predominant to viscosity µ and length because of the fourth power r4. r=µ*8l/(π*r4) residual pressure in the lower limbs, the main resistance to flow is due to the micro-circulation and varies with the microvascular caliber variations. at the venous end of the capillaries, the venous pressure supplied by the arterial pressure is called residual pressure (rp) while the gravitational hydrostatic pressure is due to the height of the venous blood column and varies independently. δp=pa–pv=f*r=f*µ*8l/(π*r4) rp=residual pv=pa–f*r=pa–f*µ*8l/(π*r4) therefore, rp and flow vary mainly with the modification of the microvascular vasomotion. rp is increased particularly by the heat (thermoregulation), inflammation and the muscular activity that dilate the microvascular vessels. a high diastolic flow due to low resistance is shown in daily practice by doppler on the arterial side of the microcirculation. this phenomenon is maximal in arterio-venous fistulae (congenital, traumatic or therapeutic) where the rp may raise up to the arterial pressure and leads to signs of venous insufficiency. rp increases also when a resistant obstacle blocks the venules and/or veins, because it slows the velocity of the microvessels where consequently the resistance decreases according to the poiseuille law and leads to a reflex vasodilatation of the arterioles and micro-shunts opening. whatever the mechanism, this increase of rp is attested by daily practice. this accounts for the venous tributary dilation in case of a venous blockage and is called open vicarious shunts (ovs) because they are forced and overloaded by the consequent raise of rp, not only in the case of a deep venous obstacle but also when the superficial veins are occluded, e.g. after extensive flow ablation of superficial varicose veins. the venous claudication may occur while walking in the case of a venous obstacle because the excessive rp at rest is increased by the additional microvascular dilation and muscular pump pressure. the extreme effect of the downstream resistance excess can lead to an arterial flow stop responsible for ischemic phlegmasia cerulea. muscular pump pressure the peripheral muscles act as an alternative pump (mp) such as the cardiac pump, i.e. contraction (systole) and relaxation (diastole) when the venous valves like the cardiac establish a unidirectional flow. its action is limited to the action of walking, running, etc.). mp contributes to pumping the increased stress flow towards the heart and at the same time fractionates the gsp in order to reduce the venous pressure below the knee in an upright position. the energy supplied by the muscular activity is physiologically converted in a cardiopetal gradient pressure and flow. it can be more or less converted in cardiofugal gradient pressure and flow (reflux) whilst the dfhp is impaired according to the degree of venous valve incompetence. the flow of the superficial veins is not directly activated by the muscular pump (except for the lejars foot sole pump) but may be aspirated through the perforators distally to the pump by the diastolic aspiration effect and proximally by venturi’s effect during the systole. what happens in the case of a superficial venous segment where all the valves are incompetent, from the deep-superficial junction (perforators, sfj, sspj) proximal to the muscular pump down to a deep-superficial junction located distally to the muscular pump? the valve incompetence makes the superficial reflux possible during the mp diastole that aspires back into the deep distal veins, part of the proximal deep venous flow through the proximal incompetent point (called escape point) then into the incompetent superficial segment and finally into the distal deep-superficial junction (called re-entry point whatever the competence of its valves). this phenomenon overloads its physiologic draining flow with deep flow that restitutes back part of the energy lifted up during the systole whilst the dfhp impairment does not permit a distal ghp fractioning. this closed circuit is called closed shunt (cs). therefore the css are overloaded during the diastole of the mp. in case of an obstacle, the ovs are overloaded by the systolic pressure of the mp. both systolic and diastolic effects of the mp on the magnitude and direction of the venous flow is easily assessed by us duplex during rest and stress manoeuvers. squeezing/relaxing the calf is a usual method to test the venous competence but it is not properly physiologic such as the muscular pump activity in the manner that the cardiac massage reproduces the physiologic cardiac activity. some tests such as the paranà manoeuver try to reproduce more closely the physiological body functioning. respiratory pump pressure during breathing, the diaphragm, thoracic, and abdominal muscles activates the variation of the venous volume of the inferior and superior cava vein and right atrium. the respiratory pump plays the role of an additional alternate pump, diastolic during the inspiration and systolic during the expiration. the cardiopetal venous gradient increases during the inspiration thanks to the thoracic volume increase while the abdominal cava vein is gently squeezed by the diaphragm descent. in some extra respiratory circumstances like coughing, weight carrying, defecating, the conjoined contraction of the abdominal, thoracic and diaphragm muscles squeezes the intra-abdominal and intra-thoracic veins especially when the lung are full of air (i.e., at the end of a deep inspiration) and the expiration is blocked by glottis closure. this extreme blocked expiration increases the thoracoabdominal venous pressure leading to a reverse of the cardiopetal gradient of pressure into cardiofugal. the result is venous valve closure preventing the otherwise venous reflux. the test dedicated to detect the venous valve incompetence is called valsalva manoeuver, especially from the proximal ones down to the popliteal vein. this manoeuver is mainly useful for the assessment of pelvis and sfj escape points. cardiac pump pressure the cardiac pump supplies the rp during the left ventricle systole and the right ventricle increases the cardiopetal gradient of the venous pressure during the diastole. the increase of the venous pressure due to the right heart ventricle and valves impairment leading to distal edema is a regular diagnosis. transmural pressure tmp is the key parameter of the venous hemodynamics in terms of tissue drainage and the volume and diameter of the venous compartment. it results from the hydrostatic difference between intravascular lateral pressure (ivlp) and the extravascular pressure (evp) which is the sum of the atmospheric pressure (ath p) and the pressure of the surrounding tissues (tis p). volume and pressure volume and pressure in a system change according to the system features. the venous bed, especially the large and cava veins, shows a low variation of trans-mural pressure respect to the volume thanks a damn effect due to its capacitance (able to store 60-70% of the blood volume), its high passive compliance and the active tone control of the venous wall. this effect is sometimes called reservoir effect. the volume depends on the tmp, the active tone of the muscular media layer and the passive compliance of the adventitial layer. notice that the hgp variations cannot be damped by the reservoir effect because hgp only depends on the height of the fluid and never on its volume (pascal) in contrast with static pressure. capillary pressure at the capillary level the drainage depends not only on tmp hydrostatic components (ivlp and evp), but also on the osmotic gradient on either side of the capillary wall according to the starling law. this is the reason why an excessive osmotic gradient can show the same signs (hampered drainage) as an excessive tmp when the protein rate is too low inside the plasma or excessive inside the interstitial fluids (macro-proteins trapped by lymphatic excessive pressure or lack of lymphatic vessels). references 1. klabunde re. cardiovascular physiology concepts. 2nd ed. philadelphia, pa: lippincott williams & wilkins; 2011. 2. bar–meir g. basics of fluid mechanics (version 0.3.1.1). available from: http://www.potto.org/ accessed: december 21, 2011. 3. tyberg jv. how changes in venous capacitance modulate cardiac output. pflugers arch 2002;445:10-7.[crossref][pubmed] 4. franceschi c. dynanamic fractionizing of hydrostatic pressure, closed and open shunts, vicarious varicose evolution: how these concepts made the treatment of varices evolve? phlebologie 2003;56:61-6. 5. franceschi c. la cure hemodynamique de l’insuffisance veineuse en ambulatoire. j mal vasc 1992;(17):291-300.[pubmed] 6. franceschi c. théorie et pratique de la cure conservatrice et hémodynamique de l’insuffisance veineuse en ambulatoire. precy-sous-thil: editions de l’armançon; 1988. 7. franceschi c. measures and interpretation of venous flow in stress tests. manual compression and parana manoeuver. dynamic reflux index and psatakis index. j mal vasc 1997;22:91–5.[pubmed] [top] hrev_master veins and lymphatics 2017; volume 6:6631 [page 20] [veins and lymphatics 2017; 6:6631] innovation in compression: smart bandage technology to improve bandage application and monitoring jerry hutchinson hutchinson woundtech limited, uk introduction although high compression delivered by elastic bandages or hosiery is widely accepted as the standard first line care for patients with venous disease but without significant arterial impairment1-6 the application of bandages in particular is subject to significant variation. in most cases the interface pressure, effectively the compression dose, is not accurately known and is likely to be different from the ideal graduated compression intended on application.7,8 furthermore, as the dimensions of the affected limb change under the influence of external compression, the interface pressure changes (ref).1 variability in the application and sustainability of interface pressure is likely to lead to variable clinical efficacy, for example, healing rates. indeed, the healing rates reported for vlu vary considerably.9-19 technical solutions to variability in application of bandages include printed ovals or rectangles that change to circles or squares at the correct bandage extension; markings on orthostatic devices that are matched to a scale; bandage application at full stretch. direct measurement of interface pressure may be used on application and for monitoring20 but pressure is usually measured at only one anatomic location. despite these solutions bandage application remains variable, and the application of reduced compression by reduced stretch in the presence of arterial impairment is largely semiquantitative at best. a new technology to report interface pressure laplace’s law governs the calculation of interface pressure applied by a material on a surface with a circular cross section. the accuracy of laplace’s algorithm is known.21 the extension of an elastic material can be measured accurately using strain gauge technology and the tension throughout its range of extension can be measured. the tension value is used with the radius of the surface to derive the interface pressure. this principle has been used to develop a functional prototype smart bandage (sb). the components of sb are an elastic bandage with the desired stretch properties into which three silver strain gauge transducers are knitted (figure 1); a connection point at a bandage extremity; digital electronics to detect the transducer output and wirelessly connect to a user interface; a bluetooth user interface, for example a smartphone or tablet, with an app that reports the consistency and values of applied pressure in real time. pressure is calculated using laplace’s law. the tension in the bandage material is derived from its known properties which are pre-programmed into the electronics. upon application the bandage extension, from which tension is computed, is reported by the transducer. limb dimensions are derived by direct measurement of the patient’s leg and manually entered via the user interface. as the bandage is applied the system uses its integrated algorithm to show a real-time visual display of the accuracy of application, reporting the interface pressure as an absolute value. a colour-based scale shows yellow when pressure is too low, green when it is as intended, and red when over the target value. the bandager can thereby adjust the extension to achieve target pressure in real time. at the time of writing, a functional prototype is developed and is subject to a development agreement with a commercial partner. the anticipated benefits of sb include higher quality of bandage application; real-time monitoring of compression in-use; improved healing through greater accuracy in bandage application and maintenance of dose; ability to account accurately for lower compression in patients with significant arterial impairment; washability in re-usable products. references 1. moneta gl, partsch h. compression for venous ulceration. in: gloviczki p, ed. handbook of venous disorders. 3rd ed. london: hodder arnold; 2009. pp 348-358. 2. mosti g, mattaliano v, polignano r, masina m. compression therapy in the treatment of leg ulcers. acta vulnol 2009;7:1-20. 3. comerota aj. intermittent pneumatic compression: physiologic and clinical basis to improve management of venous leg ulcers. j vasc surg 2011;53:1121-9. 4. kahle b, hermanns hj, gallenkemper g. evidence-based treatment of chronic leg ulcers. dtsch arztebl int 2011;108:231-7. 5. o’meara s, cullum n, nelson ea, dumville jc. compression for venous leg ulcers. cochrane database syst rev 2012;11:cd000265. 6. neumann ha, cornu-thénard a, jünger m, et al. evidence-based (s3) guidelines for diagnostics and treatment of venous leg ulcers. j eur acad dermatol venereol 2016 [epub ahead of print]. 7. lee aj, dale jj, ruckley cv, et al. compression therapy: effects of posture and application techniques on initial pressures delivered by bandages of different physical properties. eur j vasc endovasc surg 2006;31:542-52. 8. dale jj, ruckley cv, gibson b, et al. multi-layer compression: comparison of four different four-layer bandage systems applied to the leg. eur j vasc endovasc surg 2004;27:94-9. 9. ukat a, konig m, vanscheidt w, münter kc. short-stretch versus multilayer compression for venous leg ulcers: a comparison of healing rates. j wound care 2003;12:139-43. correspondence: jerry hutchinson, hutchinson woundtech limited, uk. e-mail: jhutchinson31@gmail.com this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright j. hutchinson, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6631 doi:10.4081/vl.2017.6631 figure 1. functional prototype smart bandage showing three transducers knitted into a compression bandage. no n c om me rci al us e o nly conference presentation [veins and lymphatics 2017; 6:6631] [page 21] 10. watson jm, kang’ombe ar, soares mo, et al. venus iii: a randomised controlled trial of therapeutic ultrasound in the management of venous leg ulcers. health technol assess 2011;15:1-192. 11. weller cd, evans sm, staples mp, et al. randomized clinical trial of threelayer tubular bandaging system for venous leg ulcers. wound repair regen 2012;20:822-9. 12. harding kg, aldons p, edwards h, et al. effectiveness of an acellular synthetic matrix in the treatment of heard-toheal leg ulcers. int wound j 2013;11:129-37. 13. margolis dj, allen-taylor l, hoffstad o, berlin ja. healing diabetic neuropathic foot ulcers: are we getting better? diabet med 2005;22:172-6. 14. franks pj, moffatt cj. health related quality of life in patients with venous ulceration: use of the nottingham health profile. qual life res 2001;10:693700. 15. thomas dr, diebold mr, eggemeyer lm. a controlled, randomized, comparative study of a radiant heat bandage on the healing of stage 3-4 pressure ulcers: a pilot study. j am med dir assoc 2005;6:46-9. 16. benigni jp, lazareth i, parpex p, et al. efficacy, safety and acceptability of a new two-layer bandage system for venous leg ulcers. j wound care 2007;16:385-90. 17. van lijswijk l. multi-centre leg ulcer study group. full-thickness leg ulcers: patient demographics and predictors of healing. j fam pract 1993;36:625-32. 18. lyon rt, veith fj, bolton l, machado f. venous ulcer study collaborators. clinical benchmark for healing of chronic venous ulcers. am j surg 1998;176:172-5. 19. milic dj, zivic ss, bogdanovic dc, et al. risk factors related to the failure of venous leg ulcers to heal with compression treatment. j vasc surg 2009;49: 1242-7. 20. partsch h, mosti g. comparison of three portable instruments to measure compression pressure. int angiol 2010;29:426-30. 21. thomas s. the production and measurement of sub-bandage pressure: laplace’s law revisited. j wound care 2014;23:234-46. no n c om me rci al us e o nly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: one-shot scleroembolization: a new technique for the treatment of varicose veins disease of lower extremities. preliminary results by viani mp, viani gm, sergenti j. phlebology 2013, august 9 [epub ahead of print]. stefano ricci abstract nine patients with reflux from the groin to the knee due incompetence of terminal and pre-terminal valves of gsv were treated. caliber of the gsv at the sfj ranged from 5.6 to 10 mm in standing position (mean 6.4 mm). ceap classification was c2s, in six patients and c5 in three. an endovascular straight 5-french catheter was inserted at the knee in five patients while in the other four cases the great saphenous vein at the knee was isolated surgically. under echography control one standard platinum coil (0.03500 fibered platinum coils boston scientific), 1 mm wider than the caliber of sapheno-femoral junction was then placed 1 cm below the origin of the epigastric vein, causing the prompt occlusion of the terminal portion of the great saphenous vein. a foam injection with lauromacrogol 2% was successively performed through the catheter under echography control, with foam volumes ranging from 4 to 8 cc. the leg was then compressed with an eccentric elastic bandage and the patient was recommended to stay in bed for 30 min; all patients were discharged after a short medical observation (mean time 5 h), maintaining the compression till the following day and changing to stockings class i for the following 15 days. occlusion of the great saphenous vein trunk was immediately obtained in all patients; no perioperative complications have been observed. mean follow-up was three months, occlusion being present in 8 out of 9 patients (one was re treated with foam). no migration of coil or compression of the common femoral vein was registered at three months’ us follow-up. costs are significantly lower when compared to other endoluminal techniques, (radiofrequency, laser or other minimally invasive mechanical treatments), the average cost of a coil being 120 us dollars. comment by stefano ricci this simple method (coil + foam) of achieving gsv occlusion is interesting employing simple non-expensive solutions, needing neither high technology nor a surgical setting. the only uncertainty is related to the possible unwanted mobilization of the coil. although using a coil wider than the gsv caliber, it is not well established what will the behavior of the tool, especially when if gsv is dilated or funnel shaped, considering that the flow direction is toward an increase of caliber, instead toward e smaller caliber, like the normal conditions of coil placement is. naturally, the foam injection has a fixing function, but it would be interesting to state if the coil alone could be blocked in place. if confirmed, it could become an interesting method of achieving gsv segmental blockage in a perspective of gsv stem sparing philosophy (similarly to chiva or isolated junction ligation). reply by the authors i believe that the only actual risk of the procedure is the accidental release of the coil in the common femoral vein. therefore, one-shot scleroembolization has to be performed by a phlebologist who is skilled in endoluminal techniques. for the same reason, during the learning curve i believe it is safer to use controlled-release coils, which are safer, although more expensive. in my opinion, an unwanted mobilization of the coil could happen only if you release a coil with a diameter that is smaller than the one of the saphenous vein. i agree that there are some limitations due to sapheno-femoral junction morphology as you pointed out in your comment, such as a funnel shaped saphenous veins or an aneurysm of the sapheno-femoral junction. in these cases, this technique should not be used. anyway, in the majority of patients, if the coil is released properly, there is a minimal risk of mobilization. in fact, the coil diameter is larger than the saphenous caliber. moreover, you should also consider that the coil is released in a saphenous vein in which the flow is inverted in standing position, due to the incompetence of the terminal and preterminal valves. therefore, in theory in lying position blood flow is towards the sapheno-femoral junction, but venous pressure in the saphenous vein is very low and cannot displace the coil, while in standing position the coil would not be displaced towards the sapheno-femoral junction, but towards the foot, due to flow inversion. foam injection has not a fixing function, but it is used to occlude all the shaft of the saphenous vein, as in traditional sclerotherapy. therefore, one-shot scleroembolization could also be performed according to chiva principles. nevertheless, the more coils are used the more expensive the procedure becomes. as i stated in the article, the coil placement allows using less foam, reduces the passage of foam in the deep circulation and grants a more efficient closure of the sapheno-femoral junction. in conclusion, we need to consider the coil as the endovascular evolution of the surgical knot. [top] hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, double-blind, randomized, placebo-controlled trial by kirsner rs, marston wa, snyder rj, lee td, innes cargill d, slade hb. lancet 2012;380:977–85. stefano ricci abstract standard treatment with infection control, primary dressings, and the application of high-strength compression heals between 30% and 75% of venous leg ulcers. skin autografts, sheets of cultured allogeneic adult keratinocytes, allogeneic neonatal fibroblasts cultured within a bovine collagen matrix have been successively tried with uncertain success. hp802-247 is a novel spray-applied cell therapy containing growth-arrested allogenic neonatal keratinocytes and fibroblasts. in vitro studies have allowed optimization of the cellular formulation to enhance release of essential growth factors including vascular endothelial growth factor, basic fibroblast growth factor, keratinocyte growth factor, transforming growth factor α, and, when the cells are combined, granulocyte-macrophage colony stimulating factor. here is reported a phase 2, multicenter, randomized, placebo controlled trial at outpatient facilities in the usa (34 centers) and canada (one center), between june 15, 2009, and may 5, 2011. eligible patients were at least 18 years of age, with venous reflux confirmed by duplex ultrasonography and up to three venous leg ulcers between the knee and ankle, at or above the malleolus, at least one between 2 and 12 cm2 in area without exposed tendon, muscle, or bone wound duration ranging from 6 to 104 weeks. after a 2-week run-in period during which a cadexomer-iodine dressing was applied together with four-layer compression bandaging, patients were randomly assigned in blocks of five. treatment was with vehicle alone applied every 7 days, or with cells in vehicle (either 0・5×106 cells per ml or 5・0×106 cells per ml) applied either every 7 days or every 14 days, thus creating five parallel groups with a 1:1:1:1:1 allocation. the vehicle consisted of a human fibrinogen solution and a separate human thrombin solution. growth-arrested (80 gy of γ irradiation) neonatal foreskin-derived keratinocytes and fibroblasts in a 1:9 ratio were suspended at double concentration in the thrombin component. the wound surface was treated with sequential single 130 µl sprays (first fibrinogen, then thrombin to cause polymerization). foam dressing (changed at each weekly visit) was added after the matrix had formed on the wound surface, and 4-layer compression bandaging was applied. patients attended weekly assessment visits for 12 weeks, or until healing. a total of 228 patients were enrolled, 205 (90%) patients completed the trial. cells produced a greater reduction in wound area than did vehicle alone during the 12-week treatment period. the dose of 0・5×106 cells per ml every 14 days yielded a 16% greater reduction on average than vehicle, with average decreases in the other dose groups ranging from 7・60 to 11・7% relative to vehicle. for the active treatment groups, we identified no significant effects for either high versus low dose, or for application every 7 days versus every 14 days. at week 12, mean wound area in the group assigned 0・5×106/ml every 14 days was reduced by 91% (sd 21%), compared with 80% (30%) with vehicle, while the mean decrease in area was 87% (sd 20%) for the 0・5×106/ml every 7 days group, 84% (26%) for the 5・0×106/ml every 14 days group, and 87% (23%) for the 5・0×106/ml every 7 days group. overall, patients treated with cells had higher proportions of healed wounds than did those assigned vehicle alone, but only the group assigned 0・5×106/ml every 14 days differed significantly compared with control. pain associated with the treated wound decreased steadily in all treatment groups during the 12-week treatment period. a total of 194 adverse events were spontaneously reported by 100 patients: most resolved, and generally did not interrupt the patient’s continuation in the trial; 18 serious adverse events, one of which (wound infection) potentially related to treatment. immunotoxicity testing did not identify any meaningful treatment-induced alloantibody formation or induction of autoimmunity. results suggest that cell treatment can be expected to close 60–70% of chronic venous leg ulcers of 2–12 cm2 in area within 12 weeks. comment by stefano ricci finding the good solution for healing ulcers is one of the myths of phlebology: an advantage for both patients and industries. due to the large number of subjects presenting ulcers, patients will be advantaged by the discovery of a cheap method while industries look forward to technological suggestions with better gain possibilities. compression treatment is the gold standard for ulcer healing, according to international evidence. its outcome could even be better if compression would be better applied by compression pressure measurement that represents the dosage of this treatment and is the only determinant of compression effectiveness (mosti – phlebology forum, jul-sept 2012). however this treatment is hated both by patients (more the bandage than the hosiery) ugly, uncomfortable, difficult, slow and by industries – low cost, low profits, limited innovations. as a consequence new ideas are interesting and well accepted, often independently from their true efficacy. in this case, ulcers healing time was 21 days shorter with the best treatment compared the control group, a good result but not exciting, considering what above-mentioned about compression. and what about the costs? it would be really interesting to know if, in terms of cost-effectiveness, treatment is worthwhile to shorten the healing time only by 20 days (mosti – phlebology forum, jul-sept 2012). finally, it is surprising to read about 194 adverse events on the 228 randomised patients. even excluding minor events, the more than 5% of new skin ulcers and cellulitis reported are not encouraging at all. reply by the authors (kirsner&slade) venous disease, ulceration and their complications are common, representing a significant public health issue. using a rigorous methodology to study a potential new therapy, we described the best treatment response reported to date for refractory venous leg ulcers. we would characterize this as exciting. not only did patients heal faster but also as mosti fails to point out, substantially more patients healed in a relatively short 12-week study. three weeks less compression therapy is likely to be very meaningful to patients, and healing more refractory patients in a shorter timeframe is likely to be cost effective.1 equally important is that the effect of improvement persisted for at least 6 months after the end of the 12 week study, where the standard care group continued to show 25% fewer wounds healed.2 no amount of additional time with standard care is likely to achieve the same high rates of healing as with cell therapy in the population studied. adverse events with chronic wounds are common, but most of our observed adverse events were simply a reflection of the population under study and the rigor that was used to collect adverse event information. more than 2000 medications were taken by the 228 study participants indicating the health state of these subjects. importantly, there was no pattern or suggestion of adverse events caused specifically by the cell therapy. ideally the most effective and least costly approach to venous leg ulcers should be avoidance. external compression alone may be effective, while in certain cases it will be necessary to ablate the vessel(s) experiencing venous hypertension. we do not yet understand why some wounds fail to heal with standard care. we do know that the longer they remain unhealed, the more resistant they become to therapy.3 chronically open wounds are a burden to the patient, and ineffective treatments are a financial burden to the healthcare system. cell-based therapies offer the possibility of healing more wounds initially, and particularly healing wounds, which have become chronic and resistant to standard care.4 references 1. augustin m, vanscheidt w. chronic venous leg ulcers: the future of cell-based therapies. lancet 2012;380:953-5.[pubmed] 2. kirsner rs, marston wa, snyder rj, et al. durability of healing from spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a 6-month follow-up. wound repair regen 2013;21:682-7.[pubmed] 3. lantis jc 2nd, marston wa, farber a, et al. the influence of patient and wound variables on healing of venous leg ulcers in a randomized controlled trial of growth-arrested allogeneic keratinocytes and fibroblasts. j vasc surg 2013;58:433-9.[pubmed] 4. kirsner rs, marston wa, snyder rj, lee td, cargill di, slade hb. spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, double-blind, randomised, placebo-controlled trial. lancet 2012;380:977-85.[pubmed] [top] hrev_master veins and lymphatics 2013; volume 1:e17 [page 60] [veins and lymphatics 2013; 2:e17] spontaneous thrombosis of primary external jugular veins aneurysms sergio gianesini, erica menegatti, michele zuolo, savino occhionorelli, simona ascanelli, paolo zamboni vascular disease center, university of ferrara, italy abstract external jugular vein (ejv) aneurysms represent a rare condition whose origin, evolution and consequent best therapeutic options still need further investigations. we present herein two peculiar clinical cases. in the first one, an ejv aneurysm developed around a malformed valve which embedded a spontaneous thrombosis. transverse cutaneous nerve compression by the aneurysmatic mass was identified. in the second case, a recurring thrombosed ejv aneu rysm was found pinched among the platysma muscle and the superficial layer of the cervical fascia. a pertinent literature review is also presented in order to interpret the findings herein never previously described. introduction external jugular veins (ejv) aneurysms are isolated saccular or fusiform dilations that are rarely considered to lead to complications.1,2 nevertheless, this general belief is biased by the rareness of the pathological condition, which hasn’t allowed large case series studies so far.3 the ejv aneurysms are usually located at the supraclavicular region and its etiology remains uncertain among congenital (elastic tissue dysplasia) and acquired hypothesis (trauma, inflammation, thoracic outlet syndrome, neoplasms, parietal disease, venous hypertension).4,5 we herein present two peculiar ejv aneurysms clinical cases. in the first one the aneurysm was topographically at the neck mid-portion and associated with a retroauricolar parestesia. the second was responsible for a recurrent swimming-induced thrombosis. a pertinent literature review is presented in ordered to clarify the pathogenetic mechanisms underlying the unusual pathological conditions described herein. case reports case 1: the higher than the usual external jugular vein aneurysm with retroauricular parestesia a 62-year-old female was evaluated for a swelling in the left neck mid-portion, which appeared 1 year prior and that had been slowly but progressively enlarging over time. in the last month the bulging increased faster than before, becoming harder at the compression and associated with a retroauricular parestesia. the patient’s history reported just a goiter under medical control. no previous trauma or chronic illness was reported. blood tests and genetic tests for coagulation disorders were normal. the physical examination revealed a 2.5x3 cm partially compressible non-tender, non-pulsative, fixed swelling, just above the sternocleidomastoid muscle and to the left of a mildly enlarged thyroid gland. no bruit was audible on ausculatation. the bulging was not affected by the valsalva manoeuver, but partially diminished from the standing to the supine position. chest and neck radiographs were normal. ultrasound investigation (ecd) was performed using mylabtm (esaote group, genoa, italy) 70 (7.5-10 mhz linear array), setting the prf (explain abbreviation) between 0.8 and 1.4 khz. ecd revealed a 2.7x3.1 cm ejv aneurysm, partially compressible, filled in by an organized thrombus with initial recanalization signs. the upper and lower ejv thirds were patent but extremely narrow, collapsing whenever moving the patient from the supine to the standing position, not-exhibiting an ecd-detectable flow, even at the lowest prf scaninng. the patient was operated under local anesthesia. a 2 cm long incision was performed on a skin crease at the neck mid-portion. a partially thrombosed ejv aneurysm was found adherent to the transverse cutaneous branch of the great auricular nerve. an accurate dissection identified several tiny aneurysm collaterals, which were embedded in an inflammatory tissue (figure 1). the aneurysm was then ligated at both ends and excised. once the aneurysm was opened, a malformed monocuspid valve was identified in its lower third. the leaflet was enlarged, hypomobile and, surprisingly, reversed upside-down, with the cusp concavity facing the cranial side and filled in by the thrombus (figure 2). during the immediate post-operative time, the retro-auricular paresthesia mildly worsened, totally disappearing at the one month follow up. no others minor or major complications were reported. considering the malformed valve finding, at the 1 month follow up, a detailed ecd evaluation was precisely aimed to detect an eventually present chronic cerebro-spinal venous insufficiency, according to zamboni’s protocol:6 no pathological criteria were reported. at 6 month follow up the patient was clinically and echographically in physiologic conditions. case 2: the swimming-induced recurrent thrombosed external jugular vein aneurysm a 12-year-old female was evaluated for a tiny but bothering black dot on the neck skin. it suddenly appeared to the right of thyroid cartilage while the patient was swimming. the lesion was almost immediately followed by a craniallylocated ejv enlargement, with a consequent pain that forced the girl to get out from the water. patient’s history, blood tests and genetic tests for coagulation disorders were unremarkable. the physical examination identified a 2x3 mm, not compressible, not movable, not pulsating, superficial, nodule-like structure, which was unaffected by active manoeuvres like valsalva or straining. a mildly enlarged ejv was found running cranially to the mass. correspondence: sergio gianesini, vascular disease center, university of ferrara, via aldo moro 8, cona, 44100 ferrara, italy. tel. +39.0532.236524 fax: +39.0532.237144. e-mail: sergiogianesini@hotmail.com key words: external jugular vein, aneurysm, thrombosis. contributions: sg, design, data acquisition, analysis and interpretation, manuscript drafting; em, data acquisition, manuscript drafting; mz, data acquisition; so, sa, analysis and interpretation; pz, design, analysis and interpretation, manuscript revision. conflict of interests: the authors declare no potential conflict of interests. acknowledgments: we thank dr. elly wardle for her english revision of the manuscript. received for publication: 20 may 2013. revision received: 17 june 2013. accepted for publication: 4 july 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s. gianesini et al., 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e17 doi:10.4081/vl.2013.e17 no nco mm er cia l u se on ly case report [veins and lymphatics 2013; 2:e17] [page 61] interestingly, this vein was positive at the milking test, but with a delayed draining. the ecd was performed using the same case 1 setting. it identified a mildly enlarged ejv (diameter, 2 mm), showing a not ecd detectable at all the prf values ranging from 0.8 to 1.4 assessments. the vessel was compressible and ended in saccular thrombosed 1.8x2.7 mm dilation on the superficial layer of the cervical fascia (figure 3). the patient was treated for 1 month by means of low molecular weight heparin at therapeutic dosages. at the end of the therapeutic time, the patient referred a progressive pain disappearance and no abnormal clinical signs were detected. the ecd assessed just a physiological 1mm wide ejv. nevertheless, after another month, the clinical case recurred exactly in the same way, after the patient came back swimming. under local anesthesia a micro-incision was performed above the nodule-like mass. the surgical exploration revealed an ejv 1.5x2 mm aneurysm that was entrapped among the superficial layer of the cervical fascia and the platysma muscle fibers. a delicate isolation led to the aneurysm excision after its both ends and collaterals ligation. the aneurysmatic sac inner inspection identified the spherical-shaped thrombus. neither major nor minor complications were reported. at 7 months follow up, the clinical case never recurred and the patient got back swimming. discussion the ejv aneurysm is an usual pathological condition, whose etiopathogenesis and therapeutic approach still remain unclear.1,7 moreover, just because of this condition rareness, both the clinical consequences and the potential complications of this condition needs further investigations.2,3 the first case presented herein offers several hints for a deeper analysis in future. the ejv usually presents both a bicuspid valve at the subclavian confluence and in its middle portion.8 the higher than the usual ejv aneurysm localization of case 1 coincides with the site of the reversed and malformed valve, found out on the surgical harvesting. the internal and external jugular venous systems constitute collateral circulations with the thyroid veins and several others networks (such as lingual, facial, pharyngeal ones).9,10 we can assume that the patient’s goiter could have constituted an extrinsic compression, thus representing an overload flow source for the jugular system. it is reasonable that this overload then encountered a malformed valve as an obstacle to the drainage. consequently, this led to the increase in valve cusp transmural pressure, which is a well-known triggering factor for both aneurysmatic dilation and thrombotic complications.11 an obvious parallel is provided by the saphenous aneurysms, precisely occurring right after the subterminal valve.12 certainly, it is not possible to discover if that leaflet enlargement and hypomobility is the cause or rather the consequence of the thrombotic pressure. nevertheless, the coincidental aneurysmatic localization in a reversed valve site paves the way for further investigations in the aneurysms origin. moreover, this clinical case points out a never-previously described cause of retroauricular paresthesia. along its course, the ejv crosses the transverse cutaneous branch of the great auricular nerve, running parallel to the latter in its upper third.13 it becomes evident how an inflammatory reaction could be triggered by an enlarging ejv aneurysm, pushing against the nerve, so resulting in a retro-auricular paresthesia. the immediate post-operative paresthesia worsening could be linked to a dissectioninduced mild nerve shock, which spontaneously recovered over time.14 on the other hand, the second clinical case introduces the still unclear pathogenesis of cervical muscle entrapments and anomalies.15,16 many variations have already been reported concerning the ejv, the great auricular nerve and the platysma muscle anatomy.17 the clinical case that was observed could be interpreted as an ejv nutcracker syndrome among a too narrow cervical fascia piercing and the platysma muscle. the head lateral turning during swimming represents a plausible triggering factor for the pathological onset. nevertheless, neither diagnostic nor histologic evaluations allowed us to exclude a congenital or primary venous disease. moreover, to our knowledge, this case depicts a never-previously reported recurrent ejv thrombosis. both the pathological scenarios described herein open up the discussion to what is to be considered as the best therapeutic approach. considering the rareness of the condition, up to now we are unaware of the real thrombotic and embolic risk linked to an ejv aneurysm. in case of thrombosis, we have limited data to properly set our anti-thrombotic measurements. are we going to consider it as a lower limb segmental superficial venous thrombosis and therefore not even administer heparin? or are we ready to face the possible anti-thrombotic collateral effect to counteract a superfifigure 1. intraoperative external jugular vein aneurysm (ejvan.) isolation, crossed by the transverse cutaneous nerve (n.). the great auricular nerve is isolated and gentlylaterally tractioned in order to avoid iatrogenic lesions. many collaterals are embedded inside an inflammatory tissue figure 2. external jugular vein aneurysm post-operative opening. a reversed monocuspid fixed valve with a leaflet thickening is identified, together with the thrombus deposition above it. figure 3. ultrasound pre-operative scanning of a thrombosed 1.8x2.7 mm external jugular vein aneurysm, among the platysma layer and the cervical fascia. no nco mm er cia l u se on ly case report [page 62] [veins and lymphatics 2013; 2:e17] cial venous thrombosis?18 the surgical approach has been considered relatively easily in the few previous reports.7,19,20 nevertheless, our data points out the importance of a delicate dissection because of the possible nervous structures anomalies and adherences to the same ejv:13,17 a potential cause of post-operative complications and legal consequences. the same gold-standard treatment definition appears not to be so scientifically evident: what are the exact surgical indications? the present work added some, yet definitely significant data to the amount of evidence that is still needed on this topic, paving the way for further investigations. conclusions ejv aneurysms represent a rare condition, whose origin still needs further investigations. according to our findings, a previously not so deeply evaluated, hemodynamic role seems to be mainly involved in the pathogenetic mechanism, leading to primary venous aneurysmatic dilations. both the prognosis and, in particular, the thrombo-embolic risk of this condition remain unclear. wider case studies will be required to elucidate the best therapeutic approach. references 1. calligaro kd, ahmad s, dandora r, et al. venous aneurysms: surgical indication and review of the literature. surg 1995:117;1-6. 2. karapolat s, erkut b, unlu y. multiple aneurysms of the left external jugular vein. turk j med sci 2005;35:43-5. 3. ioannou cv, kostas t, tsetis d, et al. external jugular vein aneurysm: a source of thrombotic complication. int ang 2010; 29:284-5. 4. ekim h, özen s. primary venous aneurysm of the external jugular vein. eur j med 2002;7:24-5. 5. battal b, dursun e. external jugular vein aneurysm: clinical and radiologic imaging findings. internet j head neck surg 2009; 3:1a4e. 6. nicolaides an, morovic s, menegatti e, et al. screening for chronic cerebrospinal venous insufficiency (ccsvi) using ultrasound: reccomendations for a protocol. funct neurol 2011;26:229-48. 7. debaiyoti m, bhupendra kj, pankaj kg, anupama t. external jugular venous aneurysm: a clinical curiosity. j nat sci biol med 201;41:223-5. 8. nisihara j, takeuchi y, mijake m, nagahata s. distribution and morphology of valves in the human external jugular vein: indications for utilization in microvascular anastomosis. j oral maxillofac surg 1996;54:879-82. 9. zamboni p, consorti g, galeotti r, et al. venous collateral circulation of the extracranial cerebrospinal outflow routes. curr neurovasc res 2009;6:204-12. 10. werner jd, siskin gp, mandato k, englander m, herr a. review of venous anatomy for venographic interpretation in chronic cerebro-cpinal venous insufficiency. j vasc interv radiol 2011;22:1681-90. 11. karino t, motomiya m. flow through a venous valve and its implication for thrombus formation. thromb res 1984;36:24557. 12. pascarella l, al-tuwaijri m, bergan jj, et al. lower extremity superficial venous aneurysms. ann vasc surg 2005;19:69-73. 13. lawrence e, eicher g, eicher sa. great auricular nerve: anatomy and imaging in a case of perineural tumor spread. am j neuroradiol 2000;21:568-71. 14. sharif-alhoseini m, rahimi-movaghar v, vaccaro ar. underlying causes of paresthesia. in: imbelloni le, ed. paresthesia. intech; 2012. available from: http://www. intechopen.com/books/paresthesia/underlying-causes-of-paresthesia 15. takano t, adachi h. on the anomalies in the infrahyoid muscles expecially in the omohyoid muscle. acta anat nippon 1954; 29:5-6. 16. gianesini s, menegatti e, mascoli f, et al. the omohyoid muscle entrapment of the internal jugular vein. a still unclear pathogenetic mechanism. phlebology 2013. [in press]. 17. horacio j, aboudib jh, cardoso de castro c. anatomical variations analysis of the external jugular vein, great auricular nerve and posterosuperior border of the platysma muscle. aesthet plastic surg 1997;21:75-8. 18. colomina mj, godet c, bagò j, et al. isolated thrombosis of the external jugular vein. surg laparosc endosc pecutan tech 2000;10:264-7. 19. pandey m, kumar p, khanna ak. phlebe ctasia of the external jugular vein. int j surg 2009;19. 20. lee hy, lee w, cho yk, et al. superficial venous aneurysm. l ultrasound med 2006; 25:771-6. no nco mm er cia l u se on ly 429 too many requests you have sent too many requests in a given amount of time. hocaoglu c. clozapine-induced rabbit syndrome: a case report cerebral venous return and high altitude cerebral edema (hace): hypothesis and study protocol francesco prada,1 davide santuari,2 federico legnani,1 massimiliano del bene,1 luca mattei,1,3 luca lodigiani,4 luigi caputi,5 carlo boffano,6 davide vailati7 1department of neurosurgery, fondazione irccs “istituto neurologico c. besta”, milan; 2department of vascular surgery, a.o. s. carlo borromeo, milan; 3università degli studi di milano, milan; 4esaote s.p.a, genoa; 5department of neurology, fondazione irccs “istituto neurologico c. besta”, milan; 6radiology unit, fondazione irccs “istituto neurologico c. besta”, milan; 7intensive care unit, fondazione irccs “istituto neurologico c. besta”, milan, italy background neurological deficits represent the epiphenomenon related to acute mountain sickness (ams),10,11,17 that probably recognize a multifactorial origin. one of the possible causes is an abnormal venous drainage of the cephalic district,11,12,13,14,15 which might lead to intracranial fluid accumulation and extravasation within the interstitial and intra-cellullar spaces, determining cerebral parenchyma edema and development of neurological dysfunction such as gait ataxia, nausea and vomiting, dizziness, impaired consciousness and diencephalic dysfunction.9,18 the blood leaves the brain using the propulsion of the residual return of arterial blood pressure (vis a tergo), supplemented by anterograde postural and respiratory mechanisms (face to face). the latter consists in an increased centripetal venous flow during inhalation, thanks to an increased negative thoracic pressure which determines the intake of blood to the right atrium.16 the supine position favours the cerebral venous flow through the internal jugular veins (ijv). on the contrary in orthostatic position blood outflow is redirected through the vertebral (vv) and the azygos veins (azy). this posterior venous system becomes the main cephalic outflow route.1,2 the extra-cranial (ec) cerebro-spinal venous system (eccsv) form a complex valves deficient vascular anastomotic system with the exception of ijv, which has proximal valve systems approximately in 85% of the population.3 its physiological function is fundamental for the maintenance of normal brain function.4 the combination of morphological and hemodynamic parameters of the echo-color-doppler (ecd) high resolution represents an ideal direct and real-time method for the study of hemodynamics of cerebral venous outflow. indeed ecd has recently shown different posture related patterns of extracranial outflow vicariate in ijv and vv.5,6 furthermore doppler study for chronic cerebrospinal venous insufficiency (ccsvi) has been shown in patients with ms the existence of different hemodynamic patterns of intraand extra-cranial venous reflux and loss of postural regulation of cerebral venous outflow.7,8 the cerebral venous outflow has never been thoroughly studied in a direct, dynamic and continuous manner under physiological conditions nor in conditions of prolonged physical effort and/or at high altitude.9,10 ecd with ijv’s and vv’s assessment seems to be an ideal method to test cerebral venous outflow in those conditions. aims of the study the main aim of the study is to evalute and describe eccsv hemodynamic patterns in a homogenous population of healthy subjects at different altitude and their correlation with eventual development of neurological symptoms due to ams. methods study design and patient population descriptive prospective study. 20 healthy volunteer subjects, age > 18 years or older. procedure the subjects will undergo different clinical and laboratory testing at sea level (milano city circa 120 a.s.l.) and at high altitutude (p.es. capanna regina margherita 4559 a.s.l.). sea level evaluation: neurological evaluation blood test trans-cranial doppler (tcd) sonography: measurements of the mean diameter of the middle cerebral artery (mca) and flow velocity assessment. phased array multifrequency probe. extra-cranial doppler (ecd) sonography: the transducer used at the cervical level it is set at high frequency (7-11 mhz or more), according to the different depth of the veins in respect to the body surface where the transducer is placed. the subject should be investigated in both supine and sitting position (0°and 90°), but it has further been proposed to assess venous flow from the brain with the body positioned at 0°, +15°, +30°, +45°, +90° in both the ijvs and vvs. the extracranial doppler venous examination pathways is performed either on the ijvs and vvs by using both the transversal and/or the longitudinal cervical access. the operator uses minimal pressure over the skin in order to prevent compressing the vein and thereby affecting the measurement. we will assess the following parameters: flow direction, flow velocity, competence of the ijv valve, cross sectional area in relation to change in posture, duplex derived flow-metry and anomalous morphology. hypoxic pre-test with 10% o2 mask, followed by tcd and ecd investigation protocol as described above. high altitude evaluation the same investigations (apart from the hypoxic pre-test) will be perfomed at high altitude (p.es. capanna regina margherita 4559 a.s.l.) tcd and ecd will be perfomed the evening of the arrival at high altitude and between 10 am. and 13 am. the next day before returning down. volunteers will also be evaluated for the assessment of acute mountain sickness with ams questionnaire based on the lake louise score. expected results and impact we expect to be able to evaluate cerebral venous outflow with ecd and obtain ijv and vv measurements in all subjects, both at sea level and at high altitude. all data will be correlated to clinical and test evaluation. assessing the role of ecd in the evaluation of different cephalic venous drainage pattern and/or changes and correlating it with clinical and intrumental findings will lead us to define a new tool to evaluate those patient at risk of developing ams, identifying those patients harbouring venous pattern related to ams. ecd can be a fast, safe, dynamic, feasible and repeatable, relatively economic, precise and accurate tool that might be used both by physicians in a clinical setting as a screening for patients before going at high altitude and to assess pre-clincal symptoms of ams on-field, with the eventual help of tele-medicine. references 1. schaller b. physiology of cerebral venous blood flow: from experimental data in animals to normal function in humans. brain res rev 2004;46:243-60.[pubmed] 2. menegatti e, zamboni p. doppler haemodynamics of cerebral venous return. curr neurovasc res 2008;5:260-5.[pubmed] 3. lepori d, capasso p, fournier d, et al. high-resolution ultrasound evaluation of internal jugular venous valves. eur radiol 1999;9:1222-6.[pubmed] 4. epstein hm, linde hw, crampton ar, et al. the vertebral venous plexus as a major cerebral venous outflow tract. anesthesiology 1970;32:332-8.[pubmed] 5. eckenho je. the physiologic significance of the vertebral venous plexus. surg gynecol obstet 1970;131:72-8.[pubmed] 6. zamboni p, menegatti e, pomidori l, et al. does thoracic pump influence the cerebral venous return? j appl physiol (1985) 2012;112:904-10.[pubmed] 7. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neur neurosurg psychiatry 2009;80:392-9.[pubmed] 8. zamboni p, galeotti r, weinstock-guttman b, et al. venous angioplasty in patients with multiple sclerosis: results of a pilot study. eur j vasc endovasc surg 2011;14-116-22.[pubmed] 9. west jb; american college of physicians; american physiological society. the physiologic basis of high-altitude diseases. ann intern med 2004;141:789-800.[pubmed] 10. dellasanta p, gaillard s, loutan l, kayser b. comparing questionnaires for the assessment of acute mountain sickness. high alt med biol 2007;8:184-91.[pubmed] 11. woodburne rt. essentials of human anatomy. 7th ed. new york, ny: oxford university press; 1983. 12. kaplan ha, browder a, browder j. narrow and atretic transverse dural sinuses: clinical significance. ann otol rhinol laryngol 1973;82:351-4.[pubmed] 13. langfitt tw, tannanbaum hm, kassell nf. the etiology of acute brain swelling following experimental head injury. j neurosurg 1966;24:47-56.[pubmed] 14. lewis sl. aetiology of transient global amnesia. lancet 1998;352:397-9.[pubmed] 15. chung cp, hsu hy, chao ac, et al. detection of intracranial venous reflux in patients of transient global amnesia. neurology 2006;66:1873-7.[pubmed] 16. d’cruz ia, khouzam rn, minderman dp, munir a. incompetence of the internal jugular venous valve: spectrum of echo-doppler appearances. echocardiography 2006;23:803-6.[pubmed] 17. gallagher sa, hackett ph. high-altitude illness. emerg med clin north am 2004;22:329-55.[pubmed] 18. bailey dm, bärtsch p, knauth m, baumgartner rw. emerging concepts in acute mountain sickness and high-altitude cerebral edema: from the molecular to the morphological. cell mol life sci 2009;66:3583-94.[pubmed] [top] hrev_master veins and lymphatics 2012; volume 1:e7 [veins and lymphatics 2012; 1:e7] [page 27] hemodynamic patterns of reflux in primary sapheno-popliteal junction incompetence massimo cappelli,1 ilaria giangrandi,1 fabrizio giannelli,1 raffaele molino-lova2 1private practice; 2don gnocchi foundation, florence, italy abstract duplex ultrasound investigation (dui) has considerably improved the diagnosis of anatomical venous variations in the popliteal region: however, some pitfalls still remain concerning the hemodynamics of incompetent sapheno-popliteal junctions (spjs). aims of this study were to assess the prevalence rates of the hemodynamic patterns of reflux, either diastolic or systolic or both, in a large series of patients with spj incompetence, and to analyze the origin of the systolic components of the reflux. four hundred and fiftythree patients, 83 males and 370 females, mean age 58.0 years±sd 13.8 with primary spj incompetence (512 limbs) underwent preoperative dui using the paranà manoeuvre, a dynamic test able to develop systolic and diastolic pressure gradients through the reflex activation of muscle pumps. of the 512 incompetent spjs, 420 showed isolated diastolic reflux, 9 isolated systolic reflux and 83 systolic reflux followed by diastolic reflux. altogether, 92 spjs over 512 (18%) showed a systolic component of the reflux, which originated from the popliteal vein in 78 cases (15%) and from the gastrocnemius veins (gvs) in 14 cases (3%). in these latter cases, the short saphenous vein and one or more gvs showed a common trunk. our findings show that the detection of a systolic component of the reflux in incompetent spjs is not an uncommon event and suggest that treatment strategy should be differentiated according to the origin of the systolic reflux, given their different hemodynamic behavior. introduction the outcome of short saphenous vein (ssv) surgery is often unsatisfactory owing to the higher complication and recurrence rates when compared to long saphenous vein surgery.1-4 standard surgical technique for the treatment of ssv varicose veins is based upon ssv ligation flush with the popliteal vein (pv) and subsequent ssv ablation.5 however, one of the most frequently reported causes of recurrence is the failure to identify the saphenopopliteal junction (spj),1,2 and the more aggressive surgical dissection seeking for the spj, along with the anatomical complexity of the popliteal fossa, might be responsible for the higher complication rates. the reasons for the failure to locate and identify the spj are, probably, accounted for by the complex embryological development of the popliteal region that may lead to several anatomical venous variations.6 the widespread use of preoperative duplex ultrasound investigation (dui) has considerably improved the diagnosis of the anatomical venous variations in the popliteal region:6-8 however, some pitfalls still remain concerning the hemodynamic behavior of incompetent spjs. in fact, in some patients with primary spj incompetence dui shows a systolic component of the reflux, which occurs during muscle contraction. in this study we systematically examined all incompetent spjs by using the paranà manoeuvre,9 with the aim of assessing the prevalence rates of the hemodynamic patterns of reflux, either diastolic or systolic or both, in a large series of patients with incompetent spj and of analyzing the origin and the direction of the systolic component of the reflux. materials and methods four hundred and fifty-three patients, 83 males and 370 females, mean age 58.0 years±sd 13.8 (min 19, max 89) underwent preoperative dui on 512 incompetent spjs. patients with clinical history and/or instrumental findings suggesting previous deep venous thrombosis or primary deep vein incompetence were excluded from the study. according to the clinical, etiological, anatomical, and pathophysiological (ceap) classification,10 the characteristics of the study sample were: c=26s; e=p; a=s2-4, p17-18; p=r. ultrasound assessment was performed using a high-resolution duplex scanner (esaote ‘mylab 50’, genoa, italy, equipped with a 7.5-12 mhz linear phased-array and a 58 mhz micro-convex probe for imaging, with a 5 and 6.6 mhz doppler, respectively, for flow analysis). in the course of the examination, we systematically performed the paranà manoeuvre,9 a dynamic test able to develop systolic and diastolic pressure gradients through the reflex activation of muscle pumps. specifically the manoeuvre, which was proposed by franceschi in 1997, consists in gently pushing from behind the patient in standing position to shift forward the center of gravity (figure 1). this activates the proprioceptive reflex aimed at maintaining balance and the efferent arch of the reflex results in calf muscle contraction. flow analysis was performed in both cross-sectional and longitudinal scans. results of the 512 incompetent spjs, 420 showed isolated diastolic reflux, 9 isolated systolic reflux and 83 systolic reflux followed by diastolic reflux. altogether, 92 incompetent spjs over 512 (18%) showed a systolic component of the reflux that originated from the pv in 78 cases (15%) (figure 2a) and the gastrocnemius veins (gv) in 14 cases (3%). all the latter cases showed a common trunk formed by the ssv and one or more gvs s (figure 2b). of the 78 cases of systolic component of the reflux originating from the pv, 75 were directed towards the giacomini’s vein (giav) (figure 3a) and 3 towards the ssv (figure 3b). in the 14 cases of systolic component of the reflux originating from the gvs, the reflux was directed towards the giav or the thigh extension of ssv (te-ssv) and the physiological systolic forward flow of gvs directed towards the pv was always detectable (figure 4). table 1 shows the overall distribution of the direction of the 512 refluxes that are schematically drawn in figures 5-7. in 10 of the 56 cases that showed a reflux directed towards the giav during the systole and towards the ssv during the diastole, the giav, along with the systolic ascending flow resulting from a systolic escape point, either the pv or the gvs, also showed a diastolic descending flow. correspondence: massimo cappelli, via datini 46, 50132 florence, italy. tel. +39-055-689713 fax: +39-055-6584891. e-mail: massimo.cappelli@dada.it key words: duplex ultrasound investigation, sapheno-popliteal junction, hemodynamics, systolic reflux. conflict of interests: the authors declare no potential conflict of interests. received for publication: 15 june 2012. revision received: 30 november 2012. accepted for publication: 4 december 2012. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright m. cappelli et al., 2012 licensee pagepress, italy veins and lymphatics 2012; 1:e7 doi:10.4081/vl.2012.e7 no nco mm er cia l u se on ly article [page 28] [veins and lymphatics 2012; 1:e7] discussion in this study we assessed the prevalence of the hemodynamic patterns of reflux in a large series of patients with incompetent spjs and we found that a systolic component of the reflux was present in 18% of cases, suggesting that this is not an uncommon event. systolic components of the reflux in incompetent spjs have already been reported by ourselves (european venous meeting, faro, portugal, 2000, unpublished data) and by cavezzi et al.11 however, in those studies the prevalence of the systolic component was considerably lower (9% and 6%, respectively) when compared to the prevalence found in this study (18%). with regard to our previous study, this discrepancy might be accounted for by the fact that the systolic component of the reflux originating from the gvs was not considered and that the paranà manoeuvre was not performed systematically. in fact, dynamic tests, such as the paranà manoeuvre, mobilize larger volumes of blood in the deep then in the superficial venous system. on the contrary, passive tests, such as the squeezing manoeuvre, mobilize larger volumes of blood in the superficial then in the deep venous system. as a consequence, the pressures developed in the deep venous system using dynamic tests are higher then those developed using passive tests. in terms of general hemodynamics, a systolic component of the reflux is related to the development, during muscular contraction, of a pressure gradient directed from the deep to the superficial venous network. in the case of primary spj incompetence, i.e. without clinical or instrumental signs of previous deep venous thrombosis or of primary deep vein incompetence, the phasic systolic increase in the deep venous pressure may be related: i) either to the increased resistances to the physiological flow directed towards the heart, probably due to an ab extrinseco compression exerted by muscles and/or tendons somewhere along the course of proximal deep veins, or to the presence of small, or relatively small with regard to the flow,12 popliteal and femoral veins; ii) or to anatomical geometrical characteristics of the junction, such as the size or the angle with respect to the popliteal vein axis.13 based upon the above hemodynamic considerations, we can reasonably hypothesize that the systolic component of the reflux originating from the pv and directed towards the giav or the te-ssv represents a derivative way aimed at by-passing the functional or anatomical obstruction of the physiological forward flow in the popliteal or femoral veins. accordingly, this type of systolic reflux should not be interrupted as the suppression of a derivative way might expose the deep venous network to a hemodynamic derangement and, as a consequence, to figure 1. parana manoeuvre (conceived by claude franceschi). figure 2. origin of the systolic reflux. table 1. overall distribution of the direction of sapheno-popliteal junction refluxes. direction total systolic systo-diastolic diastolic short saphenous vein 413 2 1 410 giacomini’s vein 43 5 28 10 giacomini’s vein+ 56 56 0 56 short saphenous vein (giacomini’s vein) (short saphenous vein) no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e7] [page 29] recurrent varicose veins. on the contrary, the systolic reflux originating from the gvs does not represent a derivative way, as documented by the detection in all these cases of the physiological flow directed from the gvs towards the pv. as we found in our series, the systolic reflux originating from the gvs was always directed towards the giav, suggesting that the anatomical characteristics of the junction, and in particular the continuity of the gvs with the giav, might account for the direction of the reflux towards the giav (figure 8). before concluding, other findings of this study deserve some comments. first, with regard to the 56 cases that showed a systolic reflux directed towards the giav and a diastolic reflux directed towards the ssv, they raise the intriguing question of why the systolic reflux was not directed also towards the ssv, in spite of the clear-cut incompetence of ssv valves, documented by the diastolic ssv reflux. actually, in all these cases we found a systolic anterograde flow in the ssv, originating from the foot muscular pump and from the fascial compression of the ssv, with consequent systolic increase in ssv pressure able to counteract the systolic reflux towards the ssv. second, with regard to the 5 cases of isolated systolic reflux directed towards the giav, pieri et al.14 have suggested that the absence of a concomitant systolic reflux directed towards the ssv might be accounted for by the competence of proximal ssv valves, such as the pre-ostial valve. however, this explanation can be considered as satisfactory only in the cases in which the ssv does not show any systolic anterograde flow, while when the ssv shows a systolic anterograde flow, the absence of a systolic reflux directed towards the ssv is accounted for by the systolic anterograde flow itself, independent of ssv valve competence. in conclusion, our findings show that the presence of a systolic reflux in incompetent spjs is not an uncommon event and that the two types of systolic reflux show a different hemodynamics. thus, the operational messages coming from this study are: i) in all cases of spj incompetence, the use of dynamic tests, such as the paranà manoeuvre, to detect and characterize, by its origin and direction, any possible systolic reflux is strongly recommended; ii) surgical strategy for the treatment of incompetent sfj should be differentiated based upon the hemodynamics. however, future studies are needed to confirm our hypothesis on a broader scale and to verify through a randomized controlled trial whether hemodynamic-based surgery15 on incompetent spj might lead to better results than established surgical technique. with regard to endovascular techniques, which always leave an open stump, they might be considered as an alternative approach for the treatment of spj incompetence limited to the figure 3. superficial network involved by the systolic reflux originating from the popliteal vein. figure 4. superficial network involved by the systolic reflux coming from the gastrocnemius vein. figure 5. refluxes in the short saphenous vein. no nco mm er cia l u se on ly article [page 30] [veins and lymphatics 2012; 1:e7] cases with systolic reflux and to those cases with diastolic reflux in which a big giav with descending flow or a common trunk formed by the ssv and one or more gvs warrant an optimal wash out of the stump able to prevent the leukocyte adhesion that triggers the inflammatory cascade leading to recurrences. references 1. winterborn rj, campbell wb, heather bp, earnshaw jj. the management of short saphenous varicose veins: a survey of the members of the vascular surgical society of great britain and ireland. eur j vasc endovasc surg 2004;28:400-3. 2. doran fs, barkat s. the management of recurrent varicose veins. ann r coll surg engl 1981;63:432-6. 3. tong y, royle j. recurrent varicose veins after short saphenous vein surgery: a duplex ultrasound study. cardiovasc surg 1996;4:364-7. 4. critchley g, handa a, maw a, et al. complications of varicose vein surgery. ann r coll surg engl 1997;79:105-10. 5. perkins jm. standard varicose vein surgery. phlebology 2009;24 suppl 1:34-41. 6. farrah j, saharay m, georgiannos sn, scurr jh, smith pd. variable venous anatomy of the popliteal fossa demonstrated by duplex scanning. dermatol surg 1998;24:901-3. 7. vasdekis sn, clarke gh, nicolaides an. quantification of venous reflux by means of duplex scanning. j vasc surg 1989;10:670-7. 8. labropoulos n, leon m, nicolaides an, et al. superficial venous insufficiency: correlation of anatomic extent of reflux with clinical symptoms and signs. j vasc surg 1994;20:953-8. 9. franceschi c. measures and interpretation of venous flow in stress tests. manual compression and parana manoeuver. j mal vascul 1997;22:91-5. 10. porter jm, moneta gl. reporting standards in venous disease: an update. international consensus committee on chronic venous disease. j vasc surg 1995;21:635-45. 11. cavezzi a, tarabini c, collura m, et al. hémodynamique de la jonction saphénopopliteé: évaluation par ‘echo-doppler couleur. phlébologie 2000;53:15-22. 12. blanchemaison p. physiopathologie de la petite veine saphène. phlébologie 1997;50 suppl:501-2. 13. franceschi c, zamboni p. principles of venous hemodynamic. hauppauge, ny: nova science publisher, inc; 2009. 14. pieri a, vannuzzi a, duranti a, et al. la valvule prè-ostiale de la veine saphène externe. phlébologie 1997;50:343-50. 15. franceschi c. theorie et pratique de la cure conservatrice et hemodynamique de l’insuffisance veineuse en ambulatoire. précysous-thil: editions de l’armançon; 1988. figure 6. refluxes only in the giacomini’s vein. figure 7. refluxes in both giacomini’s and short saphenous vein. figure 8. angle between the grastrocnemius vein and the giacomini’s vein. no nco mm er cia l u se on ly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: defence’s argument for stripping without high ligation (plaidoyer pour le stripping sans crossectomie) by creton d. phlébologie 2013;66:49-53. stefano ricci abstract stripping without high ligation (hl), although commonly practiced by many centers, is still disputed. it is now assumed that hl is not necessary when gsv incontinence is not due to junction incompetence but depends from perineal, giacomini, perforating or lymphatic-ganglion veins. following the traditional knowledge, leaving a long stump at the junction, like after a stripping without hl or an endovascular procedure should be followed by a high incidence of recurrence. surprisingly, 6 months and 2 years follow up stripping + hl versus laser randomized studies do not show any difference in recurrences. moreover, 2 and 3 years follow up randomized studies comparing stripping + hl versus radiofrequency report similar results. finally, the closure fast study, concerning 295 gsvs shows very good results at 3 and 5 years. at the opposite it is now proved that hl induces neovascularization, as in the evolves study or a recent 5 years follow up study1 ( 33% in hl versus 0% in no hl). stripping without hl was studied in 195 cases with recurrence in 1.8% at two years,2 and in a randomized trial comparing stripping with (60 cases) and without (60 cases) hl:3 at 8 years f.u. clinical recurrence was 29% versus 9.8% , while ultrasound showed 32.2% versus 11.4% recurrences. in the author’s experience of 8595 cases from 1997 to 2008, the stripping without hl replaced totally the traditional technique since 2005. comment by stefano ricci this paper touches one of the most respected dogmas of phlebology (and vascular surgery): the junction must be fully dissected and all the tributaries must be interrupted. as underlined by the author, ultrasound facilities and favorable results of endovascular procedures (including sclerotherapy) show that an open residual junction not necessarily correspond to a surgical failure. this probably may explain why so many patients badly operated (with long residual stumps) live and run happily all around. the reason why other long stumps develop recurrences is not clear, as many other aspects of varicose disease. as in the comment published for casoni’s paper (bybliolab 2014), it is a pity that the authors did not cite, in particular, dortu’s pioneering work, published on the french journal phlébologie,4 concerning 596 patient operated by what he called supra-fascial crossectomy. minumum follow up was three years. over 125 cases (149 limbs), blindly chosen inside the patients list of the period 1982-1988, he could find 146 very good results, 2 recurrences on posterior accessory and 1 on anterior accessory (15 years after). from the technical point of view, it would be interesting to know where the skin incision is made (if low may be more visible), how large is it, how long the residual stump should be. and what about the anterior accessory saphenous vein (the most common source of recurrence)? should it be spared? moreover, are there cases (other than the ballooning dilatations you cited) where hl is better indicated, like f.e. when a refluxing tributary is present? references 1. disselhoff bc, der kinderen dj, kelder jc, moll fl. five years results of a randomized clinical trail of endovenous laser ablation of the great saphenous vein with and without ligation of the saphenofemoral junction. eur j vasc endovasc surg 2011;41:685-90.[abstract][pubmed] 2. pittaluga p, chastanet s, guex jj. great saphenous vein stripping with preservation of the sapheno-femoral confluence: hemodynamic and clinical results. j vasc surg 2008;47:1300-4.[abstract][pubmed] 3. casoni p, lefebvre-vilardebo m, villa f, corona p. great saphenous vein surgery without crossectomy. j vasc surg 2013;58:173-8.[abstract][pubmed] 4. dortu j. la crossectomie sus-fasciale au corse de la phlebectomie ambulatoire du complexe saphenien interne à la cuisse. phlébologie 1993;46:123-37.[pubmed] [top] early access veins and lymphatics editorial the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. eissn 2279-7483 https://www.pagepressjournals.org/index.php/vl/index publisher's disclaimer. e-publishing ahead of print is increasingly important for the rapid dissemination of science. the early access service lets users access peer-reviewed articles well before print / regular issue publication, significantly reducing the time it takes for critical findings to reach the research community. these articles are searchable and citable by their doi (digital object identifier). veins and lymphatics is, therefore, e-publishing pdf files of an early version of manuscripts that have undergone a regular peer review and have been accepted for publication, but have not been through the typesetting, pagination and proofreading processes, which may lead to differences between this version and the final one. the final version of the manuscript will then appear in a regular issue of the journal. e-publishing of this pdf file has been approved by the authors. all legal disclaimers applicable to the journal apply to this production process as well. veins and lymphatics 2023 [online ahead of print] to cite this article: andrea migliorelli, andrea ciorba. cerebral venous outflow abnormalities and inner ear: an underestimated piece of the puzzle? veins and lymphatics. 2023;12:11585. doi:10.4081/vl.2023.11585 ©the author(s), 2023 licensee pagepress, italy https://www.pagepressjournals.org/index.php/vl/index early access veins and lymphatics editorial the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. cerebral venous outflow abnormalities and inner ear: an underestimated piece of the puzzle? andrea migliorelli, andrea ciorba ent & audiology unit, department of neuroscience and rehabilitation, university hospital of ferrara, italy corresponding author: andrea ciorba, audiology unit, department of neuroscience and rehabilitation, university hospital of ferrara, 44124 ferrara, italy. e-mail: andrea.ciorba@unife.it mailto:andrea.ciorba@unife.it early access veins and lymphatics editorial the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. chronic cerebrospinal venous insufficiency (ccsvi) is a medical disorder initially documented by zamboni, which is distinguished by the impeded drainage of cerebrospinal fluid through the extracranial venous system. this obstruction mostly arises from the constriction or blockage of veins located in the cranial region and neck. this syndrome has the potential to result in the development of collateral circles, venous reflux, and iron accumulation within the central nervous system1,2. in the year 2011, a set of five ultrasonography parameters were identified and published, which precisely indicate anatomical and functional changes in the venous blood flow within the neck. these parameters were essential in establishing the distinct characteristics associated with ccsvi. the most suitable approach for investigating ccsvi involves the assessment of venous flow using echoenhanced doppler, in conjunction with transcranial doppler. this combined method enables the evaluation of both deep cerebral veins and potential reflux. the role of ccsvi has been investigated as a potential etiological component in the development of many neurological and/or neurosensory conditions, including multiple sclerosis (ms)2-4. nevertheless, in recent years, some investigations have also established a potential correlation between the existence of ccsvi and inner ear disorders (ied). the venous drainage of the inner ear primarily consists of three veins: the cochlear aqueduct vein, also referred to as the cochlear canaliculus vein; the vestibular aqueduct vein; and the labyrinthine vein, alternatively known as the internal auditory vein. the venous drainage occurs via the inferior petrous sinus, which ultimately connects to the internal jugular vein (ijv)5-9. in a preliminary investigation conducted by menegatti et al.4, it was shown that individuals diagnosed with both ms and ied had a greater prevalence of ccsvi as measured by abnormal internal jugular vein (ijv) function, in comparison to a control group consisting of individuals without any known health conditions. the authors have provided evidence to support the notion that both groups had a notably larger occurrence of valvular system in the ijv compared to healthy participants. furthermore, it was observed that these patients exhibited a malfunctioning valvular system, characterized by a higher prevalence of monocuspid valve. undoubtedly, meniere's disease (md) has garnered significant attention from the scientific community as one of the most prominent manifestations of ccsvi. md is a clinical disorder distinguished by symptoms such as vertigo, sensorineural hearing loss, and tinnitus, as evidenced by several scholarly sources7-12. at present, the genesis of md remains uncertain. among the several explanations proposed, one of the most widely recognized in the academic literature is the hypothesis early access veins and lymphatics editorial the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. suggesting that md may be attributed to the inner ear's excess accumulation of endolymph, leading to the development of a condition known as endolymphatic hydrops (eh). according to some reports, the presence of an obstruction in the extracranial venous outflow may eventually lead to intracranial venous hypertension; this, in turn, can impede the reabsorption of cerebrospinal fluid (csf), resulting in an elevation of csf pressure. consequently, these changes in pressure could give rise to variations in endolymphatic and perilymphatic pressures. some authors have also attributed the hydropic ear to a dysregulation/impairment of the inner ear blood flow7,13, in particularly reporting that a venous obstruction may cause changes in the inner ear microcirculation, consequently hampering the function of the stria vascularis, and therefore of the outer and inner hair cells, as well as of the saccular, utricular and ampullary hair cells13. interestingly, it has been suggested that the presence of distinct ultrasonography ccsvi vascular patterns may be associated to the manifestation of different clinical disorders, such as ms and md. in the disease known as ccsvi the duration of blood flow via the neck is extended primarily as a result of functional stenosis caused by either the inadequate opening of faulty jugular valves or muscular entrapment. the ms pattern is distinguished by stenosis in the j1 segment (located at the confluence with the brachio-cephalic venous trunk), alterations of the trunk in the j2 segment (associated with the ipsilateral thyroid lobe), a higher occurrence of alterations in the medial-distal j1-j2 segments, and the presence of compensatory collaterals along with the vertebral venous system. the md pattern is distinguished by the presence of modified trunks in the j3 region, specifically in the superior segment located at the carotid bifurcation and the mandibular angle. additionally, there is a higher occurrence of medial-proximal modifications in the j3-j2 region, together with vertebral venous hyperplasia, without any other observable collateral vessels8. according to the available literature1,2, percutaneous angioplasty (pta) has demonstrated excellent outcomes as the sole treatment for md, making it the only ied to be effectively managed by this approach. specifically, in 2014, bruno et al. conducted a pta procedure on the ijv and azygos vein in patients with both md and ccsvi. their study reported favorable outcomes in terms of the severity of symptoms and the rate of recurrence. the potential involvement of cerebral venous outflow abnormalities could be considered also in the pathogenic mechanism of further neurosensory diseases, including other ied disorders; in this way, some authors have also considered a possible link between ccsvi and sudden sensorineural hearing loss (ssnhl)5,14. the etiology of ssnhl remains unknown and continues to be a subject of ongoing early access veins and lymphatics editorial the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. scholarly discourse. the vascular hypothesis (the impairment of the cochlear microcirculation) is widely supported as one of the potential etiological factors contributing to the development of this disease. due to this rationale, certain researchers have also explored a potential correlation between severe ssnhl and ccsvi. the initial research findings indicate an elevated occurrence of ccsvi in individuals with severe ssnhl compared to those without the condition, as evidenced by some studies4,5,15. despite the intriguing and encouraging first findings, the current body of literature lacks a substantial number of publications that assess the true impact of venous outflow blockage on the development of ssnhl. furthermore, in recent studies, a possible correlation has been established between ccsvi and the occurrence of recurrent benign paroxysmal positional vertigo (bppv)6. the etiology of recurrent bppv as per other inner ear disorders, remains unknown at now. nevertheless, some investigators have proposed the notion of inner ear microcirculation impairment as a potential mechanism. it is possible to hypothesize that a slowed venous drainage may damage the inner ear at different sites; if the damage is prevalent at the level of the stria vascularis, this could cause md, while if the injury is prevalent at the level of the utricular macula, this could cause damage to the neuroepithelium and subsequent otolithic detachment generating recurrent bppv1,4. in summary, our current understanding of the pathophysiology of ied remains limited15-19. given the intricate nature of the inner ear circulation and the challenges associated with its in vivo assessment using current diagnostic methods, drawing definitive conclusions regarding the role of inner ear microcirculation in these disorders remains challenging. enhancing our comprehension of the correlation between venous blood flow and ied could be very important for advancing our understanding of the pathophysiology of ied and subsequently assessing prospective targets for therapeutic intervention. early access veins and lymphatics editorial the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. references 1) zamboni p. the big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. j. r. soc. med. 2006;99:589–93. 2) zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry. 2009;80:392-9. 3) zamboni p, morovic s, menegatti e, et al. screening for chronic cerebrospinal venous insufficiency (ccsvi) using ultrasound--recommendations for a protocol. int angiol. 2011;30:57197. 4) menegatti e, tessari m, vannini me, et al. high resolution m-mode evaluation of jugular vein valves in patients with neurological and neurosensory disorders. curr neurovasc res. 2017;14:31622. 5) ciorba a, tessari m, mazzoli m, et al. cerebral inflow and outflow discrepancies in severe sudden sensorineural hearing loss. curr neurovasc res. 2018;15:220-5. 6) ciorba a, tessari m, natale e, et al. cerebral outflow discrepancies in recurrent benign paroxysmal positional vertigo: focus on ultrasonographic examination. diagnostics (basel) 2023;13:1902. 7) alpini dc, bavera pm, di berardino f, barozzi, s., et al. bridging the gap between chronic cerebrospinal venous insufficiency and ménière disease. veins and lymphatics 2016;5:1-8. 8) bavera pm, di berardino f, cecconi p, et al. chronic cerebro-spinal insufficiency in multiple sclerosis and meniere disease: same background, different patterns?. veins and lymphatics 2017;6:14. 9) toro ef, borgioli f, zhang q, et al. inner-ear circulation in humans is disrupted by extracranial venous outflow strictures: implications for ménière’s disease. veins and lymphatics 2018;7:1-12. early access veins and lymphatics editorial the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 10) frau gn, pagani r, maronato f, et al. the role of omohyoid muscle entrapment of the internal jugular vein and is surgical transection in ménière’s disease and other inner ear disorders. veins and lymphatics 2019;8:1. 11) müller lo, zhang q, contarino c, et al. multi-compartment mathematical model for cerebrospinal fluid mechanics coupled to the systemic circulation: application to transverse sinus stenosis. veins and lymphatics 2019;8:1. 12) bruno a, califano l, mastrangelo d, et al. chronic cerebrospinal venous insufficiency in ménière’s disease: diagnosis and treatment. veins and lymphatics 2014;3:1-4. 13) foster ca, breeze re. the meniere attack: an ischemia/reperfusion disorder of inner ear sensory tissues. med hypotheses. 2013;81(6):1108-15. 14) alpini d, bavera pm, di berardino f, barozzi s, cesarani a. bilateral sudden sensorineural hearing loss and chronic venous cerebrospinal insufficiency: a case report. phlebology. 2013;28:2313. 15) tessari m, ciorba a, mueller lo, et al. jugular valve function and petrosal sinuses pressure: a computational model applied to sudden sensorineural hearing loss. veins and lymphatics 2017;6:16. 16) zamboni p, menegatti e, conforti p, et al. assessment of cerebral venous return by a novel plethysmography method. j vasc surg. 2012;56:677-85. 17) veroux p, giaquinta a, perricone d, et al. internal jugular veins out flow in patients with multiple sclerosis: a catheter venography study. j vasc interv radiol. 2013;24:1790-7. 18) zamboni p, galeotti r, menegatti e, et al. a prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. j. vasc. surg. 2009;50:1348–58. early access veins and lymphatics editorial the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 19) zamboni p, galeotti r, salvi f, et al. effects of venous angioplasty on cerebral lesions in multiple sclerosis: expanded analysis of the brave dreams double-blind, sham-controlled randomized trial. j endovasc ther. 2020;27:1526602819890110. stefano ricci part ii: history of local anesthesia stefano ricci the success of the discovery of the effect of cocaine, announced in september 15th1 was so immediate that already the 11th of october 1884 a report on the event appeared on the new york medical record2 followed by koller’s publication in lancet.3 the community was stroked by the novelty, which was rapidly applied to other mucous membranes (nose, mouth, larynx, trachea, rectum and urethra). after one year more than 100 articles had been published in the scientific literature of europe and america.4,5 in december 1884, at the new york roosevelt hospital outpatient department, william halstead and his associates (r. hall in particular) were able to obtain the block of the sensory nerves of the face and the arm;6 after repeated self-experimentation trials of the anesthetic power of the solution, they demonstrated that the anesthetic effect of cocaine could be transmitted to deeper structures, in all the parts of the body, through an injection who could block the transmission of the nervous sensation.2 in 1885 halstead published his practical comments on the use and abuse of cocaine:7,8 based on the experience of more than 1000 of cases treated in local anesthesia at the johns hopkins hospital. he submitted to publication very few other papers on the subject and his contribution to the development of local anesthesia was stated only in later years. however from unpublished data it is evident that many of the further evolutions: oral and dental local anesthesia; brachial plexus, posterior tibial nerve, pudendal nerve blocks; skin anesthesia with dilute solutions, prolongation of anesthetic effect reducing circulation rate. halstead is one of the most important surgeons of american medical history. he was able to hide, although not completely, the tragic event of becoming addicted to cocaine as a consequence of self-experimentation. it seems that he could obtain cocaine weaning, but at the price of a morphine dependence for the rest of the life. many other colleagues involved in the initial experimentation experienced tragic cocaine addiction too.2,4 carl l. schleih, a german surgeon, suggested the possibility of administrating local anesthesia by direct tissues infiltration: he tested a diluted cocaine solution (1/2 gram × 1000 cc of saline) announcing at the surgical congress in berlin (1892) that narcosis was no longer justified; his revolutionary idea was strongly rejected at that time.9 broun, in 1900, demonstrated the efficacy of adrenaline association to anesthetic solutions for obtaining the chemical lace effect, in place of the elastic lace used till then, with the purpose of getting better effect and lesser toxicity.10 spinal anesthesia, although promptly suggested by corning,11 ought to wait 14 years to obtain a clinical application. in 1899 in kiel, august bier12 tried to inject cocaine through lumbar puncture in 6 patients obtaining a very poor anesthesia, but rather vomit and headaches. he decided then to experience personally the method allowing his assistant, dr. hildebrandt, to perform on him a lumbar injection (the assistant too received on turn the same treatment by bier). bier noted after 23 minutes: a strong blow with an iron hammer against the tibia was not felt as a pain. after 25 minutes: strong pressure and pulling on a testicle were not painful.12 that night both complained a terrible headache which lasted 9 days, correctly ascribed to the spinal liquid leakage.13 the clinical use of spinal anesthesia will be developed slowly by the time, with the improvement of quality of the drugs and instruments. despite it's beneficial effects, cocaine evidenced heavy limits for the toxicity and the addition risks. in the first 7 years of its clinical use, at least 13 cases of death were reported.14 this strongly stimulated the search of an ideal substitute of cocaine; once discovered it's chemical structure (methyland benzoylester of the alkaloid egconin), more than 100 compounds were tested, until procaine was found, by einhorn in 1904.15 procaine has been the synonymous of local anesthesia for nearly half a century due to its effectiveness, devoid from the toxic effects of cocaine. in 1948 löfgren and lundquist, while studying the alkaloid gramine, succeeded in synthesizing lidocaine which turned out to be strong, stable, rapidly diffusing in tissues, with low toxicity.16 all the local anesthetic agents subsequently developed trying to enhance the effectiveness and reduce the collateral effects (mepivacaine, bupivacaine, ropivacaine) belong to this chemical family. differently from cocaine, all the local anesthetic agents are devoid from potential habituation. the clinical demand of agents fit to achieve trans-dermal anesthesia brought to the development (1994) of a cream, emla (acrostic of eutetic mixture of lidocaine and prilocaine), based on an emulsion oil-in-water of two anesthetic agents. inside the small drops of the emulsion a very high concentration of the agents is present , while the overall concentration is very low.17 the maximum depth of anesthesia achievable is approximately 5 mm, very interesting for superficial skin lesions and limited superficial surgery. references noyes hd. the ophthalmological congress in heidelberg. med rec 1884;26:417-8. olch pd. william s. halsted and local anesthesia: contributions and complications. anesthesiology 1975;42:479-86.[pubmed] koller c. on the use of cocaine for producing anaesthesia on the eye. lancet 1884;2:990-2. rutkov im. surgery: an illustrated history. st. louis: mosby-year book; 1993. de jong rh. local anesthetics: from cocaine to xylocaine. in: local anesthetics. st. louis: mosby-year book; 1994. pp 4-5. hall rj. hydrochlorate of cocaine. n y med j 1884;40:643-4. halsted w. practical comments on the use and abuse of cocaine, suggested by its invariably successful employment in more than a thousand minor surgical operations. ny med j 1885;42:327. nunn db. dr. halsted’s addiction. john hopkins adv stud med 2006;6:106-8. goerig m. carl ludwig schleich and the introduction of infiltration anesthesia into clinical practice. reg anesth pain med 1998;23:538-9.[pubmed] bonica jj. cancer pain. in: bonica jj, ed. the management of pain. 2nd ed. philadelphia-london: lea-fibiger; 1990. pp 400-455. corning jl. spinal anaesthesia and local medication of the cord. ny med j 1885;42:483. bier akg. experiments in cocainization of the spinal cord, 1899. in: faulconer a, keys te (trans). foundations of anesthesiology. springfield, il: charles c. thomas; 1965. pp 854. calverley rk. anesthesia as a specialty: past, present, and future. in: barash pg, cullen bf, stoelting rk, eds. clinic anesthesia. 3th ed. philadelphia, pa: lippincott-raven; 1996. pp 3-28. petersen rc. history of cocaine. nida res monogr 1977;series 13:17-34.[pubmed] link wj. alfred einhorn, sc. d: inventor of novocaine. dent radiog photog 1959;32:1-20. löfgren n, lundquist b. studies on local anaesthetics. svenks kem tidskr 1946;58:206-17. emla. astra zeneca in anesthesia. summary of products characteristics. zeneca s.p.a., bisaglio (mi), italy. available from: http://www.astrazeneca.co.uk/medicines/neuroscience/product/emla [top] hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: drop foot, a rare complication following müller’s phlebectomy by otters efm, van neer pafa. phlebology 2012;27:1-2. stefano ricci case report a 43-year old woman had previously undergone bilateral surgical stripping of the great saphenous vein and the right small saphenous vein and subsequent sclerottherapy. she later presented with reticular visible asymptomatic varicose veins on the dorsolateral side of the right upper leg up to shortly below her knee. a phlebectomy was performed by local anesthesia (non-tumescent) with approximately 15 cm3 lidocaine 1%. immediately after phlebectomy, the patient noticed weakness of the right foot, right foot drop, without neurological pain. the drop foot disappeared spontaneously after several hours without therapy. the sciatic nerve runs behind the femur from the buttock to the lower thigh where it divides into the common peroneal nerve (cpn) and tibial nerve. the cpn then descends along the lateral side of the popliteal fossa to the head of the fibula. it winds round the head of the fibula and divides into the superficial peroneal nerve and the deep peroneal nerve. the deep peroneal nerve is responsible for dorsiflexion of the foot. injury to this branch produces weakness or paralysis of the muscles responsible for these actions. in this case, the anesthesia infiltrated around the fibula head caused temporary blockage of the cpn. when operating in the field of the lateral knee, the area around the fibula head should be avoided or managed with extreme caution. comment by stefano ricci muller’s phlebectomy is easy, safe, and effective. as for all the handicrafts, craftsmen must care for details. as an example, many can make a pizza, but only a few people can make a good pizza. robert muller (unfortunately not cited in references) described many of these details and many others were later reported by his pupils. but it is ourdestiny that, in the field of medicine, the pearls are lost over time because of a kind of bibliographic laziness. this is the case of the anesthesia used for this patient: a concentration of 1% lidocaine is very high, given that a dilution to 0.4 (or lower) has been shown to be completely adequate. at this concentration, the nerve is more easily involved in infiltration. furthermore, injections should remain superficial (subcutaneous) and not perforate the fascial sheet covering the nerve structures. finally, surgeons should always be aware of the potential dangers in particular areas (head of fibula, foot, anterior aspect of tibia, distal ssv) when performing muller’s phlebectomy. this case report has the merit of reminding us of some of those forgotten details. final remark: muller is a french swiss and the u is simple; another sign of its bibliographic oblivion. reply by the author these comments were sent to the author but no reply arrived till now. [top] hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: the office based chiva by passariello f, ermini s, cappelli m, delfrate r, franceschi c. j vasc diagnostics 2013:1:13-20. stefano ricci abstract the office based (ob) – chiva (conservative and hemodynamic treatment of venous insufficiency in outpatients) is a slightly modified chiva strategy designed to use some technical facilities adopted in ablative procedures. currently available choices for chiva crossotomy are: section ligature, isolated ligature, the clip and the triple saphenous flush ligation (tsfl) technique. the ob-chiva was introduced in order to reduce the required resources and generic surgical risk, especially risks associated with chiva crossotomy. in addition, ob-chiva tries to answer the often faced but never solved issue of a minimally invasive surgical chiva intervention. it is not only a technical but rather a conceptual variation of chiva, thus the two methods cannot be considered the same thing. the essential difference is the reduced length of saphenous treatment, which is much shorter than the length generally treated in laser procedures. unlike chiva but similar to laser and rf, ob-chiva leaves some tributaries of the arch and uses them as washing vessels (draining crossotomy). the research protocol includes only ob-chiva cases with crossotomy performed with alternative methods (laser, rf, and steam). chemical agents were excluded. the prerequisite for treatment is sfj terminal valve incompetence; thus, we need to know: i) whether the gsv reflux is deviated or not (shunt i) towards at least one incompetent tributary; and ii) if the latter is the case, does the gsv trunk reflux disappear while pressing the tributaries with a finger? (positive reflux elimination test [ret]+, shunt iii) or not? (negative reflux elimination test [ret]-, shunt i+ii). for laser draining crossotomy, the tip of the laser fiber is placed at the end of the last washing tributary, at a variable and personalized distance from the junction worth sfj-free cm and one variable and personalized l length segment is treated until the first draining tributary. in the fixed variant of the procedure, starting as described after the last washing vessel, a fixed 7 cm length of the trunk is treated instead. for radio frequency draining crossotomy, the electrode at the tip of the catheter is 7 cm long, though a new available electrode provides a length of 3 cm. though it is a fixed length procedure, the choice of the smaller electrode could fit a detailed length to be treated. steam draining crossotomy is at present only a fascinating hypothesis while mechanical draining crossotomy is a good candidate to compete with laser for its precision. tributary disconnection can be performed classically by a flush phlebectomy, which is already an ambulatory/office quick procedure. also, laser and foam can be used with different effects. devalvulation of a competent trunk gsv valve, if requested, may be performed during a flush phlebectomy or may be wire guided, using a 18 gauge needle, a wire guide, and a dilatator, generally included in the catheter kit. a follow-up examination will be performed soon after the procedure at 1-week, 1-month, 6 months, 1-year, and 2-years. comment by stefano ricci words by the master: la cure chiva est conservatrice et se pratique en ambulatoire (chiva treatment is conservative and is performed in office).1 if in the method definition the procedure is office based, it may be questioned why a group of chiva fans try to find a way of making the same method office based. moreover, i know for sure that at least two of the authors of the paper already practice their chiva treatment in office. probably the authors try to change traditional chiva crossotomy (a quite demanding operation) in a more easy operation, employing commonly used tools (laser, rf, etc) in the attempt to popularize the method, but in this way, they commit the capital sin of accepting an incomplete sfj interruption, something that claude franceschi (one of the authors) would have never accepted in the past. going more through the protocol analysis, one may wonder why the simple gsv interruption at 3-4 cm from the junction by stab extraction, ligation (at two cm) and section like suggested and practiced by several french colleagues and by myself has not been included, although being easily performed in office, in local anesthesia, at a very low cost compared to the suggested methods. somebody could see in the suggested association of two methods (i.e., chiva + laser) a better reimbursement mechanism, which is surely not in the intent of the authors. furthermore, the gsv anatomy of the last centimeters reveals many variations so that the given protocol should be revised as far as the sfj tributaries are concerned.2 in fact, a punctual laser vein closure seems at least unpredictable, while no date are available about the minimum length of the saphenous stem needed to maintain obstructed the vein. concerning devalvulation, no indications are given about the treatment of consequent thrombosis, an event that commonly occurs after the procedure, according to franceschi (personal communication). finally, the costs of the suggested protocol execution will rise highly, while the purpose of an office based procedure should be simplification and cost saving. reply by the authors thanks for the very interesting criticism. a short premise about the reasons why to implement ob chiva: • chiva uses a difficult diagnostic assessment and operators have a generally long learning curve; • ob chiva uses some simple diagnostic maneuvers and a flow chart provides a computer-aided decision, to help everyone to perform the diagnostic/strategic step; • chiva requires a traditional day surgery environment, more complex than actually required by all the ablative endovascular procedures; • ob chiva is a completely office based procedure; • chiva is performed essentially by surgeons, excluding all phlebologists not trained in surgical procedures; • ob chiva can be performed also by phlebologists with a limited surgical knowledge, but experienced in endovascular procedures. detailed answers. [...] if in the method definition the procedure is office based, it may be questioned why a group of chiva fans try to find a way of making the same method office based... this issue isn’t specific of chiva but is common to all venous ablative procedures as they all were and are today more and more applied in outpatients and in day surgery environments. a common trend for them is to search for more simple procedures declared as office based. for instance, the famous cx vascular meeting in london dedicated in the last years (and still in the next 2014 program) several sessions to the office based venous procedures, as they were a new treatment behavior. maybe the explanation is that the old term ambulatorial was referred to simple operating rooms, while the modern office based term requires a much smaller number of resources for the intervention. [...] the authors try to change traditional chiva crossotomy in a more easy operation, employing commonly used tools (laser, rf, etc) in the attempt to popularize the method... why not? shifting to endovascular procedures can be a natural extension, in a world that is practically dominated by these devices. [...] capital sin of accepting an incomplete sfj interruption, something that claude franceschi (one of the authors) would have never accepted in the past... and in the present claude franceschi thinks the same too! more than one page in the paper is used to explain that chiva and ob chiva are two different strategies, which use also different tactics. however, this depends on the actual technology and on the future developments, because the greatest aim of ob chiva is to be never more a different strategy, but only one of the tactics employed in chiva. [...] why the simple gsv interruption at 3-4 cm from the junction by stab extraction, ligation (at two cm) and section like suggested and practiced by several french colleagues and by myself has not been included, although being easily performed in office, in local anesthesia, at a very low cost compared to the suggested methods... we were not aware of this method so it was not included, though it could. nevertheless, the real difference is the need of planning the trunk interruption (using washing and draining vessels), searching for a personalized intervention instead of a standardized one, everywhere and for everyone. in addition, 3-4 cm from the sfj can be a long distance. depending on the length and the type of tributaries, leaving a long patent stump will sometimes transform the intervention in an old-style bad practiced crossotomy, leaving almost all the tributaries of the arch. the least important requirement in ob chiva is to use washing vessels at the junction. they are tolerated because sfj flush treatment is hardly afforded by endovascular procedures, while they could be simply not used if sfj would be treated surgically with a flush ligation (not as an office based procedure). [...] suggested association of two methods (i.e., chiva+ laser) a better reimbursement mechanism... it depends on the country. for instance in some european countries, traditional surgical and endovascular procedures are included in the same category of reimbursement, while in usa instead the endovascular approach has a better reimbursement. [...] the gsv anatomy of the last centimeters reveals many variations so that the given protocol should be revised as far as the sfj tributaries are concerned... though not written clearly in our paper, refluxing tributaries of the arch cannot be used as washing vessels. independently of the presence/absence of the valves, washing vessels feed the junction in the anterograde direction and draining vessels in a retrograde fashion. this occurs by definition owing to the pre-requisite of the sfj intervention in ob chiva, i.e. the incompetence of tv and ptv. in case of treatment of high arch refluxing tributaries (aasv) using laser or mini-surgical approach, the method is already office based and the ob chiva protocol has nothing new to add. [...] in fact, a punctual laser vein closure seems at least unpredictable, while no data are available about the minimum length of the saphenous stem needed to maintain obstructed the vein... agree! one of the aims clearly declared in the paper is the study of the evolution of the sfj stump and the relationship between the gsv closure persistence and the length of the treated segment, which was never investigated before. thus the research protocol faces this issue and as soon as data will show a clear success/failure of the reduced length procedure, the protocol will be changed/discontinued in favor of one or the other method. [...] concerning devalvulation, no indications are given about the treatment of consequent thrombosis, an event that commonly occurs after the procedure... classical devalvulation is already office based, performed during a flush phlebectomy of the tributary. using the wire-guided method or the virtual dissection variant is only a tactical change. no indication is given about thrombosis after devalvulation, because post-devalvulation thrombosis and its evolution and treatment are already described for classical chiva interventions. [...] the costs of the suggested protocol execution will rise highly, while the purpose of an office based procedure should be simplification and cost saving. the office based environment aims essentially to simplify the procedures, though very often cost saving proceeds together. however, a reduction of costs occurs also owing to a reduced number of resources comparing with mini-surgery/day surgery. for instance the reduced number of personnel required by sanitary law and surgical materials as sutures and medications. references 1. franceschi c, ed. theorie et pratique dela cure chiva. dijon: editions de l’armacon; 1988. p 106. 2. dickson r, hill g, thomson ia, van rij am. the valves and tributary veins of the saphenofemoral junction: ultrasound findings in normal limbs. veins and lymphatics 2013;2:e18. [full-text] [top] stefano ricci comment to: postoperative varicose recurrence at the junctions. a multicentric study of 1056 patients by the italian society of phlebolymphology. preliminary conclusions by corcos l, aloi t, alonzo u, et al. acta phlebol 2014;15:69-78. stefano ricci abstract in spite of a history and evidence of efficacy, numerous attempts have been made to replace traditional surgery with new techniques in the hypothesis that the surgical trauma and high pressure on the venous wall are responsible for the development of neovascularisation by neoangiogenesis (nn) and, consequently, high postoperative recurrent rates. to verify the anatomical causes of postoperative varices recurrence (vr) at the sfj and spj fourteen centres belonging to the italian society of phlebolymphology collected the requested data from 1056 patients (1081 limbs, 25 bilateral) who were either previously subjected to ligation-interruption of sfj and/or spj (927 between 2001-2010) or treated in the last two years (154 between 2011-2012); 611 limbs (56.5%) were examined by dus only, 470 limbs (43.4%) were subjected to dus examination and surgical revision (270 with li technique). the residual saphenous stump (ss), all residual tributaries with their outflows into the stump or directly into the common femoral or popliteal veins and their anatomical variants were investigated; neovascularisation by neoangiogenesis was investigated, searching for thin and tortuous veins measuring <2 mm in diameter and connected with an ss, with the common femoral vein or with thinner subcutaneous veins. the majority of the ss were found to be combined with residual identified or unidentified tributaries. in many cases, the vr consisted of a complex varicose collateral circulation (cvc). the residual ss (n=711, 65.7%) was the most common finding, followed (by decreased frequency) by the anterior accessory of the gsv (n=298, 27.5%), ut at the sfj (n=290, 26.8%), superficial iliac circumflex vein (n=127, 11.7%), residual gsv (most likely from a previous duplicity), (n=95, 8.7%), superficial epigastric (n=60, 8.8%) a large number of cases with development of a cvc (n=386, 35.7%) were found in the supra-fascial subcutaneous. the anatomical residuals, which were single or multiple and variously combined, were found in a total of 939 operated junctions. neovascularisation was suspected or demonstrated in a total of 142/1081 cases (13.1%). the data obtained from the different centres appeared to be scarcely detailed to define the various tributary veins involved in the mechanism of recurrence; nevertheless, it is possible to assess the prevalence of ss connected with residual tributaries as major causes of recurrence in both the sfj and spj. nn was recently described as the most dangerous enemy of surgeons and patients operated on for varicose veins. the word neovascularisation seems more appropriate to indicate the appearance of new vessels produced by the phenomenon of neoangiogenesis and does not appear to be appropriate, as it refers to pre-existing veins that remain under the impulse of the venous reflux and progressively dilate. histological observations have led to describe neoangiogenesis as a physiologic process, which follows inflammation and mainly represents a constant product of large wounds, haematomas and thrombosis). the same reparative process, leading to the appearance of specific progenitor cells, takes place in every anatomical district and in every kind of tissue, not only in veins. it can be invoked as a cause of vr in a small percentage of cases, and it seems to play a minimal role at the groin and popliteal region of the operated limbs. in many cases in which no residual tributary could be detected, except for small, weak and tortuous veins, the vr was represented by an anatomical anarchic development of the collateral circulation, similar to cavernous haemangioma. the presence of anatomical residuals at the sfj and spj has been always indicated in the past as the main cause of vr; this research confirms that residual saphenous stump and tributaries caused by inadequate surgery appear to be the main cause of vr at the saphenous junction. recent studies have clearly demonstrated that the only way to prevent vr is still traditional surgery. the only trap is represented by the presence of anatomical variants at the junctions but dus investigation systematically performed before applying any therapeutic technique can prevent such difficulties. comment by stefano ricci although gsv interruption is the base of varicose veins treatment, junctions’ recurrences are still under debate, the end of the debate moving away. while the medium term results of physical or chemical endovascular vein ablation (eva) seem to support the theory of less manipulation/less recurrences at the groin, here is a counter-current study siding the good old high ligation (±stripping), where the recurrences are due simply to inadequate surgery. the authors have performed an extremely accurate analysis of the post surgical anatomy of groin recurrences, showing with great evidence that the persistence of the junction stump is the origin of the varicose recurrence. neoangiogenesis, defined as thin and tortuous veins measuring <2 mm in diameter and connected with an ss, with the common femoral vein or with thinner subcutaneous veins is rare and most of the times suspected more than confirmed. however, devil is in the details, so that some aspects need to be analysed: a long ss connected to one or more tributaries does not mean necessarily that the tributary/ies was/were left untouched at the operation; re-connection could be due to neoangiogenesis (a physiologic process that follows inflammation). this could explain why many subjects have no recurrence even with long stumps left, if their repair process was favourable; and could explain also the cvc cases, where anarchic communications have developed. in these instances nn could be much more important and widespread. in fact, the high number of recurrences analysed is not referred to the number of operated cases so that the recurrences incidence is not known. in particular, only the big vr have been taken in account (most symptomatic), while the minor recurrences (possibly detectable only by us), the one more interesting as far as nn is concerned, are not considered. valsalva manoeuvre for confirming the junction origin of the reflux is not mentioned in methods, so that recurrences due to pelvic reflux have not been separated. no data are available concerning terminal valve competence at first operation, nor gsv diameters (correlated to the valve competence according to cappelli): these variables could condition different behaviours in tissues. no mention is made about the groin recanalization through the lamina lymphatica vein network, one of the most important pathways of the re-connection between the operated area and the residual veins. again, this event may be mediated by nn. the so-called cavernoma could involve this area. there are evidences concerning the selective high ligation of the sapheno-femoral junction (sparing the tributaries coming from the abdomen); their sparing corresponds to the effect of the eva techniques. a comment about chiva crossotomy would be interesting. this technique, as well known, do not ligate the tributaries but allows their drainage through the spared gsv, emptying through a perforator, with limited reported recurrences. could the non-draining ligated tributaries of the traditional surgery have a role in recurrences? authors’ reply the summary is excellent as it highlights the most significant reasons and findings of the work. every criticism becomes productive as makes possible to improve the knowledge and often represents the major impulse for further research. so please see my answers. answer 1) the probabilities of a large (>2 mm) residual tributary vein re-connection at the junction by nn is obviously lesser than the persistence of a residual large tributary vein which becomes dilated and incompetent. answer 2) this is the reason why some researchers, mentioned in the references, based their conclusions on histology which some time makes possible to detect the new vessels only. as it may happen by usd examination, histologic slides may have been performed in areas not comprising the tributaries. please see the enclosed ppt slide 1 where both the nn process and the residual tributary were detected in the same sample of a recurrent patient. answer 3) the residual ss becomes a cause for recurrence only in the cases affected with a highly progressive disease for the same reasons why an apparently normal subject becomes varicose. answer 4) in these cases nn can be more significant and represent an additional cause for the severity recurrence (in the paper nn is not cancelled as a possible cause for recurrence). this is an acceptable and interesting hypothesis, which could require further specific studies. please note that in page 71 of the published paper you can find the following information: a) ...patients with pelvic reflux were excluded... . b) the dus examinations were performed by the ...recommended criteria... . they obviously comprise the valsalva manoeuvre. however this clarification could be useful for readers. i agree. these parameters are highly predictive, however our patients came from different and sometimes unknown centres where some defects in the basic preoperative diagnostic process, more than in the surgical procedure, may have occurred. perhaps you should say …according with labropoulos who first demonstrated the relation between venous dilatation (calibre) and incompetence. i agree. in one case only the lymphatic origin of recurrence from nn was detected by surgical dissection, which, at the present time, seems to be the more predictive method. please see the enclosed ppt slide 2. perhaps it should have been mentioned in the text. in the more recent experience the dus investigation and the surgical dissection made possible to detect 2 similar cases at the groin. my personal opinion is that such evidences come from a too short follow-up. please see ppt slide 3. this graphic has been shown in some congress presentations but unfortunately there was not enough space in the journal for including it and extending the discussion. you can note that the peaks of recurrence belong to the first 7 years postoperative period. however a high number of the cases developed the recurrence from 8 up to 34 years after surgery. this can indicate 2 hypotheses: 1) residual veins can easily recur in the short term; 2) the role of nn should be mainly related with a longer term recurrence, however the responsibility of anatomical residuals must be assumed in the long term too. why not? this is what we see whenever examining and treating patients with recurrence after simple crossotomy. please see my previous answer: the residual ss becomes a cause for recurrence only in the cases affected with a highly progressive disease for the same reasons why an apparently normal subject becomes varicose. [top] hrev_master veins and lymphatics 2017; volume 6:6635 film compression bandage: a new modality to improve sclerotherapy of superficial varicosities johann chris ragg angioclinic® vein centers, berlin, germany introduction therapy for varicose veins and venous insufficiency currently undergoes a tremendous change as surgery is step by step replaced by endovenous methods. however, superficial varicosities of considerable size still are treated by phlebectomy, as simple foam sclerotherapy with cabrera-type foams is frequently leading to symptomatic inflammations, visible residuals or ugly stainings, in spite of compression protocols according to guidelines and recommendations. sclerofoam will lead to target vein occlusion, but thrombus formation is required to obtain permanent obliteration. thrombus is organized and resorbed in an inflammatory procedure over weeks, while wall inflammation generates transmural vessel connections and thus a second-phase blood entry to a vein which is actually meant to vanish. symptoms are the more evident the closer the varicose vein is to the skin and its multitude of sensitive nerves. if attempts are made to reduce such unwanted sequelae by mini-thrombectomies, practically expression or suction of thrombus from varices in local anesthesia, this is usually more painful for the patients than the whole initial treatment. as endovenous therapy can be performed pain free at high levels of comfort with immediate ambulation and no further restrictions, a more consequent compression like 4-6 weeks with bandages day and night are today no longer communicable. eccentric compression can partially solve clinical vein regression problems, but require additional efforts and continuity is limited. to approach the beneficial influence of a continuous compression and to establish a minimum of blood clot constantly for several weeks until inflammation comes to an end, a compression film bandage was developed consisting of an approved polymer film basis with hypoallergenic acrylic glue (3m inc.) and supportive layers to handle the application as a bandage (venartis inc.). the film is placed once and may stay for two to four weeks. after a first pilot study with different films now a second series of cases was performed, including a more detailed diversification of subgroups. main endpoints were the frequency of symptomatic inflammatory reactions and wearing comfort.1-11 materials and methods 354 patients (23-74 yr/o) with a total of 450 eligible legs with superficial varicosities, 5-16 mm ø, mean 7.9 mm ø, were included in the study. cases were randomized to 6 groups with equal diameter distribution (+/0.3 mm): film for 14 or 28 days with a renewal after 14 d, film plus compression stocking german class 2 for 14 or 28 days day over, and compression stocking alone day over for 14 or 28 days. prototypes of the elastic compression film bandage (d <20 µm) were applied with 1-1.5 cm overlapping, covering the target varicosities, immediately after foam sclerotherapy (aethoxysklerol 1%, 1+4 with filtrated room air, butterfly 23-25 g if <6 mm ø, correspondence: johann chris ragg, angioclinic® vein centers, berlin, germany. e-mail: ragg@angioclinic.de work group: www.venartis.org this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright j. chris ragg, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6635 doi:10.4081/vl.2017.6635 figure 1. a) diameter reduction of superficial varicosities after sclerofoam treatment, measured at week 4; b) rate of symptomatic inflammations, residuals or stainings until week 8; c) wearing comfort of different compression modes as rated by patients, 10 = perfect. film14: film compression bandage for 14 days; film28: film compression bandage for 28 days; +mcs14: film compression bandage and medical compression stocking class 2 for 14 d; +mcs28: film compression bandage and medical compression stocking class 2 for 28 d; mcs14: medical compression stocking class 2 for 14 d; mcs28: medical compression stocking class 2 for 28 d. [page 28] [veins and lymphatics 2017; 6:6635] no n c om me rci al us e o nly conference presentation micro catheter 16-18 g if >6 mm ø, phlebocath 2.0-2.3 for saphenous veins) and worn continuously. any work, sports and daily showers were allowed. for the first 24 h, a short-stretch bandage was put on top. follow-up examinations including ultrasound and photography were performed after 2, 4 and 8 weeks. results all target veins showed total closure at the first control. at the end of compression media application (28 d) vein diameters were reduced by 19.5-67.8%, while variations were depending on the modality (mean values displayed in figure 1a), but also on the degree of native vein bulging. combining film bandage with compression stockings was slightly more effective than film bandage alone. prolonged application periods (28 d) were more effective than short periods (14 d) for all modalities. symptomatic inflammations of any degree, visible or palpable indurations, or discolorations were observed within 8 weeks (considered to cover >95% of such complications) in a maximum of 62.5%, related to cases receiving stocking treatment for 14 d, and 51.3% if stockings were worn for 28 days (figure 1b). the use of the film compression bandage reduced inflammatory symptoms to 4.7-9.3% of the cases. this difference was statistically highly significant (p<0.01). the need for minithrombectomies was reduced in the same range.comfort was rated by the patients according to a 10-degree scale in which 10 was best, defined as no perception of the medium during any activities or at rest. film bandage for 14 days was the most comfortable modality (9.1) while compression stocking for 28 days was worst (4.6) (figure 1c). film bandage combined with compression stocking was more comfortable than compression stocking alone. as a rule, shorter compression periods (14 d) were better accepted than longer periods (28 d). more than 90% of the patients took showers at more than 4 days a week. the additional comfort of allowing showers, any kind of sports, any kind of clothing and even beach life in summer was greatly appreciated by the patients (figure 2). there were no relevant film-related complications: 13/300 film bandage cases showed minor skin reddening, usually near the upper margin. one case showed largearea skin reddening (14 d film only group), allergy could be excluded. marginal dissolution for 1-2 cm, again in a majority related to the upper margin, was seen in 18.2% of the cases. a few bandages had to be renewed prior to schedule (9.2%). discussion after the first pilot study10 it was not surprising how well the film bandage performed (figure 3). one particular aspect was the enormous reduction of inflammatory symptoms and staining when using the film bandage, while the diameter reduction was less impressive (figure 1a and b). figure 2. as the film bandage is very thin, invisible and waterproof it allows any kind of work, sports, clothing and even showers. figure 3. foot varicosity before and 15 min. after sclerofoam treatment with a film bandage in place. primary and long-term results have a similar appearance. figure 4. scheme, visual aspect and ultrasound of a bulging varice before and one day after sclerofoam and film bandage. [veins and lymphatics 2017; 6:6635] [page 29] no n c om me rci al us e o nly conference presentation [page 30] [veins and lymphatics 2017; 6:6635] different to common textile bandages or stockings there are significant local effects mediated by the glue: the film will form a circumferential functional unit with the skin, adding the elasticity of both components. furthermore, the unit of glue and skin will locally limit the space available for the vein when it is re-expanding after the end of spasm, to a much bigger extent than a non-gluing material can provide. this effect is the biggest at skin level and lost with increasing depth (triangle of constriction). the varicose vein shows a position shifted towards the fatty tissue, reducing the contact area to sensitive skin (figure 4). these mechanisms may explain why inflammations are less perceived and less seen even when they are detectable in ultrasound. because of these physical issues, the effects of the film bandage are the better the more a native varicose vein is bulging above skin level. inflammatory sequelae were more frequent in the group receiving stocking only than in the average of literature reports,2,5,11,12 which may be due to the large diameters included in this study. except from cases which will not tolerate to wear a compression stocking, it seems to be very useful to combine the film with a graduated stocking: stockings, if tailored correctly, will ideally cover the foot to prevent edema while the film is tricky to place circumferentially at the foot, it also might suffer from mechanical stress and moisture in this location. on the other locations, the film improves the wearing comfort of stockings, while the stockings gradually contribute to the symptomatic result of the treatment. furthermore, it is a great chance to get patients acquainted to (prophylactic) compression stockings for their daily life. after sclerofoam treatment, the type of stocking is chosen according to the patient’s general condition according to current guidelines.6,8 it will have to be studied if stockings could be class 1 instead of class 2 for c2 stages, and if additional bandages for the initial 48-72 hours could further improve the results. it is not yet clear which cases would benefit the most from a prolonged film bandage wearing time (28 d), but vein diameters above 8 mm and a doubtful quality of foam sclerotherapy (incidental mixture with blood, incomplete blood replacement) seem to be good candidates. considering the clinical and esthetic results, there is a new perspective for the treatment of superficial varicosities: there is hardly a reason to perform phlebectomy anymore, not even in very large varices, because foam and film performs very well. exceptions may be given for varices containing large loads of thrombus, when allergies to acrylic glue may be expected or not yet evaluated in very humid and hot climates. furthermore, very large varicosities at the thigh of exceedingly obese patients could remain subject to phlebectomy, as effect and fixing of the bandage might reach its limits. once a commercial product is available, foam and film should be preferred in daily practice because no anesthesia is needed and, apart from punctures, no wounds are generated, no risk of infections, bleedings or nerve lesions. supplementary foam injections, if considered for reimbursement issues, should be scheduled in order to renew the bandage at the same time (e.g. 14 d). in summary, for the first time treatments of epifascial insufficiency can be performed totally by endovenous methods. this statement is not meant as disrespect of precious vascular surgery, but in favor of the patient’s safety and comfort. conclusions the adhesive compression film bandage significantly improves vein regression of foam-treated superficial varicosities (p<0.01). it prevents symptomatic inflammations and stainings and provides a most comfortable compression. it may be used combined with compression stockings or even as stand-alone modality. there are no limitations in daily work, sports, showers or social life. references 1. fegan wg. continuous compression technique of injecting varicose veins. lancet 1963;2:109. 2. guex jj, allaert fa, gillet jl. immediate and mid-term complications of sclerotherapy: report of a prospective multicenter registry of 12,173 sclerotherapy sessions. dermatol surg 2005;31:123-8. 3. mosti g. post-treatment compression: duration and techniques. phlebology 2013;28:21-4. 4. nootheti pk, cadag km, magpantay a, goldman mp. efficacy of graduated compression stockings for an additional 3 weeks after sclerotherapy treatment of reticular and telangiectatic leg veins. dermatol surg 2009;35:53. 5. o’hare jl, stephens j, parkin d, earnshaw jj. randomized clinical trial of different bandage regimens after foam sclerotherapy for varicose veins. br j surg 2010;97:650. 6. partsch h. evidence based compression therapy. vasa 2007;34:1-39. 7. partsch h, mosti g, uhl jf. unexpected venous diameter reduction by compression stocking of deep, but not of superficial veins. veins and lymphatics 2012;1:e3. 8. rabe e, breu f, cavezzi a, et al. european guidelines for sclerotherapy in chronic venous disorders. phlebology 2014;29:338-54. 9. ragg jc. eccentric compression of large varicose veins after foam sclerotherapy using a novel silione gel pad. phlebologie 2014;43:250-6. 10. ragg jc. compression film bandage: a new modality providing continuous and sports-suitable vein compression after foam sclerotherapy. phlebologie 2015;44:249-55. 11. scurr jh, coleridge-smith p, cutting p. varicose veins: optimum compression following sclerotherapy. ann r coll surg engl 1985;67:109-11. 12. weiss ra, sadick ns, goldman mp, weiss ma. post-sclerotherapy compression: controlled comparative study of duration of compression and its effects on clinical outcome. dermatol surg 1999;25:105-8. no n c om me rci al us e o nly hrev_master veins and lymphatics 2013; volume 2:e21 [page 76] [veins and lymphatics 2013; 2:e21] short endovenous laser ablation of the great saphenous vein in a modified chiva strategy sergio gianesini, erica menegatti, michele zuolo, mirko tessari, simona ascanelli, savino occhionorelli, paolo zamboni vascular disease center, university of ferrara, italy abstract mini-invasiveness, ease of use and execution speed represent the reasons for endovenous laser ablation success. nevertheless, the strategic choice remains the ablation of the saphenous trunk. hemodynamic correction (chiva) represents an option, based on a saphenous-sparing therapeutic strategy. we tested the feasibility of a modified chiva strategy by means of endovenous lasers (el) shrinkage of segmental great saphenous vein (gsv) tracts, in networks characterized by sapheno-femoral incompetence and re-entry perforators focused on the gsv. we report the follow up of the first 2 chronic venous disease [c1,2,3sepaspr1,2,3, venous clinical severity score (vcss) 8 and 9 respectively] treated cases. at 1-year follow up both patients were c1,2,3sepaspr1,2,3 and the vcss were 1 and 2 respectively. the non-treated gsv tracts maintained their patency. els were herein used within a saphenous-sparing therapeutic plan, thanks to an accurate pre-operative hemodynamic assessment, which allowed the shrinkage of only the first saphenous trunk tract only. proper technical and hemodynamic considerations are discussed. introduction in the last decade, endovenous laser ablation (evla) has progressively dominated the chronic venous disease (cvd) therapeutic field.1 nevertheless, strategically, evla hasn’t brought any innovations, since its first description by navarro in 2001:2 the reflux abolition is obtained by the vein anatomical ablation, exactly like in surgical stripping. conversely, hemodynamic correction (chiva) constitutes an alternative strategic approach for cvd treatment: a saphenoussparing draining restoration that is characterized by a scientifically validated efficacy.3-5 in order to combine the endovenous laser (el) main technical strengths with the chiva strategy efficacy, an innovative therapeutic approach was used. after an accurate pre-operative hemodynamic assessment, the great saphenous vein (gsv) was shrunk distal to the superficial epigastric vein confluence (sev), just for 7 to 10 centimeters. the remaining trunk was left draining reversely toward a previously selected re-entry perforator. we herein present the first 2 cvd cases that were already assessed at the one-year follow up. case reports diagnostic assessment the first patient (case a) was a 47-year old male, with no co-morbidities, who was evaluated for a c1,2,3sepaspr1,2,3 cvd, which was first diagnosed 4 years before. the clinical assessment assigned a venous clinical severity score (vcss) of 8.6 the echo-color-doppler investigation (ecd) identified a positive valsalva and compression/relaxation (c/r) maneuver at the femoral side of the terminal valve,7 an incompetent below-knee gsv tributary and an effective reentry perforator on the mid-calf gsv trunk. according to chiva terminology, the patients presented a type i+n3 shunt (figure 1).8,9 the second patient (case b) was a 64-year old male with arterial hypertension in the anamnestic record. he was evaluated for a c1,2,3sepaspr1,2,3 cvd, which was first diagnosed 3 years before. the clinical assessment assigned a vcss of 9.6 the ecd revealed a reflux pattern that was overlapping with the case a one (incompetent sapheno-femoral junction, re-entry perforator focused on the gsv, incompetent gsv tributary, in this case located on the distal third of the leg, but however above the gsv re-entry perforator). case a and b hemodynamic measures are reported in table 1. operative procedure on the same procedural day, both cases underwent an accurate pre-operative echoguided mapping. case a on the mid-calf, a flush disconnection of the incompetent gsv tributary was performed, leaving the saphenous breach opened in order to directly insert a 600 mm radial fiber of a 1470 nm 6w el (figure 2). under ultrasound-guidance the fiber was then positioned just distal to the sev. a tumescent anesthesia (lidocaine 2% 5 cc + sodium bicarbonate 5 cc + saline solution 10 cc) was administered perivenously by a 25 g needle, under ecd guidance, just along the 10 cm below the sev, with a 40 cc total injection. the el was then activated, shrinking the gsv at 100 j/cm and at 80 j/cm for the first 6 and the remaining 4 cm respectively. the total energy delivery recorded the following parameters: i) laser on-time: 155 s; ii) total joules delivered: 928 j; iii) treated segment length: 10 cm. after the fiber extraction, a 7/0 running suture was performed to close the saphenous breach. case b a flush ligation of the incompetent gsv tributary was performed according to the chiva principles.8,9 since the tributary was located on the distal third of the leg, percutaneous gsv access at the distal third of the thigh was preferred: with the patient in a reverse-trendelemburg position, a 0.0035-in guide-wire was inserted through a 19 g needle into the gsv. the same case a device was then introduced (1470 nm, 6 w) and placed just below the sev. the tumescent anesthesia was performed with the same compound, and injected perivenously along the 7 cm below the sev, for a total amount of 30 cc. once the el was activated, the gsv was shrunk at 100 j/cm and at 80 j/cm for the first 5 and the remaining 2 cm respectively. correspondence: sergio gianesini, vascular disease center, university of ferrara, via aldo moro 8, 44100 ferrara, italy. tel. +39.0532.236524 fax: +39.0532.237144. e-mail: sergiogianesini@hotmail.com key words: chronic venous disease, chiva, laser, conservative, hemodynamic contributions: sg, study design, data acquisition, analysis and interpretation, manuscript drafting; em, data acquisition, manuscript drafting; mz, data acquisition; sa, so, data analysis and interpretation; pz, study design, data analysis and interpretation, manuscript revision. conflict of interests: the authors declare no potential conflict of interests. received for publication: 19 june 2013. revision received: 7 september 2013. accepted for publication: 9 september 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s. gianesini et al., 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e21 doi:10.4081/vl.2013.e21 no nco mm er cia l u se on ly case report [veins and lymphatics 2013; 2:e21] [page 77] the total energy delivery recorded the following parameters: i) laser on-time: 111 s; ii) total joules delivered: 671 j; iii) treated segment length: 7 cm. in both cases, eccentric compression with cotton rolls on the treated veins was applied underneath a 20-30 mmhg thigh-length elastic stocking that was prescribed day and night for one week and only daily for the following week. the clinical and ecd follow-up was scheduled at 1 week, then at 1-6-12 months. results the patients referred no pain linked to the periand post-procedural time. neither major nor minor complications were reported. only a minor tightness feeling was reported in case b, during the first week, all along the 5 cm distally from the el treated segment. a total relief was obtained after 3 days of nonsteroidal anti-inflammatory drugs. already at the 1 week ecd, case a showed a perfectly shrunk gsv tract from below the sev to 10 cm downward. at 1 year follow up, in both patients, the clinical evaluation assessed a c1aepaspr1 class, while the case vcss was 2 in case a and 1 in case b. table 1 reports the 1 year follow up hemodynamic parameters which were assessed at the mid-thigh gsv portion in both cases (figure 3). at the 1 week ecd, case b showed a perfectly shrunk gsv tract from below the sev to 7 cm downward wall thickening, but also a wall thickening from the shrinkage distal end to other 8 cm downward (figure 4). the tract affected by this wall thickening was compressible, vascularized and spontaneously disappeared at the 1 month follow up. in both patients, the 1 year follow-up revealed a totally patent gsv from the shrunk tract downward (negative compression-ultrasound maneuvers). at the compression/relaxation maneuver the junctional tributaries showed a systolic centripetal flow, draining into the sapheno-femoral junction (figure 2). post-operatively the stump was 10.6 mm and 10.1 mm long in case a and b, respectively. placing the pw (pulsed wave) sample on the femoral side of the terminal valve both valsalva and c/r maneuvers were negative for reflux. no ballooning during strain was observed in both cases pre-operatively the giacomini vein was found to be competent in both cases. it was not identified post-operatively. discussion the ever-increasing need for mini-invasiveness, fast recovery and painless procedures have permitted evla to become one of the main therapeutic option in contemporary cvd management.1 certainly, this technique has brought great technical advantages, but, at the same time, no improvements have been obtained in the strategic planning thus far: the procedure is based on the saphenous trunk ablation, exactly like in surgical stripping. the laser technique has brought great success in the quality of life improvement.10 nevertheless, the long term clinical and ultrasonographic results of this procedure haven’t being correspondingly satisfactory.11 the maintaining of an ablative strategy could be an explanation of the observed phenomenon and the herein presented strategy could offer an alternative model of venous hemodynamic investigation. on the contrary, the strategic table 1. morphologic and hemodynamic measurements recorded pre-operative and 1 year follow-up outcome both in case a and b. case a case b pre-op post-op pre-op post-op gsv diameter below the sev(mm) 8.4 totally shrunk 8.7 totally shrunk gsv diameter at mid thigh (mm) 8.7 3.9 8.9 3.4 reflux time (s) 2.3 down-word draining flow 2.6 down-word draining flow peak systolic velocity (cm/s) 41.7 37.4 55.6 26.5 end diastolic velocity (cm/s) −11.5 10.1 −11.7 4.3 resistance index 1.27 0.73 1.21 0.83 gsv, great saphenous vein; sev, superficial epigastric vein. figure 1. femoral vein (fv), re-entry perforating vein (rp), and great saphenous vein (gsv). a) physiological drainage: from the most superficial compartment to the deepest one, from the lowest to the upper part of the leg. b) type i +n3 shunt: pathological inversion of the physiological order of emptying from n1 compartment to n2, adding an incompetent gsv tributary (n3). a re-entry perforator is focused on the gsv (n2). this allows the sapheno-femoral junction treatment. c) type ii shunt: pathological inversion of the physiological order of emptying from n2 compartment to n3, with no compartment jump from n1 to n2. the incompetent tributary has its own rp directly draining into the n1 compartment, so that no closed circuits are formed. d) type 3 shunt: pathological inversion of the physiological order of emptying from n1 compartment to n2, adding an incompetent gsv tributary (n3). no re-entry perforator is focused on the gsv. this forbids the sapheno-femoral junction treatment: in case of a sapheno-femoral junction disconnection/occlusion together with the incompetent tributary treatment would impede the draining into the gsv trunk so leading to thrombosis. no nco mm er cia l u se on ly case report [page 78] [veins and lymphatics 2013; 2:e21] change that has been brought about by a saphenous-sparing surgical technique like chiva point towards better long term outcomes in cvd management,4 with a halved recurrence risk if compared to traditional stripping.3 interestingly, the sapheno-femoral refluxing point suppression by el confirmed the creation of a not refluxing but rather reversed flow, draining the gsv trunk toward a re-entry perforator.12 conversely, a strict application of the chiva principles would require the maintenance of the junctional tributaries draining into the gsv trunk.8,9 certainly, the proposed segmental gsv shrinkage is feasible only in case of a re-entry perforator focused on the gsv trunk (30-40% of the cvd hemodynamic patterns).8,9 therefore, from this perspective, our herein proposed therapeutic option can’t be dogmatically defined as a chiva procedure, but rather as an endovenous laser therapy to be performed according to chiva hemodynamic principles. the newly corrected flow pattern could provide a study model in the sapheno-femoral junction tributaries hemodynamic investigations, to be added to the ones that have been provided by past evla experiences. more specifically, it would be possible to implement the data concerning the recurrence rates in case of junctional tributaries ablation versus conservation.13 in our center, the idea of combining the el technique with the chiva strategy was conceived in order to melt together evla miniinvasiveness with the hemodynamic correction long term efficacy. we can postulate that a less aggressive sapheno-femoral confluence treatment could reduce the recurrence risk.14 the successful outcome of the first 2 cases paves the way for an even greater diffusion of the laser technology, together with all the other minimally invasive techniques that are able to produce a subinguinal gsv occlusion (laser, radiofrequency, steam, glue mechanical). this new technologies innovative application could increase the interest toward hemodynamic saphenous-sparing strategies also in the nonsurgical physicians.15 of course, this therapeutic option eliminates the requirements for surgical skill of traditional hemodynamic correction, but at the same time it forces all the involved physicians to possess an advanced sonographic knowledge. future randomized comparative trials among the proposed strategy, pure chiva and traditional evla could provide answers to the following questions: what is the hemodynamic role of the aspirating re-entry perforator in comparison to the gsv tributaries along the trunk in the draining maintenance? what is the minimum shrinkage length for a long-lasting sapheno-femoral occlusion? what is the most appropriate energy delivery setting? what are the hemodynamic parameters indicating a possible hemodynamic correction by el? what are the hemodynamic features of the sapheno-femoral confluence to be assessed before an endovenous chiva planning? conclusions use of saphenous-sparing el use seems to constitute an innovative and effective cvd therapeutic option. at the same time, it increases the potential efficacy of the not-surgical medical operators, and it forces all the involved physician into a deeper knowledge of the venous hemodynamics. figure 2. type 1 + 2 shunt. femoral vein (n1), great saphenous vein (n2), great saphenous vein (gsv) tributary (n3), and re-entry perforator (rp). in type 1 shunt there is a reflux constituting a pathological subversion of the physiological order of venous emptying (from the surface to the deepest compartment of the lower limb). the compartment jump (from n1 to n2) is fed by an incompetent sapheno-femoral junction. an additional compartment jump can be observed from n2 to n3 because of an incompetent tributary. a rp focused on the n2 compartment bring the shunted blood back to the n1 compartment. pure hemodynamic correction (chiva) 1 strategy indicates the suppression of the pathological n1-n2 compartment jump thanks to a high tie with junctional collateral preservation. segmental gsv shrinkage by endovenous laser ablation (evla) offers a n1-n2 jump suppression, but leaving a sapheno-femoral junction stump, where the junctional tributaries can drain. figure 3. case a outcome at 12 months follow up. the superficial epigastric vein (sev) is draining into the sapheno-femoral junction (sfj), while the great saphenous (gsv) trunk remained shrunk. cfv, femoral vein. figure 4. case b wall thickening at the 1 week follow up echo-color-doppler. the finding was extended from the distal great saphenous vein shrinkage for 8 cm downward. no nco mm er cia l u se on ly case report [veins and lymphatics 2013; 2:e21] [page 79] conclusive note the resistance index (ore resistive index or pourcelo index) is a hemodynamic parameter reflecting the resistance to blood flow. it is also related to the vascular compliance and is obtained by the following formula: [(peak systolic velocity end diastolic velocity)/peak systolic velocity, ri] practically, this represents a doppler method to extrapolate an impedance parameter, expressing with a number the bi-directional flow and energy dissipation of the reflux phenomenon. references 1. sadek m, kabnick ls, berland t, et al. update on endovenous laser ablation. perspect vasc endovasc ther 2011;23:2337. 2. navarro l, min rj, boné c. endovenous laser: a new minimally invasive method of treatment for varicose veins--preliminary observations using an 810 nm diode laser. dermatol surg. 2001;27:117-22. 3. carandina s, mari c, de palma m, et al. varicose vein stripping vs hemodynamic correction (chiva): a long term randomised trial. eur j vasc endovasc surg 2008;35:230-7. 4. pares jo, juan j, tellez r, et al. varicose vein surgery: stripping versus the chiva method: a randomized controlled trial. ann surg 2010;251:624-31. 5. zamboni p, cisno c, marchetti f, et al. minimally invasive surgical mangement of primary venous ulcers vs. compression treatment: a randomized clinical trial. eur j vasc endovasc surg 2003;25:313-8. 6. rutherford rb, padberg ft jr, comerota aj, et al. venous severity scoring: an adjunct to venous outcome assessment. j vasc surg 2000;31:1307-12. 7. cappelli m, molino lova r, ermini s, zamboni p. hemodynamics of the sapheno-femoral junction. patterns of reflux and their clinical implications. int ang 2004; 23:25-8. 8. franceschi c. theorie et pratique de la cure conservatrice et hemodynamique de l’insuffisance veinuse en ambulatoire. précy-sous-thil: ed. de l’armancon; 1988. 9. franceschi c, zamboni p. venous hemodynamics. hauppauge, ny: nova science publ.; 2009. 10. darwood rj, theivacumar n, dellagram maticas d, et al. randomized clinical trial comparing endovenous laser ablation with surgery for the treatment of primary great saphenous varicose veins. br j surg 2008; 95:294-301. 11. murad mh, yglesias fc, garcia mz, et al. a systemic review and meta-analysis of the treatments of varicose veins. j vasc surg 2011;53:49s-65s. 12. tacconi g, menegatti e, fortini p, et al. impedance and duplex haemodynamic parameters modifications induced by haemodynamic correction type 1 (chiva 1). oral presentation. 9th european venous forum, barcellona, spain, june 26, 2008. abstract 2.1. available from: http://www. europeanvenousforum.org/evf2008/book% 20of%20abstracts.pdf 13. disselhoff bc, der kinderen dj, kelder jc, moll fl. randomized clinical trial comparing endovenous laser ablation of the great saphenous vein with and without ligation of the sapheno-femoral junction: 2-year results. eur j vasc endovasc surg 2008;36: 713-8. 14. van rij am, jones gt, hill gb, jiang p. neovascualrization and recurrent varicose veins:more histologic and ultrasound evidence. j vasc surg 2004;40:296-302. 15. passariello f. office based chiva (ob chiva). acta phlebol 2011;12:26-7. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2014; volume 3:2268 [veins and lymphatics 2014; 3:2268] [page 5] phlebology in 21st century stefano ricci, editor-in-chief nowadays, it is difficult to have a clear idea of which evolution in our field – phlebology – will be considered as a true advancement or will be disregarded by the selection of experience. however that may be, we have the feeling that a sudden rush of ideas and methods is going on at the beginning of this century. phlebology is an old branch of medicine; its roots are in common with the origin of circulatory physiology, where the venous function represented a mysterious subject solved by harvey’s demonstration (figure 1).1 the diffusion of veins pathology is witnessed by the description of ulcer treatment in the ancient egyptian ebers papyrus.2 although many (and substantial) contributions during the centuries may be recalled, modern phlebology started at the beginning of 20th century by the introduction of an efficient surgical method of eliminating the incompetent great saphenous vein (gsv)3 after the suggestion of trendelemburgh,4 derived by rima hypothesis5 of gsv high interruption when involved in varices. in these same years, keller3 and mayo3 published two alternatives methods of gsv avulsion that resulted less successful in the following years but still demonstrated the particular interest on the subject at that time.3 babcock’s method (stripping of the gsv stem), made popular worldwide by t. myers of the mayo clinic,3 dominated the century and till now it is probably the most employed method around the world. throughout these nearly 100 years, gsv ablation remained nearly unchanged, with few variations for less aggressive purposes: short stripping,6 vein invagination,7 isolated junction high ligation.8 sclerotherapy proceeded simultaneously/ alternatively, most of the active solutions being suggested in the first fifty years of the 20th century.9 five milestones occurring in the second half of the century, which will have a great influence in the future, have to be underlined: i) the muller’s ambulatory phlebectomy10 (with consequent shifting of surgery toward office setting), ii) the diffusion of ultrasound facilities11 (finally starting to understand what happens to veins circulation), iii) the franceschi’s conservator ambulatory conservative hemodynamic management of varicose veins (chiva) theory12 (consequence of the former, the beginning of conservative treatments), iv) the invention of foam,13 especially when a simple method of production has been found,14 v) the endovascular gsv treatments by radio frequency15 and laser16 as an alternative to surgery. these advancements have been the basis of the new century phlebology evolution, but the true nature of change, as it probably happens in all history changes, has been the challenging of the (phlebological) leading dogma:17 all treatments must go through the radical interruption of the saphenofemoral junction (sfj) and its tributaries. several factors concurred and are presented below. first, outcome studies by ultrasound: a consensus document by perrin and colleagues18 and a paper by fischer and colleagues19 in 2001 showed a very high recurrence rate of groin dissection and high ligation in the mid (long) term. second, the vein ablation by radio frequency and laser that have been spread worldwide in the last 10 years to become the preferred alternative to surgery for many operators. these treatments achieve the closure of the gsv stem, leaving the terminal part of the sfj open, allowing the drainage of one or more tributaries (epigastric, pudendal), with good results in the midterm.20 third, the diffusion of foam sclerotherapy, achieving similar (although less favorable) results as radiofrequency (rf) and laser with lower costs and simpler settings.21 here, the terminal part of the sfj usually remains open as well, being washed out by junction tributaries. fourth, some authors reported good outcomes of saphenectomy without junction disconnection.22,23 fifth, an ultrasound (us) study of the sfj showed that not all the terminal valves are incompetent in the presence of a gsv reflux.24,25 more refined preoperatory us investigation of the junction is mandatory for evaluation of whatever surgical techniques. currently, no study reports preoperative data on the terminal valve, making the interpretation of surgical results doubtful. sixth, chiva operators achieved stable results by high ligation of the junction, preserving the junction tributaries and the gsv stem, the blood being redirected through gsv perforators.26 seventh, isolated phlebectomy of varicosities may reduce the gsv caliber and eliminate reflux.27-29 as a consequence, although insufficient groin dissection due to poor surgical skill was considered as the cause of groin (and limb) recurrence for many years and in a plethora of papers, at present time exactly the opposite seems to be true: an excessive dissection may favor neo vascularisation of the groin area. challenging the dogmas stimulated new ideas: gsv occlusion by steam as heating mechanism;30 vein endothelial damage by a rotating device before sclero-injection;31 gsv occlusion by special glue.32 furthermore, varicose disease was submitted to outstanding changes. limbs venous disease stimulated the research of cerebral venous flow as a cause of neurological diseases opening a never ending debate.33 moreover, new oral anticoagulation agents are promising a better quality of life to thrombotic patients.34 radiologists became able to produce three dimensional images35 and venous stenting began to be more diffused.36 we, as the veins and lymphatics journal’s group, are willing to spread these novelties together with all the other scientific media involved. we are minor and back in the list of phlebology issues, but we have the feeling of being in the right place at the right moment, using the best diffusion tool, freely accessible by those who have something to say and those who want something to learn. for the future we expect the following: a varicose veins cause explanation; an evolution of gsv incompetence treatment patient-oriented and effective from a phamaco-economic point of view, possibly simple and office-based; compression devices that patients are happy to put on; new treatments of lymphatic disorders; an open mentality avoiding dogmas; new technologies possibly less expensive than those going to be replaced. as always, time and evidence will decide what will be a cornerstone in our practice, what will be forgotten (and probably reinvented at other times), what will be juts helpful somehow. anyway, what is sure is that veins correspondence: stefano ricci, e-mail: editor-in-chief@veinsandlymphatics.org received for publication: 15 january 2014. accepted for publication: 15 january 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s. ricci, 2014 licensee pagepress, italy veins and lymphatics 2014; 3:2268 doi:10.4081/vl.2014.2268 figure 1. harvey’s demonstration of venous valves. no nco mm er cia l u se on ly editorial [page 6] [veins and lymphatics 2014; 3:2268] and lymphatics will keep open its eyes to witness these events. references 1. harvey w. exercitatio anatomica de motu cordis et sanguini in animai bus. frankfurt: the warnock library; 1628. available from: http://www. rarebookroom.org/control/hvyexc/index.html 2. bryan pw. the papyrus ebers. london: geoffrey bles; 1930. 3. rose ss. historical development of varicose veins surgery. in: bergan jj, goldman mp, eds. varicose veins and telangectasias. diagnosis and treatment. st. louis, mo: quality medical publ.; 1993. 4. trendelenburg f. uber die unterbindung der vena saphena magna bei unterschenkelvarizen. beitr klin chir 1890;7:195. 5. ricci s. who discovered saphenous vein incontinence. in: ricci s, georgiev m, goldman mp, eds. ambulatory phlebectomy. 2nd ed. boca raton: taylor and francis group; 2005. 6. negus d. should the incompetent saphenous vein be stripped to the ankle? phlebology 1986;1:33-6. 7. van de stricht j. saphenéctomie par invagination sur fil. presse med 1963;71:1081. 8. large j. surgical treatment of saphenous varices, with preservation of the main great saphenous trunk. j vasc surg 1985;2:886-91. 9. goldman mp, guex jj, weiss ra. sclerotherapy treatment of varicose and telangiectatic leg veins: introduction. 5th ed. london: elsevier; 2011. 10. muller r. traitement des varices par la phlebectomie ambulatoire. phlébologie 1966;19:277-9. 11. luizy f, franceschi c, franco g. a method of venous study by real time ultrasonography associated with directional and continuous doppler ultrasonography. ann med interne 1986;137:484-7. 12. franceschi c. theorie et pratique de la cure conservatrice et hémodynamique de l’insuffisance veineuse en ambulatoire. précy-sous-thil: editions de l’armacon; 1988. 13. cabrera j, cabrera garcia olmedo jr. nuevo método de esclerosis en las varices tronculares. patología vascular 1995;4:5573. 14. tessari l. nouvelle technique d’obtention de la sclero-mousse. phlébologie 2000;53: 129. 15. chandler jg, pichot o, sessa c, et al. treatment of primary venous insuffi ciency by endovenous saphenous vein obliteration. vascular surg 2000;34:201-14. 16. navarro l, min r, boné c. endovenous laser: a new minimally invasive method of treatment of varicose veins. preliminary observations using an 810 nm diode laser. dermatol surg 2001;27:117-22. 17. bergan jj. surgical procedures for varicose veins. in: bergan jj, yao jst, eds. venous disorders. philadelphia: wb saunders company; 1991. pp 201-16. 18. perrin m, guex jj, ruckley cv, et al. recurrent varices after surgery (revas). cardiovasc surg 2000;8:233-45. 19. fischer r, linde n, duff c, et al. late recurrent saphenofemoral junction reflux after ligation and stripping of the greater saphenous vein. j vasc surg 2001;342:23640. 20. spreafico g, piccioli a, bernardi e, et al. six-year follow-up of endovenous laser ablation for great saphenous vein incompetence. j vasc surg 2013;1:20-5. 21. guex jj, isaacs mn. comparison of surgery and ultrasound guided sclerotherapy for treatment of saphenous varicose veins: must the criteria for assessment be the same? int angiol 2000;19:299-302. 22. dortu j. la crossectomie sous fasciale au cours de la phlébectomie ambulatoire du complex saphénien à la cuisse. phlébologie 1993;46:123-36. 23. pittaluga p, chastanet s, guex jj. great saphenous vein stripping with preservation of sapheno-femoral confluence: hemodynamic and clinical results. j vasc surg 2008;47:1300-4. 24. somjen gm, donlan j, hurse j, et al. venous reflux at the sapheno-femoral junction. phlebology 1995;10:132-5. 25. cappelli m, molino lova r, ermini s, et al. hemodynamics of the sapheno-femoral complex: an operational diagnosis of proximal femoral valve function. int angiol 2006;25:356-60. 26. carandina s, mari c, de palma m, et al. varicose vein stripping vs haemodynamic correction (chiva): a long term randomized trial. eur j vasc endovasc 2008;35: 230-7. 27. vidal-michel jp, bourrel y, emsallem j, bonerandi jj. respect chirurgical des crosses saphènes internes modérement incontinentes par “effet siphon” chez les patients variqueux. phlébologie 1993;46: 143-7. 28. pittaluga p, chastanet s, rea b, et al. varicose vein treatment and restoration of saphenous vein competence: the french asval method. phlebology 2006;21:45. 29. zamboni p, cisno c, marchetti f, et al reflux elimination without any ablation or disconnection of the saphenous vein. a haemodynamic model for venous surgery. eur j vasc endovasc 2001;21:361-9. 30. milleret r. great saphenous vein ablation with steam injection: results of a multicentre study. eur j vasc endovasc 2013;45: 391-6. 31. elias s, raines jk. mechanochemical tumescentless endovenous ablation: final results of the initial clinical trial. phlebology 2012;27:67-72. 32. almeida ji, julian jj, mackay e, et al. first human use of cyanoacrylate adhesive for treatment of saphenous vein incompetence. j vasc surg 2013;1:174-180. 33. zamboni p, menegatti e, occhionorelli s, salvi f. the controversy on chronic cerebrospinal venous insufficiency. veins & lymphatics 2013;2:e14. 34. einstein investigators, bauersachs r, berkowitz sd, et al. oral rivaroxaban for symptomatic venous thromboembolism. new engl j med 2010;363:2499-510. 35. uhl jf, verdeille s, martin-bouyer y. three-dimensional spiral ct venography for the pre-operative assessment of varicose patients. vasa-j vascular dis 2003;32: 91-4. 36. neglén p. endovascular treatment of chronic iliofemoral venous obstruction. a review. phlebolymphology 2003;43:204-11. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2015; volume 4:5531 [veins and lymphatics 2015; 4:5531] [page 59] saphenous sparing laser modern options (comment to gianesini et al., veins and lymphatics 2013;2:e21 and veins and lymphatics 2015;4:5246) enrique luis ferracani private cvs surgeon, former chief of navy hospital, argentina dear editor, in your journal i really liked reading the papers by gianesini et al. short endovenous laser ablation of the great saphenous vein in a modified chiva strategy,1 and laser-assisted strategy for reflux abolition in a modified chiva approach.2 saphenous sparing procedures demonstrated competitive results whenever compared with ablative ones.3,4 for this reason, in the last years i also experimented an innovative laser procedure with the aim of sparing the saphenous vein. the strategy is to reduce the enlarged great saphenous vein calibre by creating only partially shrunk rings of decreased calibre in the preterminal valve region of the great saphenous vein and then every 5 cm downward, covering a total length of 20 cm (figure 1). the procedure is performed by a 1470 nm laser. neither crossectomy nor total vein occlusion is done. in this way it is possible to spare the drainage of the junctional tributaries and to avoid the receck paradox concerning the post-procedural network predisposition to recurrence.5 phlebectomy of the incompetent tributaries along the leg completes the procedure. the rings of decreased calibre constitute an area of increased resistance, so counteracting the reflux coming from the incompetent junction during the diastole. during the muscular systole the flow accelerates through the reduced calibres following the castelli law, consequently reducing the shear stress and thus the inflammation on the vessel wall. technically these rings are created delivering 24 j/cm. up to now we treated 17 patients (c24epaspr) presenting an incompetent saphenofemoral junction and a great saphenous vein reflux, with a great saphenous vein junctional calibre greater than 6 mm. in a 3 years follow up we experienced 2 recurrences due to a hunterian and anterior accessory sapheonus vein incompetence. in all the other patients the sapheonus calibre remained reduced without any detectable reflux. the procedure is performed in an operating room, under sedation but without tumescence. we deliver 4 w for 6 s, never increasing the leed over 24 j/cm in order to avoid an excessive damage of the wall. after every ring shrunk a sonographic check is performed. the targeted percentage reduction is 50% of the pre-operative calibre. following our oral presentation at the xv pan american congress of phlebology and lymphology of lima peru on may 13, 2012, our work was awarded with the 1st prize of the xx argentine and international phlebology congress safyl 2013. we presented our preliminary experience also at the xvii world congress of the uip boston 2013 and published the pilot study on the journal of phlebology of the argentinean society.6 correspondence: enrique luis ferracani, private cvs surgeon, former chief of navy hospital, argentina. e-mail: eferracani@gmail.com key words: letter to editor; saphenous sparing procedures. received for publication: 30 september 2015. accepted for publication: 30 september 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright e.l. ferracani, 2015 licensee pagepress, italy veins and lymphatics 2015; 4:5531 doi:10.4081/vl.2015.5531 figure 1. rings of calibre reduction favoring a systolic anterograde flow and a diastolic retrograde draining flow into a re-entry perforator. no n c om me rci al us e o nly letter to the editor [page 60] [veins and lymphatics 2015; 4:5531] references 1. gianesini s, menegatti e, zuolo m, et al. short endovenous laser ablation of the great saphenous vein in a modified chiva strategy.. veins and lymphatics 2013; 2:e21. 2. gianesini s, menegatti e, zuolo m, et al. laser-assisted strategy for reflux abolition in a modified chiva approach. veins and lymphatics 2015;4:5246. 3. carandina s, mari c, de palma m, et al. varicose vein stripping vs haemodynamic correction (chiva): a long term randomised trial. eur j vasc endovasc surg 2008;35:230-7. 4. bellmunt-montoya s, escribano jm, dilme j, martinez-zapata mj. chiva method for the treatment of chronic venous insufficiency. cochrane database syst rev 2015;6:cd009648. 5. cestmir r. the hemodynamic paradox as a phenomenon triggering recurrent reflux in varicose vein disease. int j angiol 2012;21:181-6. 6. ferracani e. internal laser valvuloplasty and venous remodeling using 1470laser. initial experience. flebologia 2013;3:39-40. no n c om me rci al us e o nly early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. eissn 2279-7483 https://www.pagepressjournals.org/index.php/vl/index publisher's disclaimer. e-publishing ahead of print is increasingly important for the rapid dissemination of science. the early access service lets users access peer-reviewed articles well before print / regular issue publication, significantly reducing the time it takes for critical findings to reach the research community. these articles are searchable and citable by their doi (digital object identifier). veins and lymphatics is, therefore, e-publishing pdf files of an early version of manuscripts that have undergone a regular peer review and have been accepted for publication, but have not been through the typesetting, pagination and proofreading processes, which may lead to differences between this version and the final one. the final version of the manuscript will then appear in a regular issue of the journal. e-publishing of this pdf file has been approved by the authors. all legal disclaimers applicable to the journal apply to this production process as well. veins and lymphatics 2023 [online ahead of print] to cite this article: jianping deng, xiaoyin zhu, xin du, et al. chiva treatment for pelvic leak points in men. veins and lymphatics. 2023;12:11271. doi:10.4081/vl.2023.11271 ©the author(s), 2023 licensee pagepress, italy https://www.pagepressjournals.org/index.php/vl/index early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. chiva treatment for pelvic leak points in men jianping deng, xiaoyin zhu, xin du, lei su, yijian gu, qiang zhang dr. smile medical group, shanghai, china corresponding author: qiang zhang, sijun surgical clinic, hongxin medical technology center, no. 675 minbei road, minhang district, shanghai, china. tel. 021-60758889; 15000013163. e-mail: qiang.zhang@drsmilehealth.com key words: chiva, varicose veins, pelvic leak point (plp), hemodynamics. authors’ contributions: all the authors made a substantive intellectual contribution. all the authors have read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work. conflict of interest: the authors declare no potential conflict of interest. funding: none. ethics approval and consent to participate: no ethical committee approval was required for this case report by the department, because this article does not contain any studies with human participants or animals. informed consent was obtained from the patient included in this study. mailto:qiang.zhang@drsmilehealth.com early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. availability of data and materials: all data generated or analyzed during this study are included in this published article. early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. abstract pelvic leak points (plps) are a possible cause of varicose veins of the lower limbs even in men, and can be easily overlooked without a thorough assessment, or leading to incorrect treatment with high recurrence rate. chiva is a minimally invasive approach by recorrecting hemodynamic changes, preserving the venous drainage network in lower extremity. in this study, we present two cases of male patients with symptomatic varicose veins related to plps that were successfully treated with the chiva method. with proper venous hemodynamic assessment and strategic support, chiva could be a safe and effective way to treat plps in men. early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. introduction according to a national survey on the management of varicose veins in china, stripping and ablation were the most common treatments for varicose veins 1. in a separate survey of uk practices, 9% of the 100 respondents who treat varicose veins do not recognize pelvic venous reflux, and 11% do not investigate or treat it. coil embolization is used in 89% of treatments, and only 5% of respondents treat more than 10 patients annually, with just 14% using duplex ultrasound for follow-up2. recurrences after stripping have been related to pelvic venous reflux, evaluated as 17% but not specifically anatomically defined or treated3,4. thanks to echo-color-doppler investigation (ecd), different pelvic leak points (plps) responsible for varicose veins in the lower limbs have been detected and successfully treated using reflux ablation at the plps level5-9. accurate ultrasound hemodynamic assessment of each specific plps, as well as a specialized surgical technique, appear to be key to achieving satisfactory outcomes. the chiva method has been confirmed to be both safe and effective in treating this disorder. case reports diagnostic assessment two male patients presented to our vein center with aesthetic complaints and symptoms. the first patient (case a) was 50 years old and had edema and pain in his right lower extremity with visible varicose veins in the calf. he was evaluated for a c3epaspr cvd, which was first diagnosed twenty years before, and had a venous clinical severity score (vcss) of 6. the ecd revealed an escape point from the obturator leak point (op) that drained into the saphenous vein arch, between the terminal valve (tv) and pre-terminal valve (ptv), resulting in a type 4+2 shunt (figure 1a). the second patient (case b) was 35 years old who concerned with a pain and edema of the right leg early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. and had right lower extremity varicose veins with a vcss of 4. he was evaluated for a c3epaspr cvd. the ecd showed an inguinal leak point (ip) reflux in the right superficial ring of the inguinal canal, resulting in a type 4+2 shunt (figure 1b). the hemodynamic measures for both cases are reported in table 1. operative procedure chiva is an office-based treatment for varicose veins performed under local anesthesia. the aim of the technique is to lower veins transmural pressure in the superficial as well as deep venous system, preserve the venous drainage avoiding wide destruction of veins, and above all preserving the great saphenous vein (gsv) for any need of vascular surgery. the mainstay of this approach is a correct hemodynamic evaluation. a complete duplex scan is performed in a patient standing or in lying position if necessary to correctly determine the source of pressure overloads. haemodynamic manoeuvre are necessary to check the venous system: the hyperpressure valsalva manoeuvre as well as the gravitional paranà manoeuvre, or the static gravitional squeezing manoeuvre. the deep ambulatory non invasive measurement of the deep venous pressure10,11 is also necessary to highlight an increase of the residual pressure12-16. the strategy uses ligatures/disconnections targeted to interrupt escape points and fractionate hydrostatic pressure. case a various strategies can be employed, including ligation of the obturator point during saphenofemoral disconnection in the presence of associated terminal valve incompetence, or simple high ligation of the saphenous vein just below the superior collaterals of the junction. given the satisfactory function of the terminal valve, we opted for the latter approach and disconnection of type 2 shunts (figure 2a). early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. case b based on the plexus that runs through the subcutaneous fascia and connects to the collaterals of the anterior, bypassing the saphenous femoral junction (sfj), we chose disconnection of the ip at the subcutaneous fascia in the inguinal region and disconnection of type 2 shunts (figure 2b). local anesthesia with 5 ml of 1% lidocaine is administered to the incision site. both cases had their n2-n3 reflux tributary of the leg ligated with a total of 3 small incisions made in each patient. the patients were discharged 30 minutes after the operation, and instructed to wear compressive stockings as per our postoperative routine. clinical and ecd follow-up was scheduled at 1, 6, and 12 months. results one month after treatment, both patients reported reduced symptoms and no major or minor complications were observed. at the six-month follow-up visit, the patients reported no pain or heaviness and noted an improvement in their quality of life, with significant shrinkage of the varicose veins in the calf. at the one-year follow-up, no systolic valsalva recurrence at the ip in case b, no gsv systolic valsalva in case a, where of course there is a reversed valsalva negative drainage flow (chiva flow), and the diameter of the great saphenous vein was significantly smaller than before treatment. we took a complete photographic record before and after treatment (figure 3, figure 4). discussion plps have been found to contribute towards lower limb venous insufficiency with leg varicose veins. early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. varicose veins of pelvic origin in the male are not so rare, but some leakage points are infrequent. the valsalva manoeuvre is mandatory for a correct plp evaluation. delfrate17 specified that pelvic leaks points in men can be of different types: i) medial muscolar circumflex vein, anterior branch of the obturator vein, to be considered in the study of valsalva from the terminal valve or saphenous arch; ii) anterior and posterior pampiniform plexuses with possible reflux into the inferior epigastric vein but also with a direct collector in the saphenous arch; iii) scrotal perforator veins fed indifferently from the homoor contralateral pampiniform plexus; iv) penile root collector receiving reflux supply from the superficial dorsal penile vein, which in turn is in communication with the superficial or deep dorsal penile plexuses widely communicating between them. emma b dabbs suggests investigating pelvic vein reflux and considering pelvic vein embolization in such cases18. however, endovascular procedures can be more invasive and carry serious risks, such as the need for a main venous access, radiation exposure, and embolization-related complications19. in contrast, the chiva strategy is a minimally-invasive surgical approach that aims to correct imbalances in the venous system while preserving the gsv and venous network, which is important for future bypass and venous drainage. in our study, two male patients with symptomatic right lower extremity varicose veins and aesthetic concerns underwent chiva treatment under local anesthesia, and follow-up data was consistent with existing literature. in recent years, the chiva procedure has become the preferred method in our vein centers for treating varicose veins due to its advantages over traditional stripping or ablation treatments, including minimal invasiveness, reduced bleeding, less nerve damage, decreased postoperative pain, faster recovery, office-based treatment, lower recurrence rates, and most importantly, preservation of the saphenous veins. however, despite its demonstrated feasibility and safety in several studies, managing patients with lower extremity varicose veins caused by plps remains particularly early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. challenging5,6,8,20. plps act as perforating veins that supply superficial veins with reflux. the primary points of leakage are the perineal point (pp), fed by the internal pudendal vein or deep penile venous, and the inguinal point (ip), fed by the round ligament vein of the uterus or spermatic veins. most vulvar or perineal varices are fed by one of these two leakage points, which may extend to the superficial veins of the ipsilateral and/or contralateral lower extremity via anastomoses. attempting neovalvulation, ligation, or embolization of the veins in this single, incontinent network is doomed to fail because it will be promptly circumvented, and pressure or leakage through ip and/or pp will persist. to treat lower extremity superficial venous reflux of pelvic origin effectively, the leak points must be ligated in the same way as a refluxing perforating vein or junction. recurrence due to collateral flow will follow proximal or distal ligation without ligation of ip and/or pp. claude francheschi et al. (2005) presented the treatment of lower extremity venous insufficiency in women caused by plps. the article described the definition and functional anatomy of plps as well as its diagnostic and therapeutic strategies. the authors concluded that treatment of ip and pp location leads to simple and effective treatment of previously difficult-to-treat varicosities7. in 2019, roberto delfrate et al. assessed 273 plps free of pelvic congestion syndrome (pcs) with a minimum 12-month follow-up who underwent minimally-invasive procedures. of the 273 plps treated, 267 (97.8%) did not show any plps reflux recurrence. plps reflux recurrence was detected in 6 (2.2%) plps. three patients with plps reflux recurrence underwent a redo surgery (1.1%). in the remaining 3 patients with reflux redo, sclerotherapy was proposed. no cases of deep vein thrombosis, pulmonary thromboembolism, or death occurred. no bruises, subcutaneous inguinal or perineal hemorrhage, saphenous nerve neuralgia, wound infection, or superficial phlebitis occurred, with the exception of one inguinal bleeding that required immediate surgical exploration21. early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. according to rabe et al. (2015), embolization may not be necessary when treating leg varices of pelvic origin without pcs. patients with vulvar or pudendal varicose veins have achieved good results with foam sclerotherapy or phlebectomy. however, if pelvic vein embolization is performed prior to plps reflux ablation, a residual plps reflux may persist, which requires additional superficial treatment. therefore, pelvic varicose embolization should only be considered if plps reflux is resistant or if plps is associated with pcs22. the effectiveness and safety of the chiva method in treating male plps have already been established. as our understanding of the disease and its treatment improves, an increasing number of patients will benefit. however, this also emphasizes the need for all physicians involved to possess advanced knowledge of sonography and hemodynamics. conclusions we present two cases of successful treatment of male plps using the chiva strategy and surgical tactic planned thanks to the haemodynamic cartography. accurate ultrasound assessment and a deeper understanding of venous hemodynamics appear to be crucial for achieving satisfactory outcomes. we find this individualized strategy to be highly beneficial for these patients, as it enables precise blockage of escape points, preservation of the gsv trunk, and a quick return to normal work and daily activities. early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. references 1. zhang m, qiu t, bu x, et al. a national survey on management of varicose veins in china. j vasc surg venous lymphat disord. 2018;6:338-346.e1. 2. campbell b, goodyear s, franklin i, et al. investigation and treatment of pelvic vein reflux associated with varicose veins: current views and practice of 100 uk vascular specialists. phlebology. 2020;35:56-61. 3. perrin mr, labropoulos n, leon lr jr. presentation of the patient with recurrent varices after surgery (revas). j vasc surg. 2006;43:327-34. 4. reich-schupke s, mendoza e, dörler m, et al. frequency of refluxive tributaries of the junction region in the groin in patients with recurrent varicose veins of the thigh. phlebologie. 2016;45:149-53. 5. franceschi c. anatomie fonctionnelle et diagnostic des points de fuites bulbo-clitoridiens chez la femme (point c). journal des maladies vasculaires. 2008;33:s42. 6. franceschi c, bahnini a. points de fuite pelviens viscéraux et varices des membres inférieurs[j]. phlébologie. 2004;57:37-42. 7. francheschi c, bahnini a. treatment of lower extremity venous insufficiency due to pelvic leak points in women. annals of vascular surgery. 2005;19:284-8. 8. franceschi c, zamboni p. principles of venous hemodynamics[m]. nova biomedical books, hauppauge, ny, usa. 2009. 198 pp. 9. ricci s. phlebology in 21st century. veins and lymphatics. 2014;3:2268. 10. bartolo m, nicosia pm, antignani pl, et al. noninvasive venous pressure measurements in different venous diseases. a new case collection. angiology. 1983;34:717-23. 11. bartolo m. antignani pl, nicosia pm, et al. noninvasive venous pressure measurement and its early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. validation. int angiol. 1988;7:182-9. 12. franceschi c. théorie et pratique de la cure conservatrice et hémodynamique de l’insuffisance veineuse en ambulatoire. precy-sousthil, france, editions de l’armançon. 1988. 13. delfrate r. a new diagnostic approach to varicose veins: haemodynamic evaluation and treatment. lorena dioni publisher. 2014. 14. zamboni p, mendoza e, gianesini s. saphenous vein-sparing strategies in chronic venous diseases. springer, new york, usa. 2018. 15. mendoza e. duplexsonographie der oberflächlichen beinvenen. springer, new york, usa. 16. faccini f p. franceschi claude and ermini stefano editors. hemodynamic saphenous preserving procedures in chronic venous disease: can, and should, we preserve the saphenous vein? 2022. 17. delfrate r. anatomy of pelvic leak points in the context of varicose veins. phlebologie. 2021;50:42-50. 18. dabbs e b, dos santos s j, shiangoli i, et al. pelvic venous reflux in males with varicose veins and recurrent varicose veins. phlebology. 2018;33:382-7. 19. lopez aj. female pelvic vein embolization: indications, techniques, and outcomes[j]. cardiovascular and interventional radiology. 2015;38:806-20. 20. saphenous vein-sparing strategies in chronic venous disease. springer, new york, usa. 2018. 21. delfrate r, bricchi m, franceschi c. minimally-invasive procedure for pelvic leak points in women. veins and lymphatics. 2019;8:7789. 22. rabe e, pannier f. embolization is not essential in the treatment of leg varices due to pelvic venous insufficiency. phlebology, 2015;30:86-8. early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. table 1. morphologic and hemodynamic measurements recorded both in case a and b. early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 1. a) type 4+2 shunt (op): pathological inversion of the physiological order of emptying from obturator point into gsv arch and trunk (n2), competent terminal valve, n2-n3 and n2-n4t additional escape points, reversed flow in n3 and n4t, re-entery points through n3 (n3-n1), and also through the n4t (n2-n4t-n2-n1; n4t-n1). a re-entry direct perforator is focused on the gsv (n2-n1). b) type 4+2 shunt (ip): pathological inversion of the physiological order of emptying from inguinal point through an arch tributary into gsv (n1-n3-n2), competent terminal valve, incompetent gsv preterminal valve, paranà diastolic reverse flow in the thigh gsv arch; two direct re-entry perforators on the gsv (n2-n1), and n2-n3 escape point below the knee: the incompetent tributary has its own rp (n3-n1). dv-n1, deep vein; gsv-n2, great saphenous vein; ssv-n2, small saphenous vein; ep, escape point; rp, re-entry point; op, obturator point; ip, male inguinal point. early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 2. the green double arrows(↔) show the location of the incision for surgical treatment. both cases had their n2-n3 reflux tributary of the leg ligated with a total of 3 small incisions made in each patient. early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 3. case a. a) preoperative; b) 1 month postoperative; c) 4 month postoperative; d) 12 month postoperative. early access veins and lymphatics case report the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 4. case b. a) preoperative; b) 1 month postoperative; c) 12 month postoperative. alessandro rasman letter to veins and lymphatics alessandro rasman to the editor corner paolo zamboni, md sir, i read with interest the article titled transvascular autonomic modulation: a modified balloon angioplasty technique for the treatment of autonomic dysfunction in multiple sclerosis patients of arata and sternberg published in the journal of endovascular therapy. 1 it seems that pta also stimulates the vagus nerve with improvement of sleep and other symptoms impacting the quality of life. dr. arata and his team suggests this new theory, with previous articles published in phlebology 2 and in acta phlebologica. 3 what is your opinion on this topic? alessandro rasman (trieste, italy) e-mail: alessandro.rasman@libero.it references 1. arata m, sternberg zj. transvascular autonomic modulation: a modified balloon angioplasty technique for the treatment of autonomic dysfunction in multiple sclerosis patients. endovasc ther 2014;21:417-28. [crossref] 2. sternberg z, grewal p, cen s, et al. blood pressure normalization post-jugular venous balloon angioplasty. phlebology 2013 nov 19. [epub ahead of print]. [crossref] [pubmed] 3. arata m, debarge p. transvascular autonomic modulation, initial assessment of safety. acta phlebologica 2014;15:19-23. [crossref] reply by paolo zamboni dear mr rasman, thank you for your letter and for the interesting questions regarding the intriguing article of arata and sternberg. my first consideration is that the improvement of venous outflow permits to improve csf flow. 1 this is very important because seems to be linked with lesions formations in the white matter. it has been proven that extracranial venous outflow abnormalities determine significant reduction of cerebral spinal fluid reabsorption, and this, in turn, is proportional to the number and volume of t2 lesions either in multiple sclerosis or in alzheimer disease. 2,3 moreover, pta or other surgical techniques could also improve brain perfusions, an aspect actually under investigation. 4,5 the authors are providing very interesting data about additional effects of venous pta linked with vagus stimulation in consequence of balloon inflation. my second consideration is that these further therapeutic effects may contribute to explain us the rapid recovery of autonomic symptoms referred by the vast majority of patients after balloon angioplasty, usually considered placebo effect. only the double-blinded brave dreams trial may completely clarify the latter point. 6 references 1. zivadinov r, magnano c, galeotti r, et al. changes of cine cerebrospinal fluid dynamics in patients with multiple sclerosis treated with percutaneous transluminal angioplasty: a case-control study. j vasc interv radiol 2013;24:829-38. [crossref] [pubmed] 2. beggs c, chung cp, bergsland n, et al. jugular venous reflux and brain parenchyma volumes in elderly patients with mild cognitive impairment and alzheimer’s disease. bmc neurol 2013;13:157. [crossref] [pubmed] 3. magnano c, schirda c, weinstock-guttman b, et al. cine cerebrospinal fluid imaging in multiple sclerosis. j magn reson imaging 2012;36:825-34. [crossref] [pubmed] 4. zamboni p, menegatti e, weinstock-guttman b, et al. hypoperfusion of brain parenchyma is associated with the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a cross-sectional preliminary report. bmc med 2011;9:22. [crossref] [pubmed] 5. zamboni p, menegatti e, occhionorelli s, salvi f. the controversy on chronic cerebrospinal venous insufficiency. veins and lymphatics 2013;2;e14. [crossref] 6. zamboni p, bertolotto a, boldrini p, et al. efficacy and safety of venous angioplasty of the extracranial veins for multiple sclerosis. brave dreams study (brain venous drainage exploited against multiple sclerosis): study protocol for a randomized controlled trial. trials 2012 3;13:183. [top] hrev_master veins and lymphatics 2014; volume 3:1919 [veins and lymphatics 2014; 3:1919] [page 19] multiple ligation of the proximal greater saphenous vein in the chiva treatment of primary varicose veins roberto delfrate,1 massimo bricchi,1 claude franceschi,2 matteo goldoni3 1surgery unit, figlie di san camillo hospital, cremona, italy; 2angiology consultant, saint joseph hospital, paris, france; 3department of consulting of clinical medicine, nephrology and health sciences, university of parma, italy abstract saphenous femoral disconnection is the key point of most surgical techniques in the treatment of primary varicose vein surgery. the aim of this study is to compare and analyze different techniques for conservative saphenousfemoral ligation or disconnection. these techniques can be to perform mini invasive open surgery and are suitable for implementation of the conservative hemodynamic correction of venous insufficiency (chiva) method. the aim was to present the follow-up by retrospective analysis of three different ligation-disconnection techniques of the proximal great saphenous vein (gsv) according to the chiva method at the gsv end, i.e. between the very end of the gsv and the first arch tributary, according to the chiva method. the first thecnique consisted of a surgical division (crossotomy). the other two consisted of triple superposed ligation with no. 2 non-absorbable braided coated suture without division labeled tsfl (triple saphenous flush ligation) and no. 0 polypropylenene ligation tpl (triple polypropylene ligation). the difference between tsfl and tpl was in the thickness and type of material of the thread, though both were non-absorbable. the follow up of 56 tpl procedures, 61 crossotomy procedures, and 82 tsfl procedures was analysed. the follow-up consisted of checking the sapheno-femoral junction occlusion with duplex color ultra sound. the incidence rates of neovascularization (new vessels in the ligation or surgical disconnection site with saphenous-femoral reflux during the valsalva maneuver) were: 4.9% for the crossotomy group, 6.1% for the tsfl group and 37.5% for the tpl group. the data analysed show satisfactory results with both crossotomy and tsfl. crossotomy has proven to be an effective technique for performing saphenous-femoral disconnection, but tsfl could also be a reliable, safe and low-cost varicose mini-invasive surgery in outpatients. tpl appeared to be less reliable. introduction the sapheno-femoral junction (sfj) is a key point for the venous drainage of the lower limb from the foot up to the hip and gluteus, the lower abdominal wall and lower genital tract. moreover, the disconnection of the incompetent sfj is a fundamental procedure to most open superficial venous surgery.1-5 unfortunately, most varicose recurrences are due to sfj neovascularization (recurrences) observed in 25% to 94% of recurrent varicose veins.6 conservative saphenous-femoral disconnection is a very common surgical practice according to the conservative hemodynamic correction of venous insufficiency (chiva) method.7-12 for more than a decade we have tested a technique that requires a division of the sfj and others that require only peculiar ligatures without division of the incompetent saphenous femoral tract. the simplicity of the procedure, the safety of the maneuver, and the effectiveness of the treatment have been our goals. materials and methods sfj disconnections and ligations were performed using three different techniques in patients affected by sfj reflux through the terminal and also subterminal valves responsible for clinical disorders. all the varicose patients were assessed by duplex ultra sound (us), where the sfj reflux was checked with the valsalva, squeezing and paranà maneuvers with doppler sample on the femoral side of the terminal valve, and sfj were skin marked using the duplex us scan probe (12 mhz probe). the techniques were performed in outpatients, under local anesthesia and by the same surgeon. the surgeon and other coauthors did the follow-up checkup using the same color doppler ultrasound equipment: in particular, neorevascularization was detected at the disconnection-ligation site using the color fuction during the valsalva maneuver. the valsalva maneuver was performed by having the patients to blow into a straw that was closed at one end: cremona maneuver.13 in all the cases the valsalva maneuver was performed after properly emptying of the deep venous system through the performance of a parana maneuver with the aim to prevent false negatives caused by the presence of a full deep venous system. parana is a gravitational test performed on a patient standing in front of the examiner who pushes the patient’s back off balance, either backward (posterior paranà maneuver) or forward (anterior paranà maneuver). in order to maintain balance there is an isometric reactive contraction of the muscular groups that activates venous circulation by emptying the deep venous system. all the sfjs were studied in order to rule out both a valsalva of pelvic origin and one deriving from a lateral crural perforator. surgical procedure the saphenous-femoral disconnection-ligation was performed between the sfj and the first arch tributary, preserving both the arch tributaries and the great saphenous vein (gsv) trunk (figure 1), while the refluxing tributaries were divided at their trunk connection. a titanium clip (10 mm long and 1 mm thick) was placed flush with the femoral vein in all cases of the the three groups in order to prevent the presence of a residual saphenous stump. the gsv ligation was performed with a no. 2 non-absorbable braided coated suture in the triple saphenous flush ligation (tsfl) group, and with no. 0 polypropylenene ligation in triple polypropylene ligation (tpl) group. the sfj is exposed thanks to a previous suspension on silicone loops of the superficial epigastric vein, the pudendal vein and the great saphenous vein. the first gsv ligation is performed in a layer close to tributary outflow into the sfj, the second one as close as possible to the femoral vein, and the third one in an intermediate position. the disconnection is called crossotomy when it consists of a division. it is called selective ligature when no interrution is performed. in case of crossotomy the fossa ovalis was closed with a polypropylene suture. subjects and interventions the number of interventions and patients during follow-up visits are reported in table 1. the follow-up period was longer for crossotomy than the other two groups; in particular, in the tpl group the follow-up was always ≤12 correspondence: roberto delfrate, figlie di san camillo hospital, via fabio filzi 56, 26100 cremona, italy. tel.: +39.0372.421111 – mobile: +39.334.9089110. e-mail: roberto.delfrate@icloud.com key words: saphenous-femoral disconnection, saphenous-femoral junction, neovascularization recurrences, primary varicose vein surgery. received for publication: 11 september 2013. revision received: 11 february 2014. accepted for publication: 6 march 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright r. delfrate et al., 2014 licensee pagepress, italy veins and lymphatics 2014; 3:1919 doi:10.4081/vl.2014.1919 no nco mm er cia l u se on ly article [page 20] [veins and lymphatics 2014; 3:1919] months. crossotomy is the technique that was adopted and has been commonly used since 2003, while the tsfl experience began in 2007. since 2007 the number of crossotomy procedures has therefore been reduced and this is the reason why crossotomy procedures usually require a longer follow-up. statistical analysis normally distributed variables were reported as mean; otherwise, as median (interquartile range). differences among groups for continuous variables were assessed by means of anova followed by tukey’s post-hoc test or the kruskal-wallis test followed by the bonferroni post-hoc test. differences in categorical variables were assessed by means of the chisquare test using the bonferroni correction. survival was considered as follows: i) the event was neovascularization for the crossotomy group, considered the control group; ii) the event was asymptomatic or symptomatic recanalization during the follow-up period. kaplan-meyer survival curve was calculated for the survival data followed by log-rank test with the bonferroni correction which was calculated for the survival data to assess the differences among groups. an adjusted model for age and gender was further calculated using the cox regression. all the models were repeated with and without bilateral surgery, when in the first case unilateral surgery; all the surgeries were considered as independent measures. p=0.05 was the significance value. all the statistical tests were performed with spss 20 (ibm corp., chicago, il, usa). results four hundred nine tsfl procedures where performed from january 2007 to january 2011. from january to may 2011, 82 procedures were controlled. the follow-up checks at six months and longer were only possible in 71 patients because some of the patients didn’t want to undergo an examination, saying on the phone, that they were satisfied with the operation outcome and didn’t feel that a follow-up was necessary. five recurrences due to recanalization of the ligatures with saphenous-femoral reflux were detected at the procedure site in three patients (two bilateral, one unilateral). the reflux during the valsalva test was limited to the sfj in one case, it reached the gsv right below the preterminal valve in one case, in another case one it reached the proximal third of the thigh, and in another two cases was at mid-thigh level. both patients who had had a bilateral procedure showed a reflux starting eight months after the operation and the follow-up was at 35 and 33 months for the male and at 31 to 26 months for the female. one patient who had had a unilateral procedure with saphenous-femoral reflux recurrence detected at 14 months after surgery didn’t accept any further follow-up because he was satisfied with the clinical result. whereas the two other patients were satisfied with the operation despite both showing a bilateral saphenous-femoral reflux at the thigh: in one case at the preterminal valve, and in three cases at the middle of the thigh. total recurrences amounted to 5/82=6.1% of all cases treated. the four cases of reflux below the preterminal valve represented 4.8% out of the 82 tsfl procedures. the rate of tsfl recanalizations was 4.8% below the pre-terminal valve. the valsalva reflux flew clearly below the preterminal valve only in three cases. therefore the percentage of cases in which the reflux reached the proximal third and midthigh went down to 3.6%. all the patients were pleased with the clinical results and didn’t show any visible recurrence of varicose veins. fifty-three patients who had crossotomy procedures were followed up with from january 2008 to december 2010. the average follow-up period was 29 months. saphenousfemoral reflux due to neovascularization (no residual stump was detected on the femoral side of the crossotomy) was identified thanks to the valsalva maneuver in one patient at the sfj above the preterminal valve (this means the sfj that remains after the section for the crossotomy procedure) and at proximal third of the thigh in two cases. the prevalence of neovascularization at 12 months was 0% and only three interventions showed neovascularization at 19 and two at 30 months; cumulative incidence 3/61=4.9%. no varicose veins recurrence was visible and all the patients were asymptomatic. fifty-five patients (37 female, 18 male), had triple prolene ligature procedures (2004-2005). forty-nine of them had a follow-up check one year after the operation; 21 showed recanalization with saphenous-femoral reflux; 14 were asymptomatic with moderate valsalva reflux at the upper third of the thigh and seven were symptomatic with valsalva reflux down to the lower leg. all recurrences occurred between the 3rd and 6th month after surgery. re-operation (crossotomy) under local anaesthesia and with a minimal surgical trauma, was performed in three cases. the surgical dissection showed new vessels around the polypropylene thread. the cumulative incidence of recanalization was 21/56=37.5% at one year. looking at the differences among groups (table 1), age was not significant for neither the unilateral or the bilateral patients. in the case of the bilateral patients, the age at both interventions and that at the first intervention gave no different results. the percentage of females was higher in the crossotomy group, but it did not reach significance looking at multiple comparison. however, age and gender were further considered as factors that could affect the efficacy of this method. the incidence rates were: 0.0017 event/ month/patient for the crossotomy group, 0.0037 event/month/patient for the tsfl group and 0.040 event/month/person for the tpl group. looking at survival curves (figure 2), both the crossotomy and tsfl groups were signifitable 1. characteristics of the patients. crossotomy tsfl tpl interventions 61 82 56 patients 53:45 u, 8 b 71:60 u, 11 b 55:54 u, 1 b gender 6 m/47 f 19 m/52 f 18 m/37 f age, years (bilateral=1° intervention) 57.8 (12.3) 58.3 (12.3) 62.9 (12.4) age, years (bilateral=both) 58.6 (12.6) 58.2 (12.4) 63.0 (12.3) follow-up time (months) 29.0 (18.5-34.0) 14.0 (12.0-20.0) 12.0 (6.0-12.0) tsfl, triple saphenous flush ligation; tpl, triple polypropylene ligation; u, unilateral; b, bilateral. table 2. cox regression results, using crossotomy as control group (0). b se sig. exp(b) 95% ci tsfl(1) 1.376 0.835 0.099 3.960 0.770 20.356 tpl(2) 4.306 1.026 <0.001 74.161 9.928 553.949 age 0.020 0.016 0.216 1.020 0.989 1.052 gender -0.430 0.397 0.280 0.651 0.299 1.418 b, variable coefficient in the cox regression; se, standard error; sig, significance; exp(b), exponential of b. exp(b) is the ratio of the hazards between two individuals whose values of x variable differ by one unit when all other covariates are held constant. it can be interpreted as a relative risk; ci, confidence interval; tsfl, triple saphenous flush ligation; tpl, triple polypropylene ligation. no nco mm er cia l u se on ly article [veins and lymphatics 2014; 3:1919] [page 21] cantly different from the tpl group (p<0.001), but the difference was not significant between them (p=0.08) if we consider all the surgical interventions as independent. results did not change when only unilateral interventions were considered or in the case of bilateral interventions only the first one was taken (not shown). the same model was weighted for gender and age, and the results of the cox regression model are reported in table 2 (crossotomy group was the control). gender and age were not significant, and the results substantially confirmed those of the unweighted model. discussion the conservative saphenous-femoral disconnection is performed, according to the chiva strategy, in order to preserve the drainage of the collateral veins and also to disconnect a closed shunt. the drainage of the collateral veins of the sfj is preserved in order to prevent defects of flow in these veins, that can trigger recurrences do to neovascularization. the chiva strategy focuses on the treatment of the shunt escape point in order to eliminate shunt pressure. a closed shunt is a recirculation with pressure overload caused by a district skip. the reflux arises from an escape point (n1-n2), flows into superficial veins and returns into deep veins through a reentry point again reaching again the escape point. the objective of this trial was to assess the durability of sfj closure. this trial is not a randomized controlled trial but groups are homogeneous, there being only one surgeon and three duplex scan operators. the survival curves show a clear difference of the crossotomy and tsfl groups and the tpl group, but also show that the difference was not significant between them especially if we consider the cases of recurrence with reflux at the thigh during the systole of valsava. contrary to tpl, tsfl didn’t show significant recurrences. this suggests strongly the incidence of the technique as thread features on the recanalization. the short recurrent valsalva reflux after tsfl is explained by the narrow and long residual reflux lumen (three superposed ligations along 5 to 10 mm) at the procedure site, which represents a resistance that hampers a massive consequent flow. in all the reflux recurrences in the crossotomy and tsfl groups, patients were asymptomatic and nonvaricose veins recurrence was visible. however, the difference between tpl and tsfl, both techniques of sfj disconnection without division, is evident. the analysis of tpl follow up suggests us that the polypropylene thread used, even if of size 0, may cause a necrosis with a section of the vein wall. the formation of neovascularization around the ligations may be a consequence. this conclusion has been confirmed by the evidence we saw in the three patients that underwent re-do surgery. for this reason we have decided to use a less elastic overcoated thread of larger size in order to prevent this occurance. despite these data, observation of a greater number of tsfl controls would be useful. conclusions crossotomy is the saphenous-femoral disconnection technique of reference in the implementation of the chiva strategy. crossotomy is a refined surgical technique especially in overweight patients. the efficacy of the tsfl technique could be considered equal to that of crossotomy. the practical impact of tsfl is to provide a safe, reliable and durable mini-invasive open surgery for sapheno-femoral disconnection in outpatients, while tpl ligation is not reliable. saphenous-femoral recanalizations were asymptomatic in both tsfl and crossotomy groups, thanks to the draining effect of the spared saphena trunk, and consequently thanks to the quality of the re-entry point. both crossotomy and tsfl showed no surgical complications. tsfl is easier and quicker than crossotomy because of the absence of vessel division. on the basis of what has been observed, both crossotomy and tsfl are suitable techniques for eliminating femoralsaphenous refux at the terminal valve escape point in case of incontinence of the terminal valve. both techniques are adequate to maintaine the results of the disconnection/ligation over time, with the advantage of the conservation of the drainage of all the collateral veins of the sfj. an ethics committee consultation has not been considered necessary, as the ligature of confluent veins has been used in clinical practice for years since the articles published by trendelenburg14 until today.15 references 1. zamboni p, cisno c, marchetti f, et al. minimally invasive surgical management of primary venous ulcer vs. compression treatment: a randomized trial. eur j vasc endovasc surg 2003;25:313-8. 2. zamboni p, gianesini s, menegatti e, et al. great saphenous varicose vein surgery without sapheno-femoral disconnection. figure 1. saphenous femoral disconnection with division on the left (crossotomy) and saphenous femoral multiple ligation without division on the right (tsfl). figure 2. survival curves of crossotomy (black continuous line), triple saphenous flush ligation (black dashed line) and triple polypropylene ligation (grey continuous line). crosses are censored data. no nco mm er cia l u se on ly article [page 22] [veins and lymphatics 2014; 3:1919] br j surg 2010;97:820-25. 3. carandina s, mari c, de palma m, et al. varicose vein stripping vs haemodynamic correction (chiva): a long term randomised trial. eur j vasc endovasc surg 2008;35:230-7. 4. parés jo, juan j, tellez r, et al. varicose vein surgery: stripping versus the chiva method: a randomized controlled trial. ann surg 2010;251:624-31. 5. iborra-ortega e, barjau-urrea e, vila-coll r, et al. comparative study of two surgical techniques in the treatment of varicose veins of the lower extremities: results after five years of follow-up. [estudio comparativo de dos técnicas quirúrgicas en el tratamiento de las varices de las extremidades inferiores: resultados tras cinco años de seguimiento]. angiología 2006;58: 459-68. 6. brake m, lim cs, shepherd ac, et al. pathogenesis and etiology of recurrent varicose veins. j vasc surg 2013;57:860-8. 7. delfrate r. manuale di emodinamica venosa degli arti inferiori. cremona: fantigrafica ed.; 2010. 8. delfrate r, grilli n. a new diagnostic approach to varicose veins: haemodynamic evaluation and treatment. folgaria: lorena dioni publ.; 2014. 9. franceschi c. la cure hemodynamique de l’insuffisance veineuse en ambulatoire. j malad vasc 1997;22:91-5. 10. franceschi c. theorie et pratique de la cure conservatrice et hemodynamique de l’insuffisance veineuse en ambulatoire. précy-sous-thil: de l’armançon ed.; 1988. 11. franceschi c, zamboni p. principles of venous hemodynamics. new york: nova science publ.; 2009. 12. bellmunt-montoya s, escribano jm, dilme j, martinez-zapata mj. chiva method for the treatment of varicose veins (protocol). cochrane database syst rev 2012;2: cd009648. 13. delfrate r. moderni fondamenti di diagnostica emodinamica dell’insufficienza venosa degli arti inferiori. cremona: ed. fantigrafica; 2013. 14. trendelenburg f. ueber die unterbindung der vena saphena magna bei unterschenkelvaricen. beitrage klin chir 1890;7:195-210. 15. carroll c, hummel s, leaviss j, et al. clinical effectivness and cost-efettivness of minimally invasive techniques to manage varicose veins: a systematic review and economic evaluation. health technol assess 2013;17(48). no nco mm er cia l u se on ly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: six-year follow-up of endovenous laser ablation for great saphenous vein incompetence by spreafico g, piccioli a, bernardi e, giraldi e, pavei p, borgoni r, ferrini m, baccaglini u. j vasc surg 2013;1:20-5. stefano ricci and fedor lurie abstract a prospective cohort study to assess the efficacy of endovenous laser ablation (evla) for treatment of great saphenous vein (gsv) insufficiency over a 6-year follow-up period was conducted at the multidisciplinary centre of outpatient surgery university hospital, padua (italy). patients were recruited between january 2003 and july 2004, and the follow-up phase lasted until july 2010. two hundred and four patients underwent evla procedure at the outpatient surgery unit. a 980-nm diode laser and tumescent echo color doppler (ecd) guided perivenous anesthesia were used. the most prominent varices were treated with stab-vein avulsion immediately after the evla procedure. all patients had to wear 35-mm hg elastic compression stockings for 24 h daily during the first week after evla, and then switch to second-class graduated elastic compression stockings for 4 weeks more. patients were scheduled for clinical and ecd assessments at 3, 7, 30, and 90 days after evla; and thereafter once a year, for 6 years. the main outcome of the study was the incidence of clinical (e.g., lack of improvement or worsening of leg symptoms) and ecd-confirmed (e.g., finding of measurable venous reflux in the treated segment) evla failures (ecefs) during the planned 6-year follow-up period. the ecefs were categorized as type 1 (venous reflux limited to the junction and/or the residual saphenous stump, for a maximum length of 5 cm from the junction, without reflux in its collaterals); type 2 (reflux also in a collateral vein without clinically evident recurrent varices ); or type 3 (same as 2 with clinically evident recurrent varices, either symptomatic or asymptomatic). one hundred and twenty four patients (60.8%) underwent stab-vein avulsion as well; and 65 patients (32.8%) with residual varicose veins received sclerotherapy within 12 weeks from the procedure. fourteen (6.8%) out of 204 patients were lost for follow up. no deep vein thrombosis was detected during the follow-up period. after 6 years, 168 (88.4%) patients reported a symptomatic improvement; of them, 87 patients had no residual symptoms, and 81 experienced a significant reduction of their leg complaints. fourteen patients complained of persistent symptoms, six reported unsatisfactory aesthetic results, and two patients had worsened skin alterations. of these 22 patients, only two had an ecef as well. patients with a competent saphenous junction and a persistently occluded saphenous trunk were 70.0% (133/190); therefore, 57 (30.0%) had an ecef. of them, 20 patients had a type 1 ecef, 18 had a type 2 ecef [three of which were at the anterior accessory saphenous vein (assv)], and 19 had a type 3 ecef (12 of which were at the assv). an atypical junction or one with a diameter ≥8 mm and a mean trunk diameter ≥8 mm, were highly significantly associated with ecef. expected evla results, either from a clinical or technical (ecd) perspective, were obtained in 88.4% and 70.0% patients, respectively, and persisted throughout the 6-year follow-up period. all failures were observed within the first 2 years from evla. the unexpectedly high (57/190; 30.0%) rate of ecef is possibly due to the systematic application of the valsalva maneuver during ecd; this probably accounts for the high rate of type 1 ecef. it is likely that most of the technical failures observed will soon be eliminated thanks to the use of adequate linear endovenous energy density (leed) (at least 70 joules/cm), which was not in use in the period studied, and to the latest implements now available. invited commentary by fedor lurie the reflux in the remaining proximal segment of the great saphenous vein (gsv) occurs more frequently than previously thought, and progresses mostly during the first year, and exclusively within 2 years after treatment. the relationships between clinical outcomes and the ultrasound findings after thermal ablation of the gsv are rather complex. only two of the 22 patients with clinical failure also had endovenous laser ablation failure confirmed by duplex ultrasound. conversely, only half of the patients with progressive reflux developed symptoms. how much of this failure is due to the non-venous nature of patients’ symptoms remains unknown. interestingly, the majority of clinically relevant recurrences was associated with reflux in the previously competent anterior accessory saphenous vein (aasv). authors used a prophylactic dose of low-molecular-weight heparin in 44 patients. surprisingly, the only two cases of endovenous heat-induced thrombosis (ehit) (both type 2) occurred in patients who received this prophylaxis. comment by stefano ricci my compliments to the authors for their compelling and well developed study showing long-term results of evla treatment. interestingly, final data (although filtered through specific variables and anatomical conditions) appear proximal to the results obtained with most other techniques in use for treating great saphenous vein (gsv) incompetence, though being less expensive. this is in contrast with some 100% good results claimed when evla was firstly adopted. the caliber of the gsv, either at the junction or at the trunk, seems to affect the outcome; for this reason, it is a pity that authors did not report detailed data concerning gsv calibers, especially in ecef cases. as regards the anterior accessory saphenous vein (aasv), it seems that out of 37 cases of failure (ecef 2+3), 15 patients (i.e. nearly 50%) had aasv involved, although these veins were competent at the pre-operative echo color doppler (ecd) evaluation. in fact, if laser action at the junction involves the competent terminal valve of aasv, it is likely that this vein, if supported by a sufficient antegrade flow, will re-canalize at the junction, though without a more specific terminal valve competence. probably, when an aasv is found pre-operatively, the laser action should avoid the entire confluence of the superficial inguinal veins region to save the aasv valve. the same could be possible in presence of a giacomini vein. authors' reply (g. spreafico and p. pavei) the first comment by s. ricci deals with evla efficacy. this paper reports data of our early experience with evla, between 2003-2004, and results are therefore to be considered as a sort of historical benchmark. now, ten years later, thanks to higher delivered energy and new devices, i.e. 1470 nm laser and radial fibers, re-canalized trunks are very rare, reflux on the aasv is decreased to 3.7% and isolated reflux of the junction or of the stump is about 4.9%. these are unpublished data on 174 consecutive patients recruited between 2008-2009, who underwent evla procedure by 1470 nm laser and radial fiber with a mean 3 years follow up. these results are definitely better with a percentage of good technical results of 88.4%, essentially comparable with the good clinical outcomes obtained in the published study and verified with the same very careful ecd exam. unfortunately, to my knowledge, in literature there are not similar available long term prospective studies about the other therapeutic options to face with. the mean caliper of the treated trunks of the 190 patients who completed the 6 years follow up, measured with the patient standing, was 7.1 mm (ds 1.2, range 6-12) and the mean caliper measured 2 cm below the sapheno-femoral junction was 8.8 mm (ds 2.3, range 6-16). the multiple logistic regression analysis showed that diameters of the saphenous trunk or 2 cm below the junction major than 8 mm, were statistically significative risk factors for ecef. as regard the anterior accessory saphenous vein (aasv–assv is a misprint), i totally agree with s. ricci and it should always be tested. when the patients of the study were treated, we used to place the tip of the fiber 2 cm below the junction or below a big competent saphenous branch. [top] hocaoglu c. clozapine-induced rabbit syndrome: a case report meta-analyses vs opinions paolo zamboni i get the impression that the dispute about ccsvi is a common place without the possibility of bringing out the ongoing contributions that emerge from the literature. this appears especially when some studies which denies the contribution of ccsvi to neurodegeneration, show an unexpected and unusual media coverage. this of course generates confusion among patients. but also among colleagues who do not have cerebral venous return as primary interest. in short, there are 3 meta-analyses available from: 1. laupacis a, lillie e, dueck a, et al. association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis. cmaj 2011;183:e1203-12.[pubmed] 2. tsivgoulis g, sergentanis tn, chan a, et al. chronic cerebrospinal venous insufficiency and multiple sclerosis: a comprehensive meta-analysis of case-control studies. ther adv neur dis 2013.[full-text] 3. zwischenberger ba, beasley mm, davenport dl, xenos es. meta-analysis of the correlation between chronic cerebrospinal venous insufficiency and multiple sclerosis. vasc endovasc surg 2013.[pubmed] all the 3 above-mentioned meta-analyses confirm a significant prevalence of ccsvi in ms. only six out of 19 comparable studies deny the association between ccsvi and multiple sclerosis. but while the first two meta-analysis showed heterogeneity among the studies, the third demonstrated clearly a significant double risk in having ms when ccsvi is detected, without any heterogeneity. the mass media should require a good communication of science when scientific press releases are solicited. in controversy regarding prevalence and risk factors, to consult meta-analysis is a good tool to balance the communication. [top] hrev_master veins and lymphatics 2016; volume 5:5764 [veins and lymphatics 2016; 5:5764] [page 45] effective prophylaxis of visual and neurological disturbances with an anti-endothelin drug: analysis of 1642 sclerotherapy sessions alessandro frullini,1 angelo guastini,2 demetrio guarnaccia,3 o. walter loparco,4 domenico maurano,5 sabino paradiso,6 antonio m. previtera,7 michele rendace,8 serafino viviani,9 patrizia pavei10 1studio flebologico, figline incisa valdarno (fi); 2private practice, chiavari (ge); 3vascular surgery, clinica santa lucia, san giuseppe vesuviano (na); 4studio flebologico, pescara; 5a.o. cosenza; 6centro medico paradiso, trani; 7specialist in angiology and cardiology, catania; 8vascular surgery, a.s.p. cosenza; 9private practice, castelnuovo garfagnana (lu); 10u.o.c. day surgery multidisciplinare, a.o. padova, italy abstract in the literature cases of stroke and transient neurological symptoms have been described after sclerotherapy for chronic venous disease the initial interpretation of these phenomena was that of a micro air embolism in association with a patent foramen ovale. this explanation did not always manage to justify all neurological manifestations. recent theories have demonstrated that in the area of sclerosis, a significant amount of endothelin 1. we carried out a retrospective assessment of sclerotherapy case studies on 540 patients at ten phlebological centres to search for a relationship between the use of aminaftone (a venotropic drug with demonstrated anti-endothelin action) and the occurrence of side effects after sclerotherapy was performed. significant reduction of side effects was observed in sclerotherapy for teleangectasias and in patients with migraine history. introduction sclerotherapy for lower limb varicose veins reticular veins and teleangectasias is a technique that has been used for many years; however, it was only after the introduction of sclerosing foam that its use spread across the world and it now plays an important role in the treatment of chronic venous disease.1 in addition, recently, national and international guidelines have included ultrasound guided foam sclerotherapy (ugfs) among the available selection of therapies for the treatment of varicose disease. case studies increasingly report results that substantially overlap with those obtained with methods of thermal ablation or surgery but with a significantly lower impact on qol and, if performed correctly, sclerotherapy with foam is a safe procedure with low incidence of complications.2-10 a recent meta-analysis of the complications of sclerosing foam identified a low incidence of adverse events and thus confirmed the substantial safety of treatment with foam solutions.11 however, scotomas or paresthesia occur immediately after 1.4 % of treatments, and in migraineurs the onset of a migraine crisis is not uncommon. moreover, cases of stroke and transient neurological symptoms have been described and myocardial infarction without st-segment elevation.12,13 the appearance of these serious complications, although extremely rare, has led the scientific community to seek a pathogenetic explanation. the initial interpretation of these phenomena was that of a micro air embolism in patients with a patent foramen ovale (pfo) or another type of left-right shunt; this explanation did not always manage to justify all neurological manifestations. recent theories have demonstrated that in the area of sclerosis, a significant amount of endothelin 1 (et-1), our body’s most powerful vasoconstrictor, is released.14 in the literature, the relationship between the presence of high quantities of et-1 and the cerebral and retinal vasospasm or one of the phases of the migraine crisis is clear.14 a relationship between the release of endothelin and the onset of myocardial infarction without stsegment elevation after sclerotherapy has also recently been documented.13 in previously published studies, it has been demonstrated that in an animal model of sclerotherapy, a significant increase in systemic et-1 occurs after sclerosis with polidocanol (pol) or with sodium tetradecyl sulphate (sts) both in liquid form and foam. in addition, in a study carried out in patients subjected to sclerotherapy where systemic endothelin was measured in a vein in the vicinity of the sclerosed vein, we also demonstrated a significant increase in et-1 both at systemically and locally with a significant relationship between the two values.15 some anti-endothelin drugs such as aminaftone (amna) are currently available which, in the absence of significant side effects, have proven to have significant anti-et-1 properties. in a study published in 2014, we demonstrated that in both the animal model and in the model built on human umbilical vein endothelial cells (huvec) it was possible to significantly reduce the release of et-1 after sclerotherapy by performing a pretreatment with aminaftone.16 aim of the study aminaftone is used extensively in clinical practice in italy and, for this reason, we carried out a retrospective assessment of sclerotherapy case studies at ten phlebological centres to search for a relationship between the use of aminaftone and the occurrence of side effects after sclerotherapy. due to the retrospective design of the study it was not possible to have homogeneous procedures in the treatment of patients. materials and methods aminaphtone is frequently used in the phlebological practice in italy. we carried out a retrospective assessment of the case study of treatments with sclerotherapy at ten italian phlebological centres for a period from january 2013 to february 2014. all the doctors involved had substantial experience with sclerotherapy. at the centres where aminaphtone (capillarema laboratori baldacci pisa-italy) was used, the drug was administered orally at a dose of 150 mg in two daily administrations starting the treatment three to seven days prior to sclerotherapy. the drug used is regularly recorded in italy as a vein protector and, as the study is retrospective, there was not a true randomization. the sclerosis was carried out according to the routine protocols of each centre and no provision has been issued to change the treatments that were carried out. all the centres involved had a database where the characteristics of the therapy and any adverse events were recorded thus facilitating correspondence: alessandro frullini, studio medico flebologico, piazza caduti di pian d’albero 20, figline incisa valdarno (fi), italy. e-mail: info@venevaricose.it key words: chronic venous disease; foam sclerotherapy; endothelin 1; visual and neurological complications. received for publication: 21 january 2016. revision received: 1 august 2016. accepted for publication: 12 september 2016. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright a. frullini et al., 2016 licensee pagepress, italy veins and lymphatics 2016; 5:5764 doi:10.4081/vl.2016.5764 no n c om me rci al us e o nly article [page 46] [veins and lymphatics 2016; 5:5764] data collection. the statistical analysis was performed with the statistical package spss version 23 by ibm for mac. two tails chi square statistics with the conventional significance level of 0.05 was applied for the comparison of the percentages of different outcomes in different subgroups. yates continuity correction and exact tests were performed were indicated. results 1642 sclerotherapy sessions for 540 patients were assessed. in 1212 cases, a concomitant therapy with aminaftone was used, while in 430 cases, sclerosis was not performed with associated amna therapy. no other associated therapies with potential anti-endothelin effect have been used. in patients with no associated aminaftone treatment, the sclerosis was performed with sts in 11.1% of cases while in the remaining 88.8% cases, pol was used. in the group where amna was used, 96.7% of cases had been injected with polydocanol and only 2.3% with sodium tetradecyl sulphate. the average concentration of the sclerosing agent was different to the concentration in the sts group where it was 1.78% while in patients treated with pol it was 2.6%. the mean volume of sclerosants was 4.4 ml in the group without prophylaxis and 4.1 in the amna group. the adverse events considered in this analysis were transient visual disturbances (usually scotoma), neurological disorders (typically transient paraesthesias or hyposthenias) and the onset of migraine crises. figures 1 and 2 indicate the distribution of veins subjected to sclerotherapy in the two groups. in the sessions carried out without associated therapy with aminaftone, complications occurred in 1.62% of cases (one of these even after a sclerotherapy with liquid), while in patients undergoing therapy in conjunction with the administration of aminaftone the percentage of complications was 0.57%. in particular, the analysis of just the subset of sessions carried out with aminaftone and a total amount of sclerosing agent less than 5 cc revealed a lower percentage of complications: 0.18% (p=ns). in the subgroup analysis, it was possible to identify the numerically more significant group in patients treated for telangiectasias, to determine that in the absence of a concomitant treatment with aminaftone the percentage of complications recorded was 2.3% while there were no adverse events among the treated patients (p=0.02). in other groups for example, in the treatment of recurrences, positive trends were recorded (with amna 0% adverse events recorded – without amna 4.7% adverse events recorded), but due to the limited number of observations it was not possible to reach statistical significance. in saphenous veins, percentages of complications were 1.08% (amna) and 0.95% (no amna) (p=ns) respectively, despite the analysis having been carried out in the group where a volume of foam lower than 5 cc was used. regarding the migraine crises in patients where the sclerosis was carried out without concomitant treatment with aminaftone, 3% reported a history of headaches, while in the group with aminaftone, as much as 7.6% of the sessions were carried out in a patient with a history of headaches. in 38.4% of the sessions conducted in the presence of a history of headaches and without concomitant treatment with aminaftone, an adverse event occurred. on the contrary if the patient was taking aminaftone only 3.2% of cases showed a complication (p=0.002). discussion the use of sclerotherapy in the treatment of chronic venous disease has seen a significant increase in recent years.4 current guidelines now consider that sclerotherapy, and in particular that with foam, is an adequate therapy in the case of saphenous insufficiency and some consider it more appropriate than surgical treatment.2,17 a meta-analysis conducted by jia revealed the substantial safety of the treatment with minimum percentage of transient complications and a very low incidence of major complications.11 in spite of this, it is necessary to understand the mechanism of these complications if we want to make the treatment even safer. the initial explanation of the onset of transient visual and neurological events was air microembolism. indeed, the study by guex18 revealed that the incidence of these complications increases with the introduction of sclerosing foam in clinical practice. however, the same study shows that these complications are also present, albeit at a lower percentage, in patients being treated with the sclerosing drug in liquid form. indeed, both visual and neurological complications were reported in the literature concerning sclerosis with liquid.18-20 in these cases, a cause linked to the presence of air or gas that can cause a paradoxical embolism through a pfo or another type of figure 1. vein distribution without aminaftone prophylaxis (coll, tributaries; saph, saphens; rec, recurrences; perf, perforators; ret, reticular veins; tel, teleangectasias). figure 2. vein distribution with aminaftone prophylaxis (coll, tributaries; saph, saphens; rec, recurrences; perf, perforators; ret, reticular veins; tel, teleangectasias). no n c om me rci al us e o nly article [veins and lymphatics 2016; 5:5764] [page 47] shunt cannot be established. it is also surprising that adverse events occur almost exclusively in the cerebral region or in the eye. a precise relationship between high levels of endothelin 1 and cerebral and retinal vasospasm has been described in the literature. et-1 is also one of the mediators in the vasoconstrictive phase of migraine.14-16 we published a pathogenetic hypothesis to explain these events where we assumed that the sclerosed vein releases et-1. generally, endothelin passes through the pulmonary circulation, but in the presence of a pfo a faster flow of blood rich in et-1 in the left sections of the heart may occur. indeed, endothelin has a very short half-life and pulmonary vessels are rich in et-1 receptors.14 therefore, in the event of a fast flow of blood rich in et-1 in the left ventricle, it is easy to understand how vasospastic type complications can occur (figures 3 and 4). the actual onset of these complications may be modified by a number of factors: increased release of et-1 from the sclerosed vein, which is greater using large quantities of foam or treating large endothelial surfaces. in addition, the data in the literature also indicates an increased basal release of et-1 from varicose veins; the presence of pfo or other types of shunt with a more rapid passage of endothelin in arterial circulation; incomplete venous spasm of the sclerosed segment: the formation of a lumen with an inflamed endothelium and therefore with a persistent flow will allow greater release of et-1, contrary to a spasmed vessel and therefore without flow; variability between patients: the endothelin receptor expression is variable; interaction with anti-endothelin substances. even if there is not any demonstration of the role of additional mediators in the pathogenesis of complication, the hypothesis of additional substances in this process must be considered. conclusions the role of microbubbles in the development of visual and neurological complications after sclerotherapy is greatly overestimated in the absence of valid proof of a relationship between the presence of air or gas and the symptoms. moreover, it does not explain the almost total absence of reports of complications in other locations or the onset of these complications with the use of liquid, when air or gas are not clearly present. this analysis has clear limits because it is not a prospective, randomised study but it provides significant data for the prophylaxis of complications in the treatment of telangiectasias and especially in patients with a history of migraines. indeed, in the latter, a prophylaxis with a molecule with anti-et-1 properties like aminaftone has led to a tenfold reduction in the risk of the onset of a transient complication. furthermore, in this study, there was a clear trend in favour of increased safety by limiting the total volume of 5 cc sclerosing agent per session. in view of these results and the excellent safety profile of the drug, it would be interesting to assess these preliminary results with a prospective study, which we consider highly advisable. references 1. cabrera garrido jr, cabrera garcia olmedo jr, garcia olmedo d. nuevo metodo de esclerosis en las varices tronculares. pathol vasc 1993;1:55-72. 2. rabe e, breu f-x, cavezzi a, et al. european guidelines for sclerotherapy in chronic venous disorders. phlebology 2014;29:338-54. 3. gallucci m, antignani pl, allegra c. quality of life after ultrasound guided foam sclerotherapy in elderly patients with severe invalidating cvi. acta phlebol 2011;12:83-9. 4. bradbury aw, bate g, pang k, et al. ultrasound-guided foam sclerotherapy is a safe and clinically effective treatment for superficial venous reflux. j vasc surg 2010;52:939-45. 5. wright d, gobin jp, bradbury aw, et al. varisolve european phase iii investigators group. varisolve® polidocanol microfoam compared with surgery or sclerotherapy in the management of varicose veins in the presence of trunk vein incompetence. european randomized controlled trial. phlebology 2006;21:180-90. 6. rasmussen lh, lawaetz m, bjoern l, et al. randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins. br j surg 2011;98:1079-87. 7. darvall ka, sam rc, bate gr, et al. changes in health-related quality of life after ultrasound-guided foam sclerotherapy for great and small saphenous varicose veins. j vasc surg 2010;51:913-20. 8. liu x, jia x, guo w, et al. ultrasound-guided foam sclerotherapy of the great saphenous vein with sapheno-femoral ligation compared to standard stripping: a prospective clinical study. int angiol 2011;30:3216. 9. king t, coulomb g, goldman a, et al. experience with concomitant ultrasoundguided foam sclerotherapy and endovefigure 3. endothelin 1 (et-1) circulation without patent foramen ovale (pfo). figure 4. endothelin 1 (et-1) circulation in presence of patent foramen ovale (pfo). no n c om me rci al us e o nly article [page 48] [veins and lymphatics 2016; 5:5764] nous laser treatment in chronic venous disorder and its influence on health related quality of life: interim analysis of more than 1000 consecutive procedures. int angiol 2009;28:289-97. 10. lattimer cr, azzam m, kalodiki e, et al. cost and effectiveness of laser with phlebectomies compared with foam sclerotherapy in superficial venous insufficiency. early results of a randomised controlled trial. eur j vasc endovasc surg 2012;43: 594-600. 11. jia x, mowatt g, burr jm, et al. systematic review of foam sclerotherapy for varicose veins. br j surg 2007;94:925-36. 12. gillet jl, donnet a, lausecker m, et al. pathophysiology of visual disturbances occurring after foam sclerotherapy. phlebology 2010;25:261-6. 13. stephens r, dunn s. non-st-elevation myocardial infarction following foam ultrasound-guided sclerotherapy. phlebology 2014;29:488-90. 14. frullini a, felice f, burchielli s, di stefano r. high production of endothelin after foam sclerotherapy: a new pathogenetic hypothesis for neurological and visual disturbances after sclerotherapy. phlebology 2011;26:203-8. 15. frullini a, barsotti mc, santoni t, et al. significant endothelin release in patients treated with foam sclerotherapy. dermatol surg 2012;38:741-7. 16. frullini a, da pozzo e, felice f, et al. prevention of excessive endothelin-1 release in sclerotherapy: in vitro and in vivo studies. dermatol surg 2014;40:769-75. 17. davies ho, popplewell m, bate g, et al. the impact of 2013 uk nice guidelines on the management of varicose veins at the heart of england nhs foundation trust, birmingham, uk. phlebology 2015 [ahead of print]. 18. guex jj, allaert f-a, gillet j-l. immediate and midterm complications of sclerotherapy: report of a prospective multicenter registry of 12,173 sclerotherapy sessions. dermatol surg 2005;31:123-8. 19. kunzelberger b, pieck c, altmeyer p, stuåncker m. migraine ophthalmique with reversible scotomas after sclerotherapy with liquid 1% polidocanol. derm surg 2006;32:1410. 20. deichman b and blum g. cerebrovascular accident after sclerotherapy. phlebologie 1995;24:148-52. no n c om me rci al us e o nly hrev_master veins and lymphatics 2017; volume 6:6633 [veins and lymphatics 2017; 6:6633] [page 23] shape memory textiles for functional compression management bipin kumar institute of textiles and clothing, the hong kong polytechnic university, kowloon, hung hom, hong kong compression stockings or bandages are preferred choice for the management of venous ulcers and also prevention of the recurrence ulcers.1,2 nevertheless, current textile based compression products have the following shortcomings: i) selection of stockings with proper sizing and fitting has always been a challenge for both health practitioners and manufacturers seeking better patient compliance and effective treatment; ii) using textiles, it is impossible to achieve a dynamic (massaging) compression benefit which is otherwise provided by intermittent pneumatic compression which is costly, noisy, bulky, and once attached, severely constraining the patients; iii) to apply a targeted compression or pressure level and its sustenance is a huge challenge to provide effective treatment. moreover, pressure drop is inevitable for almost all available stockings, and the replacement of stocking is needed once the pressure fall below a target level. this work aims to design and investigate smart textiles using memory polymer to overcome the existing challenges of the compression products. smart fabric was developed by incorporating memory filaments in the fabric structure (figure 1).3,4 the memory filament was used as inlay yarn in the structure and it was made from segmented polyurethane. nylon was used as ground yarn in the structure. the developed smart fabric allows to program customized shape development (figure 2). this shape control ability of the memory textile will promote the development of one size stocking that could be programmed to fit different leg sizes. this will be a huge relief to doctor or manufactures in stocking selection as different size requirements could be met by just one memory stocking. apart from shape control, the memory polymer also allows to control stress in the structure.5 as the interface pressure depends on the stress (tension) in the fabric material, correspondence: bipin kumar, institute of textiles and clothing, the hong kong polytechnic university, kowloon, hung hom, hong kong. e-mail: bipiniitd18@gmail.com acknowledgments: the author acknowledges the full guidance and support from his previous postdoc supervisors, i.e. prof. jinlian hu and prof. ning pan. most of this research has been carried out at the institute of textiles and clothing, the hong kong polytechnic university, hk. the author also acknowledges the support of team members, harishkumar narayana, h. jianping and wu you for all discussion and experimentation. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright b. kumar, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6633 doi:10.4081/vl.2017.6633 figure 2. customized shape development using the memory fabric. figure 1. smart fabric. figure 4. schematic of memory fabric performance showing dynamic compression. figure 3. customized shape development using the memory fabric. no n c om me rci al us e o nly conference presentation [page 24] [veins and lymphatics 2017; 6:6633] so it is possible to control pressure by modulating internal stress in its structure. to confirm this, we tested the memory fabric performance in changing pressure. the pressure level can be changed by changing temperature (figure 3). because of the internal stress and heat stimuli connection of memory filament, such smart fabric will allow generating massage effect (dynamic compression) using an external programmed heating source (figure 4).6 no doubt, such memory textiles possess unique functions including stress and shape control abilities. these smart functions have the potential to overcome many challenges of conventional compression products, and could provide many novel solutions in the current treatment practice including customized stocking size development just before application, external pressure control and also massage compression. the availability of such memory textile with multi-functional benefits is the dream of all the related practitioners and manufacturer in the field. herein, this dream seems to come true with the inception of smart memory fabric. although the idea is working well at laboratory level but there are still several challenges need to meet including designing and optimization of memory textile before recommending it as a successful commercial venture. references 1. mosti g, picerni p, partsch h. compression stockings with moderate pressure are able to reduce chronic leg oedema. phlebology 2012;27:289-96. 2. partsch h, clark m, mosti g, et al. classification of compression bandages: practical aspects. dermatol surg 2008;34:600-9. 3. kumar b, hu jl, pan n. smart medical stocking using memory polymer for chronic venous disorders. biomaterials 2016;75:174-81. 4. kumar b, hu j, pan n. memory bandage for functional compression management for venous ulcers. fibers 2016;4:1. 5. hu jl, kumar b, narayan hk. stress memory polymers. j polymer sci part b 2015;53:893-8. 6. kumar b, hu j, pan n, narayan hk. a smart orthopedic compression device based on a polymeric stress memory actuator. mater design 2016;97:222-9. no n c om me rci al us e o nly hrev_master veins and lymphatics 2012; volume 1:e3 [veins and lymphatics 2012; 1:e3] [page 7] unexpected venous diameter reduction by compression stocking of deep, but not of superficial veins hugo partsch,1 giovanni mosti,2 jean-fran�ois uhl3 1dermatology, medical university of vienna, austria; 2angiology department, clinica md barbantini, lucca, italy; 3urdia research unit ea4465 university paris descartes, france abstract morphological studies on the effect of compression on the leg veins are rare and mostly performed in the supine position. the aim of this study was to investigate the influence of compression applied with different pressures on the venous calibre in the standing position. standing magnetic resonance imaging was used to measure the venous diameters of superficial and deep leg veins in a patient with massive varicose veins without and with different levels of compression and realistic 3d vectorial models were built. in the standing position compression stockings with a pressure of 22 mmhg were able to reduce the calibre of deep calf veins, but not of superficial varices. these were compressed only by bandages exerting pressures between 51 and 83 mmhg. compression stockings may reduce the diameter of deep calf veins in the standing position. to empty a varicose vein after venous ablation much higher pressures are required. introduction following the conventional concept compression devices will compress a leg vein when the external pressure is higher than the intravenous pressure. in the standing position of an adult person this intravenous pressure is around 80-100 mmhg in a dorsal foot vein and around 60 mmhg at knee level corresponding to the weight of the blood column between the right heart and the measuring point on the leg. measurements of venous occlusion pressure by duplex in connection with a sphygmomanometer containing a transparent window in different body positions were in agreement with this concept.1 the following observations demonstrate that superficial and deep veins may respond to compression in a different manner which has therapeutic consequences. case report a 42-year-old male presenting with massive varicose veins in connection with a dilated and completely incompetent great saphenous vein (c2epaspr) gave his consent to take part in a magnetic resonance imaging (mri) investigation without contrast medium in the laboratory of esaote, genova, italy.2 using the g-scan® machine (esaote, genova) with a 0.25 tesla field and a hydraulic tilting table transversal scans of the lower extremity were gained in supine and standing position, without compression, with a round knitted compression stocking (german compression class ii, 23-32 mmhg at b) and after application of a moderate and a strong multi-component inelastic compression bandage (rosidal sys®, lohmann & rauscher, rengsdorf, germany). the interface pressures of these compression devices were measured at mid-calf level in the supine and standing position using the picopress® probe (microlab italia).3 in order to demonstrate that the venous diameter reductions observed under compression were not restricted to a small segmental slice only, a 3d-reconstruction using manual drawing of the t2 weighted slices and a computer software (winsurf®) was performed by jf uhl and his team in paris.4 quantitative assessment of the results was done by planimetry of the venous cross-sections and by volume calculations in the 3d model. the procedures were in accordance with the ethical standards of the responsible committee on human experimentation in italy and with the helsinki declaration of 1975 (as revised in 2008). results the pressures measured at mid-calf in supine/ standing position were 18/22 mmhg under the stocking, 39/51 mmhg under the first and 60/83 mmhg under the second bandage. in the supine position (figure 1a) large dilated varicose veins are seen (arrow), which collapse under a compression stocking exerting a pressure of 18 mmhg (figure 1b). at the same time the enlarged soleus vein and the deep leg veins are only slightly compressed. during standing (figure 2a) superficial and deep veins are slightly larger than in the lying position, a compression stocking (22 mmhg) closes the soleus veins and narrows the deep leg veins, while the diameter of the superficial varicose veins remains unchanged (figure 2b). this can also be shown in the 3d-reconstruction (figure 3, a without and b with the stocking). quantitative volumetric results are demonstrated in figure 4 in absolute terms (a) and in percent changes (b). it is clearly shown that the most intense compression effect involves the deep veins while the superficial veins stay nearly untouched. only a strong compression with a pressure of 51 mmhg using an inelastic bandage leads to a narrowing not only of the deep but also of the superficial veins (figure 5a). under a pressure of 83 mmhg in standing, both, superficial and deep veins are totally compressed (figure 5b). discussion this case is reported because of the instructive documentation obtained by mri in the standing position in a patient with large varicose veins. three normal individuals without varicose veins showed a similar pattern, especially concerning non-compressibility of the superficial veins by compression stockings during standing. compression of the leg leads to a shift of the muscle compartments which can clearly be correspondence: hugo partsch, steinhäusl 126, altlengbach, 3033 austria. tel. +43.664.1437.274. e-mail: hugo.partsch@meduniwien.ac.at key words: compression, magnetic resonance imaging, varicose veins, stockings, bandages. acknowledgements: we would like to thank dr. e. fracchia, genova, for sending the patient. the research was carried out at the mri research laboratory of esaote, genova, italy and at the urdia research unit of the university paris descartes, france. contributions: hp, outcome analysis, manuscript writing; gm, mri (in the standing position) performing, manuscript writing; j-fu, 3d reconstruction and quantitative evaluation, manuscript writing. conflict of interests: the authors declare no potential conflict of interests. received for publication: 11 march 2012. revision received: 21 may 2012. accepted for publication: 31 may 2012. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright h. partsch et al., 2012 licensee pagepress, italy veins and lymphatics 2012; 1:e3 doi:10.4081/vl.2012.e3 no nco mm er cia l u se on ly case report [page 8] [veins and lymphatics 2012; 1:e3] seen by the change of the configuration of the mri cross-section, especially in the standing position. this happens already with low pressure as demonstrated in figure 2 and is obviously associated with an occlusion of the enlarged soleus vein and with considerable narrowing of the deep veins. in contrary the superficial varicose veins do not change its calibre. using mri in the lying position downie et al. reported a greater cross-sectional area reduction under compression stockings in the deep veins (64%) than in superficial veins (39%).5 analyzing our own data with mri we found this surprising feature in the prone and in the standing position, but not in the supine position.2 actually downie’s investigations were done in the prone position. the described narrowing of deep veins in the standing and prone position, but not in the supine position points to the fact that the configuration of the muscle compartments which change in every body position plays a major role on the embedded veins. as visible result of these compartment-shifts the contour of the cross-section through the leg is getting more circular with in comparison without compression (figures 2b and 5b versus figures 2a and 5a). to narrow or to occlude superficial varicose veins in the standing position much higher pressures are needed as demonstrated in figure 5. the same was demonstrated on superficial veins of three healthy individuals by mri, in agreement with previous duplex findings on individuals without varicose veins.1 the fact that superficial leg veins are barely compressed by compression stockings in the upright position has practical implications. if we want to achieve an empty vein after any ablative intervention of varicose veins, e.g. after sclerotherapy, endovenous treatment or surgery, much higher pressure is needed in the ambulant patient than that exerted by a compression stocking. this is the most likely explanation that some authors using compression stockings with a pressure below 20 mmhg were unable to demonstrate any benefit after sclerotherapy6 or after surgery7 while others using very strong bandages8 or eccentric compression pads in order to increase local pressure9-12 showed a much better outcome, especially concerning pain and haematoma-formation. conclusions at the time being mri in the lying and standing position with and without compression is certainly the best method to demonstrate diameter reductions in clearly defined veins of the lower extremity. this short report using mri in the standing position showed surprisingly stronger comfigure 1. a) magnetic resonance imaging cross section at mid-calf level in the supine position without compression. b) the same with compression stocking (18 mmhg). the arrows point to the enlarged varicose veins on the medial lower leg. opposite are the markers attached to the skin in order to evaluate identical segments figure 2. a, b) same arrangement as in figure 1, standing position. figure 3. a) 3d reconstruction in the standing position without compression. b) with compression stocking, reducing the calibre of the deep, but not of the superficial veins. no nco mm er cia l u se on ly case report [veins and lymphatics 2012; 1:e3] [page 9] pression effects on the deep than on superficial veins. this is in complete contrast to the traditional concept that compression would affect more the superficial than the deep veins. to narrow superficial varicose leg-veins in the upright position in the demonstrated case (e.g. after endovenous procedures) a pressure of more than 50 mmhg would be needed. references 1. partsch b, partsch h. calf compression pressure required to achieve venous closure from supine to standing positions. j vasc surg 2005;42:734-8. 2. partsch h, mosti g, mosti f. narrowing of leg veins under compression demonstrated by magnetic resonance imaging (mri). int angiol 2010;29:408-10. 3. partsch h, mosti g. comparison of three portable instruments to measure compression pressure. int angiol 2010;29:426-30. 4. uhl jf. 3d multislice ct to demonstrate the effects of compression therapy. int angiol 2010;29:411-5. 5. downie sp, firmin dn, wood nb, et al. role of mri in investigating the effects of elastic compression stockings on the deformation of the superficial and deep veins in the lower leg. j magn imaging 2007;26:80-5. 6. hamel-desnos cm, guias bj, desnos pr, mesgard a. foam sclerotherapy of the saphenous veins: randomised controlled trial with or without compression. eur j vasc endovasc surg 2010;39:500-7. 7. biswas s, clark a, shields da. randomised clinical trial of the duration of compression therapy after varicose vein surgery. eur j vasc endovasc surg 2007;33:631-7. 8. mosti g, mattaliano v, arleo s, partsch h. thigh compression after great saphenous surgery is more effective with high pressure. int angiol 2009;28:274-80. 9. lugli m, cogo a, guerzoni s, et al. effects of eccentric compression by a crossed-tape technique after endovenous laser ablation of the great saphenous vein: a randomized study. phlebology 2009;24:151-6. 10. benigni jp. interface pressure measurements at the thigh under eccentric compression (mediven post op kit). int angiol 2009;28:334-5. 11. benigni jp, allaert fa, desoutter p, et al. the efficiency of pain control using a thigh pad under the elastic stocking in patients following venous stripping: results of a case-control study. perspect vasc surg endovasc ther 2011;23:23843. 12. partsch b, partsch h. which pressure do we need to compress the great saphenous vein on the thigh? dermatol surg 2008;34: 1726-8. figure 4. a) calculation of vein volume. b) its percent changes under the stocking based on the 3d reconstruction. at, anterior tibial vein; pt, posterior tibial vein; fib, fibular vein; mg, medial gastrocnemius vein; var, superficial varicose vein. figure 5. a) standing position with inelastic bandage exerting 51 mmhg. b) standing with very strong inelastic bandage (pressure 83 mmhg). no nco mm er cia l u se on ly hrev_master veins and lymphatics 2012; volume 1:e5 [veins and lymphatics 2012; 1:e5] [page 15] urinary hemosiderin: role in evaluation of chronic venous insufficiency ashish lal shrestha,1 indrani sen,1 edwin stephen,1 prabhu premkumar,1 sunil agarwal,1 sukesh chandran2 1department of vascular surgery and 2department of transfusion medicine, the christian medical college, vellore, india abstract chronic venous insufficiency (cvi) leads to skin changes with dermal hemosiderin deposition. we studied the presence of hemosiderin in the urine to assess if this could be used as a biochemical marker for cvi. hereby we present a case control study conducted in a tertiary care centre in south india. there were 100 cases with evidence of advanced cvi (the clinical-etiology-anatomy-pathophysiology classification: c5, c6) confirmed by duplex scanning. controls were 50 patients with leg ulcers due to other etiologies. all patients were subjected to urinary hemosiderin testing. in all 100 patients with cvi (c5 and c6 disease) axial venous reflux was confirmed by duplex ultrasound. superficial venous reflux was noted in 71% of patients and deep venous reflux in 54.%. primary venous insufficiency was the etiology in 81% of patients. only 4/100 patients had detectable amounts of hemosiderin in the urine. urine hemosiderin testing to determine presence or absence of cvi yielded the following values: positive predictive value-80%; negative predictive value-33%; sensitivity-4% and specificity-98%. the test could not be recommended as a marker of cvi. in indian patients urinary hemosiderin is not a useful screening test in cvi. introduction varicose veins is a common problem in india, the overall prevalence is about 6 to 25% in the adult male population.1 presentation with chronic venous insufficiency (skin changes, ulcers) is common. however the incidence and management outcomes are poorly reported. management is complicated by a low awareness about the nature of the disease, limited availability of health care resources and the long distances patients need to travel to access health care. a simple test to detect chronic venous disease and differentiate it from other causes of lower extremity ulcers would be extremely useful in management. it would help primary physicians in the community to appropriately select patients for referral to centers for intervention for varicose veins. the presence of hemosiderin in the urine is reported to be a sensitive, cost effective, non invasive and repeatable test that enables detection and progression of microcirculatory overload in patients with chronic venous insufficiency (cvi). it is also reported to differentiate venous ulcers from ischemic ulcers. hemosiderinuria score enables classification of clinical severity and is useful in follow up of intervention.2,3 we studied the presence of hemosiderin in the urine to assess if this could be used as a biochemical marker. materials and methods this study was conducted in christian medical college and hospital, vellore, an 1800 bed tertiary care centre and teaching institute in south india. it was a prospective case control study. at the start of the study, a sample size of 288 (144 cases and 144 controls) was determined using the results reported in two previous studies. in due course, since most of the tests were negative, the sample size was recalculated and 100 cases and 50 controls were studied. informed consent was obtained from all cases and controls in a language that they understood. the duration of the study was from september 2008 to august 2010. study cases were patients with leg ulcers with skin changes suggestive of cvi and venous insufficiency confirmed by duplex ultrasound (c5, c6). controls were patients with leg ulcers of other etiology with no evidence of venous insufficiency on duplex. patients with previous venous surgery, intravascular hemolytic state and lymphedema were excluded from the study. the demographic profile of the patients was studied and the clinical features recorded using the clinical-etiology-anatomy-patho physiology classification (ceap) classification. urinary hemosiderin was tested in single 20 ml early morning urine, which was centrifuged at 1200 g for 10-15 min. the remnant was mixed with perl’s reagent containing potassium ferrocyanide and hydrochloric acid and centrifuged for 5 min. then the sample was studied under a light microscope to detect hemosiderin crystals. haemosiderin, if present, appears in the form of isolated or grouped blue-staining granules, usually from 1 to 3 μm in size, they may be both intracellular and extracellular. the laboratory personnel were not given information about the study. statistical analysis data were collected and analyzed with statistical package for the social sciences (spss) for windows version 15.0 (spss inc., chicago, il, usa). descriptive statistics were calculated using the spss software. comparisons between individual groups of patients were made using chi square test where appropriate. results one hundred patients with cvi were included in this study. fifty five percent were in the age group 21-50 and 44% were 51 and above. there were 86 male and 14 female patients. the mean duration of symptoms at presentation was 6 years (range 1 month to 20 years). the average age at presentation was 57 years (range 20-79). the control group had a similar age and sex distribution, there were 45 male and 5 female patients, and the average age was 52 years. the haemosiderin positive patients did not belong to the same ethnic group. out of 100 cases with cvi 79% had c6 disease and 21% had c5 disease. on duplex ultrasound, 71% had superficial reflux, 64% had deep reflux, 8% had a combination of both. the saphenofemoral junction (sfj) was incompetent in 71% and saphenopopliteal junction (spj) in 16%. isolated sfj incompetence was seen in 10%. there were no patients with isolated spj reflux. the distribution of the patients according to the ceap classification and distribution of venous reflux is given in table 1. duplex ultrasound demonstrated evidence of prior deep venous thrombosis (dvt)/partial obstruction in 19% of patients. primary venous insufficiency was diagnosed in 81% of patients and postthrombotic syncorrespondence: sunil agarwal, department of vascular surgery, christian medical college, vellore 632 004, india. tel. +91.416.2282085. e-mail: vascular@cmcvellore.ac.in key words: urinary haemosiderin, chronic venous insufficiency. received for publication: 4 april 2012. revision received: 3 august 2012. accepted for publication: 6 august 2012 this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright a.l. shrestha et al., 2012 licensee pagepress, italy veins and lymphatics 2012; 1:e5 doi:10.4081/vl.2012.e5 no nco mm er cia l u se on ly article [page 16] [veins and lymphatics 2012; 1:e5] drome in 19%. one hundred cases and 50 controls underwent urinary testing for haemosiderin; the results are shown in table 2. based on the above results and 2x2 table, sensitivity of 4%, specificity of 2%, a positive predictive value of 80% and a negative predictive value of 66% were obtained. after cross tabulation and pearson chi square testing, a p value of 0.414 was obtained which was statistically insignificant. discussion chronic venous insufficiency is a term used to describe any chronic disorder of the veins of the limbs, this represents those patients who have developed irreversible skin changes as the result of sustained ambulatory venous hypertension. although the exact prevalence of cvi in india is not known, it is common and majority of patients present late with severe disease. this is evident from a high incidence of untreated superficial reflux (71%) in these patients. the duration of symptoms did not correlate with severity of disease as few patients with ulcers reported onset as less as a month. the average age at presentation with ulceration is at a younger age than reported in the west and this makes it a significant economic burden. the increased incidence in men might be due to reluctance on the part of women to seek medical attention. a large percentage had deep venous reflux on duplex ultrasound and in 12% this was associated with untreated superficial disease. this indicates the need for early intervention in patients with deep reflux. a significant percentage presented with sequelae of undiagnosed dvt: awareness about this also needs to be increased. in chronic venous insufficiency the characteristic skin changes are attributed to dermal deposition of hemosiderin. chronic venous stasis and impaired venous drainage is followed by microcirculatory overload leading to erythrocyte diapedesis, red blood cell extravasation into the surrounding tissue and subsequent hemolysis and dermal ferritin deposition. this ultimately gets converted to dermal hemosiderin thereby giving characteristic skin changes. this dermal and tissue hemosiderin is thought to be taken into the circulation via the lymphatics and gets deposited in the tubular epithelium and then excreted in urine. use of hemosiderinuria in cvi is a controversial issue with various unclear aspects mainly in condition of iron overload disease. in their paper, zamboni et al. show a correspondence between the test and the strictness of the disease. this point of view was confirmed also by other authors3 though without a statistically meaningful correlation between the tissue accumulation of hemosiderin and the clinical trials. the test can be positive even in other diseases such as lymphedema and connective tissue disease.3 hemosiderinuria represents a marker for intravascular hemolysis, polymorphonuclear leukocytes are able to englobe hemosiderin granules and show them in the urine. hemosiderin storage in the ulcer margin tissue also occurs in cvi.4 however there may be population differences in the renal elimination pattern and this may explain why our patients do not have hemosiderinuria. familial venous disease has an underlying genetic basis with a postulated autosomal dominant pattern with variable penetrance. mutations in the haemochromotosis gene (hfe) c 282y mutation significantly increase rates of cvi. factor xiii gene variants are also associated with venous disease. these mutations and gene variants are thought to be associated with development, healing and recurrence of venous ulcers. the hfe mutations are thought to result in a less efficient transport of iron by macrophages; increase excretion and are thought to increase leg ulceration. the mutations though not studied in cvi, are thought to be rare in the indian population.5-14 this may explain the absence of accumulation and excretion of haemosiderin-alternative disease causation is thus postulated as a mechanism of disease. conclusions chronic venous insufficiency is a common problem in the indian population and patients frequently present late. the vast majority has untreated superficial reflux and would potentially benefit from superficial venous reflux ablation. a simple screening test is needed to diagnose cvi in the community and aid in selecting patients for referral to higher centers for venous intervention. however, testing for urinary hemosiderin does not reliably differentiate cvi from lower extremity ulceration from other causes in this patient population. references 1. malhotra sl. an epidemiological study of varicose veins in indian railroad workers from the south and north of india, with special reference to the causation and prevention of varicose veins. int j epid 1972;1:177-83. 2. zamboni p, izzo m, fogato l, et al. urinary haemosiderin: a novel marker to assess the severity of chronic venous disease. j vasc surg 2003;37:132-6. 3. tan j, smith a, abisi s, et al. tissue and urinary haemosiderin in chronic leg ulcers. eur j vasc endovasc surg table 1. distribution of patients in severe chronic venous insufficiency (clinical-etiology-anatomy-pathophysiology classification: c5, c6). no. of cases c5 c6 primary secondary superficial deep perforator reflux obstruction both clinical 21 79 etiological 81 19 anatomy 71 64 79 pathology 54 19 9 table 2. results of urinary hemosiderin test. no. of cases test cvi negative positive present 96 4 absent 49 1 cvi, chronic venous insufficiency. no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e5] [page 17] 2007;34:355-60. 4. caggiati a, rosi c, casini a, et al. skin iron deposition characterises lipodermatosclerosis and leg ulcer. eur j vasc endovasc surg 2010;40:777-82. 5. dhillon bk, das r, garewal g, et al. frequency of primary iron overload and hfe gene mutations (c282y, h63d and s65c) in chronic liver disease patients in north india. world j gastroenterol 2007;13:2956-9. 6. jain s, agarwal s, tamhankar p, et al. lack of association of primary iron overload and common hfe gene mutations with liver cirrhosis in adult indian population. indian j gastroenterol 2011;30:161-5. 7. sindrilaru a, peters t, wieschalka s, et al. an unrestrained proinflammatory m1 macrophage population induced by iron impairs wound healing in humans and mice. j clin invest 2011;121:985. 8. zamboni p, tognazzo s, izzo m, et al. hemochromatosis c282y gene mutation increases the risk of venous leg ulceration. j vasc surg 2005;42:309-14. 9. zamboni p, izzo m, tognazzo s, et al. the overlapping of local iron overload and hfe mutation in venous leg ulcer pathogenesis. free radic biol med 2006;40:1869-73. 10. simka m, rybak z. hypothetical molecular mechanisms by which local iron overload facilitates the development of venous leg ulcers and multiple sclerosis lesions. med hypotheses 2008;71:293-7. 11. gemmati d, federici f, catozzi l, et al. dna-array of gene variants in venous leg ulcers: detection of prognostic indicators. j vasc surg 2009;50:1444-51. 12. gemmati d, tognazzo s, catozzi l, et al. influence of gene polymorphisms in ulcer healing process after superficial venous surgery. j vasc surg 2006;44:554-62. 13. tognazzo s, gemmati d, palazzo a, et al. prognostic role of factor xiii gene variants in nonhealing venous leg ulcers. j vasc surg 2006;44:815-9. 14. cornu-thenard a, boivin p, baud jm, et al. importance of the familial factor in varicose disease. clinical study of 134 families. j dermatol surg oncol 1994;20:31826. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2014; volume 3:3854 [veins and lymphatics 2014; 3:3854] [page 77] chronic cerebrospinal venous insufficiency in ménière’s disease: diagnosis and treatment aldo bruno,1 luigi califano,2 diego mastrangelo,1 marcella de vizia,1 benedetto bernardo,1 francesca salafia2 1vascular surgery department, clinica gepos, telese terme (bn); 2ssd audiology and phoniatrics, g. rummo hospital, benevento, italy abstract the purpose of this study was to evaluate by the means of doppler ultrasound and phlebography the relationship between ménière’s disease (md) and chronic cerebrospinal venous insufficiency (ccsvi) and to test whether angioplasty is effective in improving symptoms. phase 1: 50 patients diagnosed with definite md (american academy of otolaryngology 1995) who had gained no benefit from routine therapy, underwent echoenhanced color doppler sonography using the zamboni protocol to check for ccsvi. onehundred healthy subjects matched for age and gender acted as controls. phase 2: in 20 of echo-color doppler positive ménière’s cases we performed a venogram and the diagnosis of associated ccsvi was confirmed. these patients were simultaneously treated by angioplasty of the internal jugular vein, then re-tested respect the baseline scales of md. out of a total of 50 patients with md, an ultrasound diagnosis was made of ccsvi in 45 patients (90%). in the healthy population ccsvi is found in only 3% of cases (p<0.001). twenty patients were given venograms that confirmed the ccsvi diagnosis. finally, percutaneous transluminal angioplasty (pta) proved to be effective in 90% of patients, with significant improvement of several scales of vestibular function at six months follow-up. there is a significant prevalence of ccsvi in patients with md and treatment with pta seems useful because of an improvement in symptoms and vestibular function recorded in the majority of patients. introduction ménière’s disease (md) is an inner ear disease characterized by dizziness, hearing loss, tinnitus and a feeling of fullness, with a prevalence of 0.5/100,000 of the population.1-3 in scandinavian countries the incidence is 430 cases per million population, with the highest percentage being found in england with 1000 cases per million population. five thousand people are estimated to be affected by the disease in italy.4 although it was first described in 1861 by prospero menière,5 at present the etiology is still uncertain; one of the most likely causes is an inability of the inner ear to absorb endolymph, leading to endolymphatic hydrops.1-3 in 1995, the committee on hearing and equilibrium guidelines for the diagnosis and evaluation of therapy in ménière’s disease stated that: ménière’s disease is a clinical disorder defined as the idiopathic syndrome of endolymphatic hydrops.6 md is characterized by dizziness, tinnitus and hearing loss often associate with a feeling of fullness of the ear; it has a relapsing clinical course. acute dizzy spells may last from minutes to hours, with a negative impact on the patient’s quality of life, particularly during the acute vertiginous crisis.1-3,7 onset is usually unilateral, but over the years the disease may also affect the other ear; in long term follow up, bilateralization is reported in approximately 40% of cases, the majority in the first 5 years.2,3,8 hearing ability between attacks is recovered in the early stages, but gradually deteriorates over the years, generally with hearing loss stabilizing at levels between moderate and severe.1-3,8. with regard to the pathophysiology of md, many assumptions have been made including: i) genetic predisposition; ii) autoimmunity; iii) inflammation; iv) blocked drainage/ increased endolymphatic production; v) alteration of the endocrine system. but also: i) neuro-vegetative abnormalities; ii) viral infection; iii) dietary deficiencies; abnormal vascular system; iv) trauma, which may lead, individually or collectively, to endolymphatic hydrops.3,7,8,9 the onset is typically between the third and fourth decade of life, and diagnosis is usually easy;1,3,8,10,11 the main initial differential diagnosis is a neuroma of the 8th cranial nerve.9,11 initially, sensory hearing loss fluctuates. instrumental diagnosis relies on tonal and vocal audiometric examination, vestibular examination of auditory evoked potentials, vestibular evoked myogenic potentials, electrocochleography, glycerol test and inner ear computed tomography (ct) scan to rule out dehiscence of the bony capsule of the labyrinth or perilymphatic fistulas, as well as possible structural alterations; magnetic resonance imaging (mri) brain scan focused on the acoustic facial bundle excludes neuroma of the 8th cranial nerve.1,2,8-10,12-14 ct scan and 3-tesla mri show narrowing and shortening of the vestibular aqueduct in test patients, which might suggest a morphological modification of the isthmus.8,14 at the moment there is no definitive cure for md.1,6,8 in 2006 it was reported that patients with multiple sclerosis (ms) showed a high frequency of a modification of the veins that drain blood from the brain and the medullary apparatus, with a slowing down of the flow and the formation of collateral circulation.15-19 this condition, whose pathophysiological significance is not yet entirely clear and not accepted by everybody,20 has been identified as chronic cerebrospinal venous insufficiency (ccsvi).15-18 especially in the brain, such vascular abnormalities, slowing venous outflow, would appear to modify the mechanism of the cell adhesion molecules regulating the endothelial barrier function. this phenomenon could be due to increased permeability of the blood-brain barrier. the resulting inflammation may cause the activated endothelium to secrete proinflammatory cytokines, with secondary transformation of monocytes into antigenic elements, triggering an autoimmune reaction against myelinated nerve cells.16,19-22 among the numerous methods proposed for the diagnosis of ccsvi, the most appropriate is the evaluation of venous flow by echoenhanced doppler, combined with transcranial doppler, which also allows an assessment of the deep cerebral veins and any reflux. zamboni therefore established an ultrasound protocol for identifying the 5 characteristic parameters of ccsvi:21,23-27 i) evidence of twoway flow in one or both of the internal jugular veins (ijv) and/or in the vertebral veins (vv) in both positions (supine and upright), or bidirectional flow in one position with the absence of flow in the other; ii) evidence of two-way flow in the intracranial veins and sinuses; iii) visibility of intraluminal defects (flaps, septa or valvular defects) associated with hemodynamic changes (blocks, reflux or acceleration) and/or reduction of ijv in the correspondence: aldo bruno, via san vito 123, 82100 benevento, italy. e-mail: aldobruno@webmail.it conflict of interests: the authors declare no potential conflict of interests. key words: chronic cerebrospinal venous insufficiency, ménière’s disease. received for publication: 18 april 2014. revision received: 3 july 2014. accepted for publication: 8 july 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright a. bruno et al., 2014 licensee pagepress, italy veins and lymphatics 2014; 3:3854 doi:10.4081/vl.2014.3854 no n c om me rci al us e o nly article [page 78] [veins and lymphatics 2014; 3:3854] supine position to 0.3 cm/2°; iv) no evidence of flow in both the ijv and vv and/or absence of flow in one position and two-way flow in the other; v) �csa (cross-sectional area) of ijv enlarged or unchanged both at 90° and 0°. this article reports a first phase study on the ultrasound diagnosis of ccsvi in patients with md. so far in the literature only four papers have examined this correlation.28-31 in 2009, zamboni proposed endovascular treatment for these lesions by angioplasty in order to improve cerebral venous outflow.32 in recent years, percutaneous transluminal angioplasty (pta) procedures on neck veins and the azygos vein of patients with multiple sclerosis has become wide spread, producing good results and low morbidity,32-34 while fueling debate and controversy in the scientific community.33 this article reports also on our preliminary experience in the diagnosis and endovascular treatment of ccsvi in patients with md. materials and methods the diagnosis of ménière’s disease was made using the diagnostic scale based on clinical criteria proposed by the american academy of otolaryngology (aao) in 1995.6 from april 2013 to december 2013 we observed 50 patients, 35 females, 15 males, aged 32 to 68 years, with an average age of 46 years, suffering from definite ménière’s disease according to aao 1995.6,11 patients were diagnosed at several italian specialized otolaryngology and audiology centers. tonal and speech audiometry was performed, along with tympanometry, vestibular examination (bed-side test to detect spontaneous nystagmus, head shaking evoked nystagmus, vibration evoked nystagmus, positional and positioning nystagmus; caloric stimulation according to the fitzgerald-hallpike technique); auditory brainstem responses; vestibular evoked myogenic potentials. audiological staging followed the aao 1995 guidelines: stage 1: ≤25 db four tone average; stage 2: 26-40 four tone average; stage 3: 4170 four tone average; stage 4: >70 four tone average. the four tone average considers audiometric levels at 0.5, 1, 2, and 3 khz. the severity of vertigo in ménière’s disease was assessed using the functional level scale,6 from 1 (my dizziness has no effect on my activities at all) to 6 (i have been disabled for 1 year or longer). all patients had poor response to conventional treatment therapies (betahistine, steroids, diuretics, loop diuretics, osmotics, vasoactive drugs, etc.), with persistent dizziness, spells of acute vertigo, hypoacusis, ear fullness and tinnitus. the patients underwent echo-color doppler of the veins of the neck and intracranial venous according to the zamboni protocol; the examination was also performed on 100 agematched healthy patients, with no evidence of neurological or audiovestibular disease. twenty patients, 13 women and 7 men, were given phlebograms and endovascular treatment with bilateral pta of the internal jugular vein and an assessment of the azygos vein that was treated with pta in only three cases. six months after the endovascular procedure, patients were sent for follow-up to the audiology unit of the g. rummo hospital, for an audiovestibular assessment, through pure tone and speech audiometry and bed-side vestibular examination. endovascular procedure pta of the internal jugular vein was carried out as per the standard surgical protocol of our hospital for the treatment of ccsvi associated with multiple sclerosis: i) percutaneous right or left femoral approach under local anesthesia with lidocaine 2%; ii) direct or ultrasoundguided puncture of the common femoral vein; iii) insertion of an 8 fr or 9 fr introducer; iv) administration of 2500 iu of heparin sodium; v) selective venography of the internal jugular veins in three projections with an assessment of emptying times using 100 cm 4 fr ber hydrophilic catheters (or alternatively, 4fr cobra catheter for the azygos vein) mounted on a stiff 260 cm hydrophilic guide wire; vi) after obtaining confirmation of the presence of the lesion by echo-color doppler, we took the pta dilatation catheter with 10 to 20fr lowcompliance balloon attached to a power-assisted inflation-device applied for 120 seconds at 4-8 atm; vii) hemostasis was by compression; viii) at discharge, patients were prescribed low molecular weight heparin at therapeutic doses (bemiparin sodium: 7500 iu/day) for 20 days and subsequently mesoglycan: 100 mg/day for 12-24 months. statistical analysis differences between preand post-operative four pure tone average and between preand post-operative frequency of spells of acute vertigo were assessed through the unpaired ttest, considering a p value of <0.05 as significant, and a confidence interval of 95%. the difference in the presence of ccsvi parameters in patients suffering from md versus the control population was assessed via 2-way contingency table analysis, considering a p value of <0.05 as significant. results audiological staging twenty-five patients were stage 4; 23 were stage 3; 2 were stage 2. of the 20 patients who underwent pta, 11 were stage 4, 8 were stage 3, and 1 was stage 2, with a pre-operative four pure tone average of 65+/-12.68 db nhl. the mean speech discrimination was 80% both in the whole group and in the subgroup of 20 patients who underwent pta. functional staging twenty-two patients were functional level #3; 10 were functional level #4; 9 were functional level #5; 8 were functional level #2; 1 was functional level #6. of the 20 patients who underwent pta, 10 were functional level #3; 6 were functional level #4; 3 were functional level 5; 1 was functional level #6. the mean number of spells of acute vertigo in the period six months before treatment was 8.9+/-4.08. the echo-color doppler examination of the venous vessels of the neck and intracranial venous evidenced in 45 cases out of fifty the presence of 2 or more positive parameters for ccsvi on the side affected by md, and in 20 cases also on the healthy side. in patients with md bilateral lesions were revealed in the jugular and in three cases also in the azygos vein. no hypoplasia of the jugular vein was detected. in the control population, abnormalities compatible with ccsvi were detected by doppler ultrasound in only three patients (3%) and none had a diagnosis or symptoms of neurodegenerative disease or md (p<0.001). there was a correlation between the ultrasound diagnosis and the phlebogram in 90% of cases. in all cases it was possible to perform the endovascular procedure as scheduled. no major complications or morbidity were reported, and no disability after intervention. all patients were discharged the day after the procedure. at follow-up 6 months after the pta, 19 patients reported an improvement in both symptoms and hearing level, and fewer spells of vertigo and tinnitus. one patient did not show any significant improvement in hearing ability, but reported a subjective improvement in tinnitus and the sensation of ear fullness. the post-operative four pure tone average was 55.7+/-13.79 dbnhl; the difference between preand post-operative four pure tone average is statistically significant (p=0.03, confidence interval 95%); speech intelligibility improved from a pre-operative average value of 80% to a post-operative value of 90%. the mean number of spells of acute vertigo decreased from 8.9 +/-4.08 in the six months no n c om me rci al us e o nly article [veins and lymphatics 2014; 3:3854] [page 79] before treatment , to 0.1 +/0.3 in the six months after treatment, i.e. only 2/20 patients reported a single spell of acute vertigo (p<0.001). upon re-assessment of the functional level, 9 patients were functional level #2; 10 were functional level #3; 1 was functional level #4. one patient presented with a re-stenosis of one of the jugular veins, although the symptomatic benefit persisted. the echo-color doppler follow-up according to the zamboni method at 1, 3 and 6 months showed a recurrence in only one case, but without the loss of the benefit gained. there were no cases of auditory and vestibular symptoms returning to pre-surgical levels. discussion and conclusions phase 1 of the present study showed confirms a significant high prevalence of ccsvi screened by doppler ultrasound in md as compared to healthy controls.28-31 after the confirm of ccsvi with catheter venography in a subgroup of ménière’s patients with lesions of the ijv and azygos vein, similar to those characteristic of ms (ccsvi), with slowing of the cerebral venous outflow, we consider venous drainage as a risk factor of major importance in view of the seriousness of the disease. the results of our preliminary study confirm that pta of the internal jugular vein and azygos vein is an effective procedure. experience in treating arterial and venous lesions certainly plays a decisive role; the standardization of the method also minimizes the risk of major complications and results in a lower relapse rate than other case studies. in this study no post-procedural thrombosis of the ijv occurred, neither at short nor longer term follow-up. the absence of such a serious complication is related to the drug therapy used and reported above: no drug-related side effects were reported. this experience has led to a re-assessment of the vascular venous circulation of the neck and brain that until now was almost completely disregarded. since this assessment had not previously been performed in ménière’s disease patients, and since abnormal flow is not found in normal subjects, it certainly offers new treatment prospects. we therefore believe that endovascular angioplasty of the internal jugular and azygos veins in patients with ménière’s disease is a safe procedure associated with the current treatment, in cases where there are diagnostic criteria, and recognize the fundamental role of the specialist and ent expert in the management of this disease. improvements in subjective dizziness, number of spells of acute vertigo, ear fullness and tinnitus, as well as improved hearing and vocal discrimination allow us to consider our results encouraging. however, the major limitation of our second phase study is the short follow-up. aao6 suggests that the frequency of definitive attacks for the period 6 months before treatment should be compared with the interval occurring between 18 and 24 months after treatment... characterization of treatment response for an individual patient should not be made until the patient has been observed for 24 months after treatment. we were unable to comply with the last point due to the short follow-up, therefore we must consider our current results as non-definitive. consequently, it will be essential to extend the length of the follow-up of treated patients for a at least two years in order to assess the persistence of the therapeutic effects on the symptoms of md and to apply the criteria for therapeutic validity proposed by the aao in 1995. references 1. paparella mm: the cause (multifactorial inheritance) and pathogenesis (endolympathic malabsorption) of ménière’s disease and its symptoms (mechanical and chemical). acta otolaryngol 1985;99:445-51. 2. wladilavoski-wasserman p, facer gw, mokri b, kurland lt. ménière disease: a 30-year epidemioological and clinical study in rochester, mn 1951-80. laryngoscope 1984;94:1098-102. 3. mancini f, catalani m, carru m, monti b. history of ménière’s disease and its clinical presentation. otolaryngol clin north am 2002;35:5656-80. 4. celestino d, ralli g. incidence of ménière disease in italy. am j otol 1991;12:135-8. 5. ménière p. memoire sur des lesions de l’oreille interne dominant lieu a des symptom de congestion cerebrale apoplectiforme. gaz med (paris) 1861;16:597-601. 6. american academy of otolaryngology head and neck foundation, inc. committee on hearing and equilibrium guidelines for diagnosing the evaluation of therapy in ménière’s disease. otolaryngol head neck surg 1995;113:181-5. 7. merchant sn, adams jc, nadol jb jrpathophysiology of ménière’s syndrome are symptoms caused by endolymphatic hydrops otol neurotol 2005;26:74-81. 8. saeed s, penney s. diagnosis and management of ménière disease. ent news 2004;13:32-4. 9. de sousa lc, piza mr, da costa ss. diagnosis of ménière disease: routine and extended tests. otolaryngol clin north am 2002;35:547-64. 10. di girolamo s, picciotti p, sergi b, et al. postural control and glycerol test in ménière’s disease. acta otolaryngol 2001;121:813-7. 11. american academy of otolaryngology head and neck foundation, inc. committee on hearing and equilibrium guidelines for diagnosing the evaluation of therapy in ménière’s disease. otolaryngol head neck surg 1995;113:181-5. 12. hsu l, zhu xn, zhao ys. immunoglobulin e and circulating immune complexes in endolymphatic hydrops. ann otol rhinol laryngol 1990;99:535-8. 13. chung wh, cho dy, choi jy, hong sh. clinical usefulness of extratympanic electrocochleography in the diagnosis of ménière’s disease. otol neurotol 2004;25: 144-9. 14. naganawa s, nakashima t.cutting edge of inner ear mri. acta otolaryngol suppl 2009;129:15-21. 15. zamboni p. iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. j r soc med 2006;99:589-93. 16. valdueza jm, von munster t, hoffman o, schreiber s, einhaupl km. postural dependency of the cerebral venous outflow. lancet 2000;355:200-1. 17. bergan jj, schmid-schonbein gw, smith pd, nicolaides an, boisseau mr, eklof b. chronic venous disease. n engl j med 2006;355:488-98. 18. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:392-9. 19. zamboni p, lanzara s, mascoli f, et al. inflammation in venous disease. int angiol 2008;27:3. 20. comi g, battaglia ma, brtolotto a, et al. observational case-control study of the prevalence of chronic cerebrospinal venous insufficiency in multiple sclerosis: results from the cosmo study. mult scler 2013;19:1508-17. 21. zamboni p, morovic s, menegatti e, et al. screening for chronic cerebrospinal venous insufficiency (ccsvi) using ultrasound. raccomandation for a protocol. int angiology 2011;30;571-97. 22. haacke em, ayaz m, khan a, et al. establishing a baseline phase behavior in magnetic resonance imaging to determine normal vs. abnormal iron content in the brain. j magn reson imaging 2007; 26:256-64. 23. schreiber sj, lurtzing f, gotze r, et al. extrajugular pathways of human cerebral venous blood drainage assessed by duplex ultrasound. j appl physiol 2003;94:1802-5. 24. doepp f, schreiber sj, von münster t, et no n c om me rci al us e o nly article [page 80] [veins and lymphatics 2014; 3:3854] al. how does the blood leave the brain? a systematic ultrasound analysis of cerebral venous drainage patterns. neuroradiology 2004;46:565-70. 25. nedelmann m, eicke bm, dieterich m. functional and morphological criteria of internal jugular valve insufficiency as assessed by ultrasound. j neuroimaging 2005;15:70-5. 26. menegatti e, zamboni p. doppler haemodynamics of cerebral venous return. curr neurovasc res 2008;5:259-64. 27. baumgartner rw, nirkko ac, müri rm, gönner f. transoccipital power-based color coded duplex sonography of cerebral sinuses and veins. stroke 1997;28:131923. 28. alpini dc, bavera pm, hahn a, et al. chronic cerebrospinal venous insufficiency (ccsvi) in ménière disease case or cause? sci med 2013;4:9-15. 29. bruno a, califano l, mastrangelo d, et al. chronic cerebrospinal venous insufficiency in ménière disease: diagnosis and treatment. otorinolaringologia 2013;63:173-7. 30. filipo a., ciciarello f, attanasio g, et al. chronic cerebrospinal venous insufficiency in patients with ménière’s disease eur arch otorhinolaryngology 2013. [epub ahead of print] 31. di berardino f, alpini dc, bavera pm, et al. chronic cerebrospinal venous insufficiency (ccsvi) in ménière disease. phlebology 2014. [epub ahead of print] 32. zamboni p, galeotti r, menegatti e, et al. a prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. j vasc surg 2009; 50:1348-58. 33. salvi f, bartolomei i, buccellato e, et al. venous angioplasty in multiple sclerosis: neurological outcome at two years in a cohort of relapsing-remitting patients. funct neurol 2012;27:55. 34. ludyga t, kazibudzki m, simka m, et al. endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? phlebology 2010;25:286-95. no n c om me rci al us e o nly hrev_master veins and lymphatics 2014; volume 3:2235 [veins and lymphatics 2014; 3:2235] [page 7] progressive or degressive compression pressure profile in patients with chronic venous disorders of the lower limb giovanni mosti angiology department, md barbantini clinic, lucca, italy abstract graduated compression devices are considered the standard care for management of venous and lymphatic disorders. recently compression devices exerting a pressure over the calf higher than over the ankle have been proved to be more effective than traditional graduated devices in increasing the impaired ejection fraction (ef) from the lower leg in patients with venous disease. aim of this work is presenting an overview of the new concept on progressive compression, its potential benefits and limits. in different series of tests, the ef from the lower leg was assessed in 70 patients with severe reflux in the great saphenous vein (gsv). ef was measured by strain gauge plethysmography, in baseline conditions and after applying graduated compression devices or the new inversely graduated or progressive compression (pc) devices. the interface pressure was recorded, simultaneously with the ef, both in the gaiter area (b1 point) and at the calf (c point) in order to assess the compression pressure profile. ef, severely impaired in patients with gsv reflux, was increased by compression. so called pc devices (both pc elastic stocking and pc inelastic bandages) were significantly more effective than graduated compression in increasing the ejection fraction. the higher the pressure on the calf the higher the ef improvement. maintaining the same strong pressure over the calf by means of two progressive stockings and increasing the pressure only over the calf to restore a graduated compression didn’t improve the ef. to improve venous pumping function in the ambulant patient stronger compression of the calf is more effective than graduated compression. this can be explained by the higher amount of blood volume pooled in the calf veins. introduction compression providing a graduated pressure profile (higher over the ankle and gradually decreasing from distal to proximal) is the general principle for every kind of compression therapy and has been the standard care for thromboprophylaxis and management of venous and lymphatic disorders so far. this principle of a graduated compression is considered so important that it is mandatory in regulatory standards for elastic compression stockings.1-3 recent publications have questioned the importance of a graduated compression at least in ambulatory patients, both regarding subjective symptoms relief1-3 and improvement of objective parameters.4-6 it was clearly shown that, in patients with venous disease, the reduced ejection fraction (ef) from the lower leg can be significantly more increased by compression devices exerting a higher pressure over the calf than over the ankle area compared with compression devices exerting a graduated pressure profile. this is true both for elastic compression stockings4 and for inelastic bandages5 which are named inversely graduated or progressive compression devices. the following will give an overview of our results. materials and methods in different series of experiments a total of 70 patients (29 males and 41 females; mean age of 53.1 years; range 37-70) affected by chronic venous disease were investigated without and with different compression devices. clinically these patients corresponded to classes c2-c5 in the clinical, etiological, anatomic and pathophysiologic classification (ceap). inclusion criteria: all patients were affected by insufficiency of the great saphenous vein (gsv) with: terminal and pre-terminal valve incompetence; venous diameter in standing position 2 cm below the sapheno-femoral junction more than 1 cm; venous reflux time after manual calf compression longer than 3 seconds; able to perform the physical exercise necessary to complete the protocol; with an ankle-brachial pressure index measured by doppler higher than 0.8. exclusion criteria: patients with competent terminal and/or pre-terminal valves, with a venous diameter in the standing position 2 cm below the junction less than 1 cm, with a venous reflux time shorter than 3 seconds, those unable to perform the exercise reported in the protocol or with an ankle brachial pressure index lower than 0.8. duplex investigation (esaote mylab 60; linear probe 7.5 to 10 mhz; esaote s.p.a., genoa, italy) of the superficial and deep veins of the lower extremity was performed with the patient in the standing position for detecting venous reflux during valsalva’s maneuver and after manual compression of the calf, both at the junction of the gsv in the groin and 5 cm distally. reflux time more than 1 second was considered to be pathological. using a cross sectional view the diameter of the gsv was measured in the groin. all individuals were informed about the investigation and gave their written consent. the reported studies complied with the helsinki declaration and the rules of the local ethical committee. compression devices in different studies we used two different kinds of ready-made, knee length, elastic stockings and inelastic bandages. all the compression devices were applied either to provide a standard graduated pressure profile or an inversely graduated or progressive pressure profile. in the first study4 a standard graduated elastic compression stocking (gecs) was compared with a progressive elastic compression stocking (pecs). both elastic stockings exerted a pressure at the gaiter area between 15 and 25 mm hg. the gecs provided a degressive pressure profile, with pressures which were 20% lower than at calf level (progressivâ n’system, pierre fabre, castres, france). the pecs (pierre fabre) exerted a lower pressure at the ankle and an increasing pressure profile with pressures about 50% higher at calf level than that at the ankle. in the second study5 an inelastic multilayer, multicomponent bandage made up with rosidal k® on top of a padding layer consisting of cellona® synthetic cotton and mollelast haft® (lohmann&rauscher, rengsdorf, germany), was wrapped on the lower leg from the base of the toe to the popliteal fossa. the standard application provided a higher pressure in the gaiter region and a decreasing correspondence: giovanni mosti, angiology department, clinica md barbantini, via del calcio, 55100 lucca, italy. e-mail: jmosti@tin.it key words: graduated compression, progressive compression, inversely graduated compression, ejection fraction, venous pumping function. received for publication: 9 january 2014. revision received: 3 february 2014. accepted for publication: 3 february 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright g. mosti, 2014 licensee pagepress, italy veins and lymphatics 2014; 3:2235 doi:10.4081/vl.2014.2235 no nco mm er cia l u se on ly article [page 8] [veins and lymphatics 2014; 3:2235] pressure towards the calf [graduated compression bandages (gcb)]. this bandage was compared with a bandage applied with higher pressures over the calf than over the distal leg thereby producing a negative pressure gradient [negative graduated compression bandages (ngcb)]. in the third study,6 one pecs was compared with two pecs donned over each other and, subsequently, with one additional conventional stocking covering only the gaiter area to restore a graduate pressure profile. interface pressure measurement in all studies the pressure exerted by different compression devices was continuously measured using a validated device7,8 connected with a data logger by a special computer program (picopress®, microlabitalia, padua, italy). the pressure transducer consists of a flat plastic pressure probe (diameter 5 cm) filled with 2 ml of air for the pressure measurement. fluctuations of pressure on this probe are transformed into electronic signals (statham-element) that can be recorded continuously. two probes were used to measure pressure simultaneously: one at the distal leg, about 12 cm proximal to the medial malleolus (b1 point, which is defined by the transition of the muscular part of the medial gastrocnemius into the tendinous part)9 and one proximally, at the maximal calf circumference (c point).4 interface pressure was measured continuously in the supine and the standing position and during the exercise program. static stiffness index was calculated by subtracting supine pressure from standing pressure.10 measurement of ejection fraction of the venous calf pump using strain-gauge plethysmography (angioflow2; microlabitalia), ejection fraction was assessed following the method described by poelkens et al.11 an indium-gallium alloy gauge (diameter of 1 mm) is placed around the leg in the supine position 5 cm distally from the patella and immediately proximal to the upper border of the elastic stocking. after the calibration of the device, the investigation starts by elevating the examined leg in order to empty the veins and to record the minimal volume of the leg segment. after one minute the patient stands up and the volume increase of the calf segment encircled by the strain gauge probe, reflecting venous filling, is measured continuously. venous volume (vv) is defined as the difference between empty and filled veins. during a standardized exercise (walking on spot with 20 steps in 20 seconds) the amount of blood that is expelled towards the heart [expelled volume (ev)] reflects the quality of the venous pump. ejection fraction (%) is calculated according to the formula 100 × ev/vv. using this method we were able to assess the hemodynamic efficacy of several compression products in a completely noninvasive way.12-15 the experiments were carried out in baseline condition without compression and repeated with the compression stockings or the inelastic bandages. in every circumstance the sequence of tests (without compression or with different types of compression) was randomized. all tests on every patient were done on the same day with an interval of 15 min between each measurement. the measurements were performed 5 min after stocking or bandages application with the patient resting in the supine position in a quiet room with constant humidity and temperature. statistical analysis in all the studies median values and interquartile ranges are given. non-parametric friedman test with dunn’s multiple comparisons were used to compare the repeated measurements of ef under different compression systems with the baseline. the spearman rank test was taken as a nonparametric method for quantifying correlations. differences with a p<0.05 were considered statistically significant. the graphs and the statistically evaluations were generated by using graph pad prism5 software (graph pad, san diego, ca, usa). results ejection fraction ef was always significantly increased by both elastic and inelastic compression devices. the so called negative graduated or progressive compression was significantly more effective than the graduated compression in increasing the ejection fraction, both when applied by means of elastic stockings and by inelastic bandages (figure 1 a,b). one elastic stocking is not able to restore the normal value of ef, which is higher than 60%, while two stockings over each other restore ef in its normal range (figure 1c). maintaining the same pressure over the calf exerted by two progressive stockings and additionally increasing the pressure over the ankle in order to move from figure 1. ejection fraction in baseline conditions and with different compression devices. a) the low ef in baseline condition, increases with one gecs and increases significantly more with one pecs even if not ef was not restored into its normal range; b) the low ef in baseline conditions is restored into its by gcb, and even more with ngcb; c) one pecs increases ef, two pecs increases significantly more ef into its normal range; two pecs and a third stocking applied only on the gaiter area to restore a graduated pressure profile are not able to further increase ef. no nco mm er cia l u se on ly article [veins and lymphatics 2014; 3:2235] [page 9] a progressive to a graduated pressure profile doesn’t increase the ejection fraction (figure 1c). in contrast to compression stockings inelastic bandages are able to normalize ef when applied with a graduated pressure profile. inelastic bandages applied with a progressive pressure profile increase the ef significantly further, up into the range close to 90% (figure 1b). the increase of ef is positively related to pressure and stiffness: increasing pressure and stiffness over the calf leads to progressively higher ejection fraction.4,5 the highest ejection fraction was recorded with inelastic bandages applied with a progressive pressure profile. interface pressure in the first study comparing graduated and progressive elastic compression stockings, gecs exerted a higher pressure at ankle (median 22 mm hg) and showed a decrease of the pressure by 14% at the calf (point c). pecs exerted a lower pressure at ankle level, median 18.5 mm hg and showed a pressure increase by 57% at c (figure 2a). these pressures increased only slightly by standing up and during exercise. the highest pressures were recorded with pecs at c point in standing position (31.5 mm hg), and during exercise (32 mm hg). comparing graduated and negatively graduated compression bandages, gcb median supine interface pressure was 53.5 mm hg at b1 and 37.5 mm hg at c. with ngcb median pressure was 50 mm hg at b1 and 62 mm hg at c (figure 2b). standing pressures were significantly higher than supine pressures, both at position b1 and at c (p<0.001) for both bandages. the greatest median pressure difference was in the calf area in standing position where gcb exerted 59 mmhg and ngcb 75.5 mmhg (p<0.001). in the third study median compression pressure exerted by 2 superimposed stocking was significantly higher than with one stocking (33 vs 18 mm hg in b1 and 46 vs 27 mm hg in c) (figure 2c). with 2 superimposed progressive stocking, maintaining the same pressure of 46 mm hg over the calf, we added a third stocking applied only over the foot and ankle region which was rolled down in order not to compress the calf. this increased the pressure over the ankle from 33 to 56 mm hg and restored a graduated pressure profile. discussion our data show that the higher the pressure over the calf and the higher the pressure peaks during walking,5 the grater the effect on venous pumping function: one pecs is more effective than one gecs, two pecs superimposed over each other are more effective than one pecs, ngcb is more effective than gcb. ngcb exerting the strongest pressure over the calf compared to other compression devices is the most effective modality. the reported data confirm that the pressure over the calf is mainly responsible for the venous pump improvement independently from the pressure gradient: maintaining the same pressure over the calf with a progressive pressure profile and increasing the pressure over the ankle to restore a graduated compression did not have any significant effect the venous pumping function. in the standing position the intravenous hydrostatic pressure is maximal at foot and ankle level and progressively lower towards the upper leg and the thigh. in order to counteract this intravenous pressure profile the external pressure applied by compression stockings was postulated to be higher at ankle level with a continuous pressure reduction from distal to proximal. this graduated compression is considered an important quality criterion for compression systems and a cornerstone of standard care in venous disease. actually pressure peaks of more than 150 mmhg recorded in the solely muscle during walking16 producing inverse intravenous pressure gradients with every step are a physiological phenomenon. in addition simultaneous measurements revealed that ambulatory venous pressure decreases more in the foot than in the calf veins, both in normal and patients with superficial venous incompetence17 demonstrating that a continuous intravenous pressure gradient is not a general physiological principle during walking. an intravenous pressure which is higher at calf than at ankle level could theoretically interfere with venous return. this is obviously not the case due to the complex interplay of contraction and relaxation of different leg muscle which produces a sequence of compressions and distensions of the leg veins favoring the venous outflow from the leg. in fact the first two phases of walking, plantar dorsi-flexion and plantar leaning of the foot, empty the distal foot and ankle veins into the calf deep system; during the third phase, ankle plantar flexion, the calf muscle contraction squeezes out the blood pooled in the full calf veins even producing a very short phase of distal blood pooling which will be emptied with the following step.18 as a consequence there is not a higher calf pressure at the same time as a lower ankle pressure but a sequence of different pressures favoring the venous emptying of the leg. therefore, when applying compression devices in the ambulatory patient affected by figure 2. pressure profile from ankle (b1) to calf (c) area of different compression devices. a) with gecs (left) pressure decreases from b to c, with one pecs (right) pressure increases from b to c; b) gcb (left) produces a decreasing pressure from b to c while ngcb (right) produces an increasing pressure from b to c; c) one pecs increases pressure profile from b to c (left), two pecs (middle) shift to a higher level this pressure profile; 2 pecs plus a third stocking applied only on the gaiter area restore a graduated compression. no nco mm er cia l u se on ly article [page 10] [veins and lymphatics 2014; 3:2235] chronic venous disorder, a graduated pressure profile cannot be considered mandatory. actually compression devices exerting a progressive, pressure profile, higher on the calf than on the ankle have been proved to be more effective than graduated compression in increasing the venous pumping function assessed by measuring the ef from the lower leg.4-6 this effect can be explained by the higher external compression over the calf exerted by a progressive compression which will increase the pressure exerted on the local veins during muscle systole and will squeeze out more vigorously the great amount of blood pooled in the calf compared to the ankle area, which is covered by lower compression. in other words a negative graduated pressure profile provided by the progressive compression corresponds to the progressive intravenous pressure which is physiologically higher in the calf than in the ankle during muscle activity. it can be argued that a strong pressure of about 50 mm hg or more over the calf (exerted by double pecs or progressive inelastic bandages) could impede the distal venous emptying of the foot and ankle veins into the calf veins. the greatest increase of ef recorded with the superimposition of two pecs or with the very strong pressure of the inelastic bandages demonstrates that this is not the case. finally compression comfort must be taken into account: a graduated compression with a high pressure over the calf would require a very strong pressure over the ankle, which can be intolerable; furthermore such a pressure profile could make donning very difficult when using an elastic stocking. this is not the case for progressive compression.6 the main limit of all these studies is that the benefit of progressive stockings on venous pumping function in patients with superficial veins incompetence cannot be extended to other clinical indications like edema, superficial or deep vein thrombosis, post thrombotic syndrome, venous ulcers or compression after venous procedures. before recommending progressive compression its effectiveness in these clinical conditions needs to be carefully assessed in new studies. also the sparse data regarding the use of not graduated material for edema prevention19 and of foot-sparing compression after varicose vein surgery20 should be confirmed in future trials. conclusions negatively graduated or progressive compression devices are significantly more effective than graduated compression in increasing ejection fraction up to restoring its normal range in patients with chronic venous disorders. taking into account the reported experimental data a graduated pressure profile should not be considered as mandatory at least in ambulatory patients. at present time other objective hemodynamic data as well as clinical outcomes concerning treatment or prevention of other venous clinical conditions are not available and should be investigated in future trials. references 1. couzan s, leizorovicz a, laporte s, et al. a randomized double-blind trial of upward progressive versus degressive compressive stockings in patients with moderate to severe chronic venous insufficiency. j vasc surg 2012;56:1344-50. 2. couzan s, assante c, laporte s, et al. booster study: comparative evaluation of a new concept of elastic stockings in mild venous insufficiency. presse med 2009;38: 355-61. 3. garreau c, pibourdin jm, nguyen le c, boisseau mr. elastic compression in golf competition. j mal vasc 2008;33:250-1. 4. mosti g, partsch h. compression stockings with a negative pressure gradient have a more pronounced effect on venous pumping function than graduated elastic compression stockings. eur j vasc endo vasc surg 2011;42:261-6. 5. mosti g, partsch h. high compression pressure over the calf is more effective than graduated compression in enhancing venous pump function. eur j vasc endo vasc surg 2012;44:332-6. 6. mosti g. partsch h. improvement of venous pumping function by double progressive compression stockings: higher pressure over the calf is more important than graduated pressure profile. eur j vasc endovasc surg 2014 [in press]. 7. mosti g., rossari s. l’importanza della misurazione della pressione sottobendaggio e presentazione di un nuovo strumento di misura. acta vulnol 2008;6:31-6. 8. partsch h, mosti g. comparison of three portable instruments to measure compression pressure. int angiol 2010;29:426-30. 9. partsch h, clark m, bassez s, et al. measurement of lower leg compression in vivo: recommendations for the performance of measurements of interface pressure and stiffness. dermatol surg 2006;32: 224-33. 10. partsch h. the static stiffness index: a simple method to assess the elastic property of compression material in vivo. dermatol surg 2005;31:625-30. 11. poelkens f, thijssen dh, kersten b, et al. counteracting venous stasis during acute lower leg immobilization. acta physiol 2006;186:111-8. 12. mosti g, partsch h. measuring venous pumping function by strain-gauge plethysmography. int angiol 2010;29:421-5. 13. mosti g, mattaliano v, partsch h. inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous reflux. phlebology 2008;23:287-94. 14. mosti g, partsch h. is low compression pressure able to improve venous pumping function in patients with venous insufficiency? phlebology 2010;25:145-50. 15. mosti g, partsch h. inelastic bandages maintain their hemodynamic effectiveness over time despite significant pressure loss. j vasc surg 2010;52:925-31. 16. murthy g, ballard re, breit ga, watenpaugh de, hargens ar. intramu scular pressures beneath elastic and inelastic leggings. ann vasc surg 1994;8: 543-8. 17. stranden e, ogreid p, seem e. venous pressure gradients in patients with chronic venous disease. phlebology 1986;1:47-50. 18. gardner amn, fox rh. the venous system in health and disease. ios press, the netherlands; 2001. pp 42-73. 19. mosti g, partsch h. occupational leg oedema is more reduced by antigraduated than by graduated stockings. eur j vasc endo vasc surg 2013;45:523-7. 20. ricci s, moro l, trillo l, incalzi ra. footsparing postoperative compression bandage: a possible alternative to the traditional bandage. phlebology 2013;28:47-50. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2014; volume 3:4503 [page 60] [veins and lymphatics 2014; 3:4503] aneurysms of the superficial venous system: classification and treatment ronald g. bush, peggy bush vein experts, palm city, fl, usa abstract superficial venous aneurysms are rarely described and they may remain indolent or become the source for pulmonary emboli. a system of classification and treatment protocol according to size and location is proposed. three hundred thirty patients were evaluated for symptomatic venous disease (c2-c6) over a 2-year period. a proposed designation for venous aneurysm is described. patients fulfilling this criterion are described in reference to site of involvement, histologic findings, and method of treatment. five percent of patients met the criteria for venous aneurysm. nine aneurysms of the greater saphenous vein were identified. three aneurysms were proximal to the subterminal valve and the rest were distal. six aneurysms of the anterior accessory greater saphenous vein (aagsv) were identified. three aneurysms of the aagsv spontaneously thrombosed. two patients presented with aneurysms of the small saphenous vein. histology revealed thickened intima, smooth muscle and adventitia. aneurysm designation relates to diameter of normal and contiguous vein. all superficial venous aneurysms in close proximity to the junction of the femoral or popliteal vein should be ligated. classification of venous aneurysms should include the aagsv, which may present with spontaneous thrombosis. introduction superficial venous aneurysms secondary to venous hypertension are more common than reported in the literature. the subject of this report are those aneurysmal dilations occurring within the fascial compartments of the greater saphenous vein (gsv), small saphenous vein (ssv) or the anterior accessory saphenous vein (aagsv). many reports describing venous aneurysms include multiple sites in both the deep and superficial system. pascarella et al.1 described their experience with venous aneurysms of the lower extremity and proposed a classification based on location in the superficial system. a consensus as to the exact definition of a venous aneurysm secondary to chronic venous disease does not exist. even histological findings in venous aneurysms vary in reported studies. histological discrepancies may represent the comparison of primary venous aneurysms to aneurysms secondary to venous hypertension.2,3 the duration of hypertension may also become a factor in the histological findings. most reported cases with embolic events associated with venous aneurysms are located in the deep system.4 however, there are also reports in the literature of emboli originating in the superficial venous system. embolic sources have included the gsv, aagsv, ssv and other superficial veins of the neck and upper extremity.5-9 the purpose of this study is to examine our experience with superficial venous aneurysms secondary to venous hypertension in regard to presenting symptoms, treatment, potential complications, and histological findings. materials and methods three hundred thirty patients with symptomatic venous disease (c2-c6) were evaluated over a 2-year period. of these patients, eighteen met the proposed criteria for venous aneurysm; the vein size was 3x the normal respective vein diameter and 2x the size of the contiguous vein. five patients were male, 13 female with a median age of 55. the basal metabolic rate was greater than 30 in only two patients. results a total of 9 aneurysms were located in the gsv. three aneurysms were located at the sapheno-femoral junction (sfj). aneurysms of the sfj are localized between the terminal and subterminal valve and include the junctional branches (figure 1). two aneurysms were located just distal to the sub-terminal valve and 4 were located in the distal gsv. six patients presented with aneurysms of the aagsv. three of these patients presented with acute thrombosis of the aneurysm and associated superficial branches (figure 2). two aneurysms of the ssv were identified. one involved the sapheno-popliteal junction (spj) and one aneurysm was located at the mid ssv. one patient presented with an aneurysm of the posterior medial thigh circumflex branch. discussion no consensus exists on what the criteria for the designation of venous aneurysms should be. pascarella1 used the criteria of 1.5x the size of the contiguous vein and this is also the measurement used to describe an arterial aneurysm. many valvular dilatations in the venous system could meet this definition. other criteria for venous aneurysmal designation have included 3x the size of the normal vein, or 2x the size of the contiguous vein.10 a more rigorous criteria would include both vein diameter compared to normal and contiguous vein. based on histologic studies by the authors of both extrafascial varicose vein segments and those segments meeting the proposed size requirement for a venous aneurysm, the histologic findings are very similar (figure 3). in both the varicose segment and the aneurysmal segment, there is smooth muscle hypertrophy to varying degrees. the intima is thickened as well as the adventitia with collagen infiltration. these findings are consistent with the end results of persistent venous hypertension; muscle hypertrophy and collagen breakdown with abnormal synthesis of proteins. as the hypertension persists, more dilatation may occur with elongation of muscle fibers and disruption of the internal and external elastic membrane. histological findings may vary somewhat depending on the crosssectional study in the region of the valve, or if saccular dilation occurs as opposed to circumferential involvement. similar changes have been described previously in histological studies of the refluxing gsv at the sfj.11 these changes only occur at the location of nonfunctioning venous valves. venous aneurysms of vessels not associated with chronic venous hypertension (primary or congenital) demonstrate thinning of the medial layer of the venous wall.12 the etiology of venous aneurysmal dilatation secondary to chronic venous disease is the same as for varicosed segments; persistent venous hypertension and abnormal valve function. one theory portends a turbulent flow patcorrespondence: peggy bush, vein experts, 1257 sw martin hwy #768, palm city, fl 34991, usa. e-mail: pbush@veinexperts.org key words: venous aneurysm, superficial venous disease, chronic venous disease, venous hypertension. received for publication: 6 july 2014. revision received: 18 october 2014. accepted for publication: 20 october 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright r.g. bush and p. bush, 2014 licensee pagepress, italy veins and lymphatics 2014; 3:4503 doi:10.4081/vl.2014.4503 no n c om me rci al us e o nly article [veins and lymphatics 2014; 3:4503] [page 61] tern associated with a dysfunctional valve.13 over a prolonged period of time, the forces associated with this phenomenon can lead to the observed abnormal tissue response. turbulent flow is often visualized near the valve sinus. aneurysmal designation becomes important because increasing vein diameter makes stasis more likely, and potential thromboembolism more probable depending on the specific location of the aneurysm. also conventional treatment may have to be altered due to aneurysmal size or location as described in the section describing treatment. only aneurysmal dilatation in the respective fascial sheath alters treatment or outcome potential. aneurysms of the gsv have been classified as to location distal to the subterminal valve and in the distal thigh gsv.1 however, aneurysmal dilatation may also include the junctional branches and the sfj itself proximal to the subterminal valve. the aneurysmal dilation proximal or distal to the subterminal valve should be classified separately since treatment is different. the authors propose that aneurysmal dilations of the sfj (includes junctional branches) be classified as ia. aneurysmal dilatation distal to the subterminal valve should be classified as ib. for aneurysmal dilations of the distal gsv occurring in the region of the lower thigh perforators or upper calf paritibial perforator, a classification of ii correlates with pascarella’s1 classification. four patients in our series had aneurysmal dilatation of the distal gsv without proximal involvement. three patients presented with aneurysms in the region of hunter’s canal. one aneurysm was located in the proximity of a calf paratibial perforator. in both regions described, a valve is commonly present. when aneurysmal dilatations exist in both the proximal and distal gsv then they are classified as either iiia or iiib depending on location of aneurysmal dilation at the sfj. aneurysmal dilations have been reported in the ssv.1,14 pascarella labeled this as type iv.1 in our series, aneurysms were noted at the spj and the mid ssv. the authors propose iva to refer to the location at the spj and ivb to refer to a more distal location. aneurysmal dilation of the aagsv has rarely been described. in reviewing the literature, only one isolated case report of pulmonary emboli in a young male originating from the aagsv was found. in our series, 6 patients were identified with aneurysmal dilatation of the aagsv, accounting for 33% of the patients with aneurysmal findings. three of these patients presented with acute superficial thrombophlebitis and thrombosis of the origin of the aneurysmal aagsv. one of the 6 patients had an aneurysmal dilation of the aagsv at mid-thigh with a normal diameter proximal aagsv. the authors proposed that aneurysmal dilation of the proximal aagsv be labeled as va and distal location be labeled as vb. one patient had an aneurysmal dilation of the posterior medial thigh circumflex branch. the authors propose that aneurysmal dilation not fulfilling criteria i-v, be classified into a general group labeled vi. aneurysmal dilatations of the superficial figure 1. aneurysm is between the terminal and pre-terminal valve and includes the junctional branches type i. figure 2. thrombus in anterior accessory greater saphenous vein aneurysm. note small communication to sapheno-femoral junction. no n c om me rci al us e o nly article [page 62] [veins and lymphatics 2014; 3:4503] system (ia, iva, va) have been reported as foci of pulmonary emboli. the true incidence is unknown, but the occurrence is much lower than from the venous aneurysms of the deep system. most foci of embolization from the deep system originate from the popliteal vein.4 histologically, popliteal and femoral ane urysms are distinct from those occurring after valvular dysfunction in the superficial system, as would be expected since the etiology of these aneurysms is different. treatment superficial venous aneurysms are managed in accordance with specific location. aneurysmal dilatations that involve the sfj (ia) pose a significant threat as a source of embolization. patients presenting with spontaneous thrombosis at the sfj should be immediately anticoagulated.15 for those aneurysmal dilatations found on ultrasound that involve the true sfj, high ligation of the gsv should be considered. standard thermal ablative techniques may increase the risk of clot propagation. a large diameter vein with minimal outflow has a higher propensity for thrombus formation. aneurysms of the gsv distal to the subterminal valve (ib) may be treated with conventional thermal ablative techniques or foam sclerotherapy. since normal inflow persists, the risk of clot propagation is low. aneurysms of the distal gsv (ii) may be treated with surgical or endovascular ablative techniques. the method of treatment depends on the distance from the skin and size of the aneurysm. aneurysms that are very superficial and not resected will clot after treatment. a resultant thrombus can take months to regress and be cosmetically unacceptable and a source of prolonged discomfort. aneurysms involving the ssv are also treated according to the specific location. all aneurysms involving the spj (iva) should be resected. iva aneurysms are anatomically similar to saccular aneurysms of the popliteal vein. thermal ablation distal to these iva aneurysms may induce clotting of the spj with clot propagation or embolization. aneurysmal dilatations classified as ivb are treated in a manner similar to that described for distal gsv aneurysms. aneurysms of the aagsv are treated according to location and presenting symptoms. for those that present with spontaneous thrombosis, anticoagulation should be considered especially if the communication between the aagsv and gsv is large (>4 mm). for nonthrombosed aagsv aneurysms, 3 treatment options exist. surgical resection or ligation may be warranted in those situations where a large communication exists between the aagsv and the gsv or both are dilated. when the communication is small, either distal ablation of the aagsv trunk or foam sclerotherapy are options. two in this group were treated with foam sclerotherapy of the aagsv aneurysmal dilatation and distal phlebectomy. one patient was treated with thermal ablation of the aagsv. the aneurysmal dilatation thrombosed with no adverse sequalae. out of the 3 aforementioned patients the communication with the gsv was <4 mm. conclusions aneurysmal dilations of the aagsv, gsv, and ssv are similar histologically to varicosed segments of branched veins. the etiology is also similar to turbulent flow at a valve that is dysfunctional which may occur for a variety of reasons; volume overload secondary to pregnancy, hereditary factors and venous hypertension transmitted from the deep system. any location in the superficial system that contains a valve under less than optimal conditions may become aneurysmal. aneurysmal dilatations in the superficial system should be classified with regard to both normal vein diameter and size relationship to contiguous vein. classification of aneurysmal dilatation should include location corresponding to valves in the gsv. aneurysms of the sfj, spj and origin of the aagsv pose potential threat of thromboembolization. in addition, the aagsv aneurysmal dilatation should be added to the classification. aagsv aneurysms are more common than figure 3. a) hematoxylin and eosin (h&e) stain of aneurysm of greater saphenous vein (gsv). note thickened intima and muscle hypertrophy; b) h&e stain of branch varicosity. similar histological findings to aneurysmal dilatation of gsv, anterior accessory greater saphenous vein, and small saphenous vein. no n c om me rci al us e o nly article [veins and lymphatics 2014; 3:4503] [page 63] reported and may present as acute thrombosis of distal varices or as a source of pulmonary emboli. references 1. pascarella l, al-tuwaijri m, bergan jj, mekenas lm. lower extremity superficial venous aneurysms. ann vasc surg 2005;19:69-73. 2. seo sh, kim mb, kwon ks, et al. primary venous aneurysm of the superficial venous system. angiology 2008;59:593-8. 3. wali md, dewan m, eld ra. histopathological changes in the wall of varicose veins. int angiol 2003;22:188093. 4. sessa c, nicolini p, perrin m, et al. management of symptomatic and asymptomatic popliteal venous aneurysms: a retrospective analysis of 25 patients and review of the literature. j vasc surg 2000;32:902-12. 5. gabrielli r, rosati m, millarelli m, et al. pulmonary emboli due to venous aneurysm of extremeties. eur j vasc med 2011;40:327-32. 6 gillespie d, villavicencio j, gallagher c, et al. presentation and management of venous aneurysms. j vasc surg 1997; 26:845-52. 7. marcucci g, accrocca f, antignani p, siani a. an isolated aneurysm of the thigh anterolateral branch of the greater saphenous vein in a young patient presenting as an inguinal hernia. interact cardiovasc thorac surg 2010;10:654-5. 8. wallace j, baril d, chaer r. upper extremity venous aneurysms as the source of pulmonary emboli. ann vasc surg 2013;27: 240. 9. cavezzi a, labropoulos n, partsch, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs-uip consensus document. part ii. anatomy. vasa 2006;35:62-71. 10. gabrielli r, rosati ms, siani a, irace l. management of symptomatic venous aneurysm. sci world j 2012;6:386478. 11. stucker m, krey t, rochling a, et al. the histomorphologic changes at the saphenofemoral junction in varicosis of the greater saphenous vein. vasa 2009;29:41-6. 12. irwin c, synn a, kraiss l, et al. metalloproteinase expression in venous aneurysms. j vasc surg 2008;48:1278-84. 13. tibbs dj. varicose veins and related disorders. london: butterworth heinemann; 1992. pp 15-16. 14. chen s, clouse w, bowser a, rasmussen t. superficial venous aneurysm of the small saphenous vein. j vasc surg 2009;50:644-7. 15. kearon c, akl e, comerota a, et al. antithrombotic therapy for vet disease. antithrombotic therapy and prevention of thrombosis, 9th ed. american college of chest physicians evidence-based clinical practice guidelines. chest 2012;141: e419s-94s. no n c om me rci al us e o nly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: great saphenous vein ablation with steam injection: results of a multicentre study by milleret r, huot l, nicolini p, creton d, roux as, decullier e, chapuis fr, camelot g. eur j vasc endovasc surg 2013;45:391-6. stefano ricci abstract this open multicentre prospective cohort study carried out in four french centers report the obliteration rate of the great saphenous vein (gsv) in 75 patients treated using the steam vein sclerosis (svs) system with high energy levels. inclusion criteria were reflux at the sapheno-femoral junction (sfj) and/or from the sub-terminal valve of the gsv of more than 0.5 s, vein diameter of between 4 and 13 mm (measured 3 cm distal to the sfj) and a ceap from c2 to c5. after pre-operative duplex ultrasound scan tumescent anesthesia was administered around the previously marked vein, in between the fascias, using a 21 gauge needle to inject a solution of 1.4% bicarbonate 500 ml, plus 20 ml 1% lidocaine with adrenaline. this was also performed in patients undergoing general anesthesia or loco-regional spinal anesthesia to provide a heat sink and protect the saphenous nerve. access to the gsv under the knee was made through surgical incision or echo-guided percutaneous puncture placing a 16 g infusion catheter. then, a flexible stainless steel svs catheter covered with teflon and with a diameter of 1.2 mm was inserted through the infusion catheter to a level of 2 and 3 cm below the sfj. the svs generator was calibrated to emit one pulse of steam with 60 j of energy every 1.8 s. the steam temperature delivered at the tip was 120°c. two (for up to 7 mm) or three (for over 7 mm) or four (for large trunks over 12 mm) pulses were emitted for every cm of vein treated with the catheter stationary. post-operative treatment consisted of 2 weeks of compression by class ii stockings worn during the day and pain-killers (ibuprofen) at the patient’s discretion. patients were then followed up at 1, 6 and 12 months with clinical examination, duplex ultrasound scanning, quality of life and safety assessments. a total of 75 patients (88 limbs-13 bilateral) underwent surgery with a median treatment time of 35 min (range 12-85) including patient preparation time; the median length of vein treated was 42 cm (range 15-57 cm). at 6-month visit the obliteration rate was 96% [95% ci: 89-99] at 12 months was 92% [95% ci: 83-97]. vein diameter improved at 6 months from a median of 8 mm (range: 4-12 mm) to 1 mm (range: 0-9 mm) at mid-thigh. there were no adverse events either during or after the surgical procedure. the majority of adverse events occurred by day 8, the most common being ecchymosis at the entry site and pain in seven patients. at 1 month, inflammation of the venous pathway occurred in two patients and hypoesthesia in one patient. one protrusion of thrombus in the femoral vein (less than 1 cm) occurred fully resolved in 8 days under treatment by low molecular weight heparin. an ongoing study is focused on the treatment of tributaries. this could be a significant improvement as it allows an all-in-one endovenous procedure. comment by stefano ricci interesting preliminary results of another system other than laser, rf and chemical sclerotherapy to achieve saphenous stem closure. twelve-month obliteration at 92% is comparable to the other heat based systems and better than sclerotherapy reports, probably with fewer adverse effects. the flexible nature of the steel catheter that not needs a guide wire is particularly interesting. when a new system is suggested to the medical community, its success is ligated to its advantage in relation to the already acquired methods, in particular if the same methods surprisingly obtain good results. in the case of svs, as the obliteration results are similar to what achieved by other methods, only the possible lower cost would correspond to an advantage. it will be important to know something about. the possible good outcome on tributaries treatment for an all-in-one procedure, now in study, could represent another advantage over the alternatives in use, even if laser tributary treatment has been favorably indicated in a recent study by myers et al.1 reply by the authors thank you for your interest. your review and comments are quite good, i agree with them. as you suggested the main advantage of steam is the treatment of large tortuous varices, i plan to write a paper on this application for your journal during the quiet period in august. references 1. myers ka, clough a, tilli h. endovenous laser ablation for major varicose tributaries. phlebology 2013;28:180-3.[pubmed] [top] hrev_master veins and lymphatics 2015; volume 4:5095 [veins and lymphatics 2015; 4:5095] [page 1] the european professional phlebologist alessandro frullini associazione flebologica italiana, figline valdarno (fi), italy what is phlebology? who are the phlebologists? these could seem obvious questions but the answer may not be so simple. the peculiarity of phlebology is that this deals with a very common disease that crosses the expertise of many disciplines: vascular surgery, angiology, dermatology, general surgery, interventional radiology and many more. also in different geographical areas phlebology is generally practiced by very different professionals: in central europe or in the usa it has always been practiced mostly by dermatologists as in many other countries is mainly practiced by surgeons. a peculiarity of phlebology is that with relatively little equipment you can make a high level phlebology that is highly profitable for those who practice it. furthermore, most of the phlebological activities may be performed in an office setting, with a possible widespread diffusion. the gray aspect of phlebology is, at the opposite, that every physician making a sclerotherapy or a bandage may consider himself as an expert without a true and extended knowledge. this explains the stagecoach that we have seen to what until a few decades ago it was considered the cinderella of vascular diseases. in this situation it is needed to respond appropriately to the questions with which i began this editorial. in us it was established in 2007 the american board of venous and lymphatic medicine (abvlm; http://www.abvlm.org) that certifies the phlebologist after a training course and an examination and in some countries such as argentina phlebology is the subject of university education (in buenos aires, for example, there is a chair of phlebology; http://medi.usal.edu.ar/medi/flebologia-cursouniversitario-flebologia-eco-doppler-color). the australasian college of phlebology has three specific programs of training and certification, the basic phlebology training which lead to the title of certified sclerotherapist, a two years course diploma and the advanced phlebology training with which the status of fellowship is achieved (http://www.phlebology. com.au). the training program is both theoretical and clinical with a minimum of procedures that must be performed by the trainee. in 2010 the international union of phlebology (uip) has proposed its curriculum of phlebology1 but in europe there is not currently a precise answer to the request for qualification in phlebology. the european college of phlebology (ecop) has been recently established in order to write common phlebological guidelines and to standardize education and training. for this reason the ecop has supported the creation of a multidisciplinary commission at the european union for medical specialists (uems).2 in italy the italian college of phlebology (cif) is proposing the evaluation of the practitioner made by an anonymous commission, which should determine the skill of the phlebologist;3 the italian society of clinical and experimental phlebology (sifcs) is advocating a school of excellence and a certificate of phlebology (http://www.phlebologycourses.org). courses organized by scientific societies or universities or even private organizations (http://www.valet.it) are available but there is not a real shared path in the various european countries leading to the definition of a professional phlebologist. in order to overcome this situation the european registry of phlebologists has been recently established with the initial participation of italy, germany, portugal, hungary, poland, greece romania and czech republic. those countries have or are organizing corresponding national registries and the project is open to all european countries. in italy the registro italiano dei flebologi is jointly sponsored by italian phlebological association (afi) and italian society of phlebology (sif). the register is to certify the training of the physician and to verify the possible lack of training in the various aspects of the phlebological practice (http://www.registroitalianoflebologi.it). by the inclusion in the registry he or she will be able to acquire the title of professional phlebologist which will be guaranteed by the inclusion of this category in the esco catalog (european classification of skills/competences, qualifications and occupations). all these similar but inhomogeneous attempts to achieve the target of the phlebologist qualification although demonstrating the great difficulty in finding a common pathway among european countries, however testify a strong desire of giving to phlebology the independence it deserves. i think that a specific (and shared among european countries) training program on the model of the australasian college of phlebology will be the best way to form the european phlebologist and i really hope that in the boundaries of the ecop this will be achieved in the future, but for now the registry of phlebologist remains, at least in my opinion, the best way to define the european phlebologist. references 1. parsi k, zimmet s, allegra c, et al. international union of phlebology. phlebology training curriculum. a consensus document of the international union of phlebology (uip) 2010. int angiol 2010;29:533-59. 2. wittens cha, neumann ham, rabe e, davies ah. the future of phlebology in europe. phlebology 2013;28:121. 3. collegio italiano di flebologia. certificazione di qualita� del professionista in flebologia; 2014. available from: http://www.collegioitalianodiflebologia.it/h ccpcif/gest/private/index.php?p=informativa correspondence: alessandro frullini, associazione flebologica italiana (afi), piazza caduti di pian d’albero 20, 50063 figline valdarno (fi), italy. tel.: +39.055.9157158. e-mail: a.frullini@associazioneflebologicaitaliana.it received for publication: 12 february 2015. revision received: 16 february 2015. accepted for publication: 19 februaruy 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright a. frullini, 2015 licensee pagepress, italy veins and lymphatics 2015; 4:5095 doi:10.4081/vl.2015.5095 no n c om me rci al us e o nly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: ultrasonography study on the segmental aplasia of the great saphenous vein by oguzkurt l. phlebology 2013 [epub ahead of print]. stefano ricci abstract this is a prospective study to assess the frequency and anatomic distribution of the segmental absence or aplasia of the gsv using ultrasonography. 670 limbs of 335 consecutive patients who had signs and symptoms related to venous insufficiency of the leg were evaluated. venous clinical severity scores ranged from 0 to 20the gsv was examined for its diameter, its relation with the fascial compartments and venous reflux on both legs. diagnosis of segmental absence of the gsv was established when ultrasonography showed that the saphenous vein left the compartment and there was not any other saphenous vein in it. if a normal diameter or smaller than normal diameter vein remained in the compartment all along its course, this was not considered segmental aplasia and excluded from the study. segmental aplasia was classified into three subgroups. type 1: the gsv leaves the saphenous compartment in the leg and joins it at any point in the thigh. type 2: the gsv leaves the saphenous compartment in the leg and joins it in the leg just below the knee. type 3: the gsv leaves the saphenous compartment in the thigh and joins it more cranially in the thigh. the current study showed that the segmental aplasia of the gsv was seen in one-third of limbs on each side and was mostly unilateral; it was always present in its mid portion below or above the knee . it was found in 223 of 670 limbs (33%) in the whole patient population. it was type 1 in 59%, type 2 in 29%, and type 3 in 12% of the patients. it was was seen in 65 of 189 limbs (34.4%) with gsv insufficiency and 45 of 146 limbs (30.8%) with normal gsv on the right side, and 65 of 194 limbs (33.5%) with gsv insufficiency and 44 of 141 limbs (31.2%) with normal gsv on the left side. there was no relation between the presence of segmental aplasia of the gsv and the presence of gsv or ssv insufficiency in the same limb among patients with ceap scores 1 and above. aplasic segment of the gsv may prevent progression of any kind of endovenous device such as surgical stripper, laser fiber, or radiofrequency ablation probe. care must be taken not to cause thermal damage during endovenous thermal ablation of the insufficient connecting or bridging vein as this vein comes closer to the skin after leaving the saphenous compartment. this vein was named as accessory saphenous vein or tributary vein. an alternative term such as the saphenous connecting vein or bridging vein regarding its function or the saphenous bow regarding its shape might be more appropriate. the etiology of segmental aplasia or hypoplasia of the gsv is unknown. it was assumed to be due to a developmental prevalence of vessels with the most favorable hemodynamic condition over the greater vessels that underwent atrophy. comment by stefano ricci veins anatomy studied through ultrasonography made a great advancement in the knowledge of phlebologists. the suggestion of the saphenous eye by bailly in 19931 made easy the gsv identification, leading to better comprehension of the multiple aspects of varices pathology. several studies followed, summarized in 2006 by cavezzi et al.2 this paper repeats the observation of gsv aplasia, but do not add useful data to the current knowledge of the subject, except for that gsv aplasia is as frequent in normal subjects as in varicose patients, in contradiction to other authors’ analysis. this report could be interesting like all the divergent opinions, if it was performed following the guidelines suggested by previous authors, but this is not the case. for example, as correctly reported, saphenous fascia was difficult to understand around the knee region. for this reason ricci and cavezzi (cited as ref. 8) suggested to employ the tibial-gastrocnemious angle sign to state if an examined vein in that area could be assigned as gsv, but no mention of this sign can be found in this study, probably missing several cases. concerning the gsv aplasia in its most proximal part, replaced completely by the aasv, the authors did never encounter this condition, but, again, to distinguish the aasv from the gsv bailly, in 1993, suggested to employ the alignment sign, also ignored in the study (cited in ref. 2). in citing references, aplasia and hypoplasia cases are mixed up, suggesting ambiguous conclusions. concerning the name of the connecting vein, collateral vein was suggested in the same n. 8 citation, according to oxford dictionary collateral definition: side by side, parallel, subordinate but from same source, contributory, connected but aside from main subject. reply by the author (oguzkurt) dear editor, i agree with your comment on following the guidelines published to date. it would have been better if we could comment on the tibiogastrocnemius sign and alignment sign in our study. however, both signs are well known to us before and during this study.3 the tibiogastrocnemius sign is important when the gsv could not be identified by ultrasonography around the knee. the sign can also be useful to demonstrate whether the gsv is patent, hypoplasic or aplasic in the same region. however, the sign is not the only way to diagnose if there is hypoplasia or aplasia of the gsv around the knee. we examined the vein from above to below and from below the above all along its course in each patient. absence of the gsv in the saphenous compartment beyond the point where a vein leaves the compartment was diagnostic for segmental aplasia. one does not need to follow the tibiogastrocnemius sign. we believe there was no case missed or misdiagnosed in this respect. in their series considering the tibiogastrocnemius sign, ricci et al.4 found the total prevalence of hypoplasia or aplasia as 29% (types d and e). our study showed that segmental aplasia only had a prevalence of 33%. this higher rate could also support the fact that that we did not miss cases of segmental aplasia by not depending on the tibiogastrocnemius sign for definition of segmental aplasia of the gsv. in our study, we did not encounter segmental aplasia in the most proximal and most distal parts of the gsv. it was always present in its mid portion below or above the knee. we were again aware of the study of bailly, in 1993, suggesting to employ the alignment sign to distinguish the anterior accessory great saphenous vein (aasv) from the gsv. alignment sign simply explains that gsv is always more medial to the femoral vessels and any vessel similar to gsv but aligned with the femoral vessels should be called the aasv. sometimes, there is only one vein in the proximal thigh, which aligns with the femoral vessels. this condition was called the complete replacement of the gsv by the aasv. although there is mention of this subject in the proximal thigh, we could find only one report about it.5 the condition was seen in only one of 674 limbs studied (1 of 84 limbs with segmental hypoplasia). therefore, it is rare and it is not surprising that we did not see it. the alignment sign, we believe, is again important but should not be the only determinant to diagnose complete replacement of the gsv by the aasv. one needs to see that the gsv goes out of the saphenous compartment leaving no vein or a very narrow vein in the saphenous compartment proximal to this point. concerning the name of the vein, not only collateral vein, but also accessory saphenous vein, and tributary vein were used by the same authors in three different publications. the name tributary is probably a misnomer, because a tributary of the saphenous vein drains blood from some part of the subcutaneous tissues to the saphenous vein. there are two defined accessory veins of the gsv, which are the anterior and posterior accessory saphenous veins. this collateral vein is different from each of the defined accessories. the name collateral may fit to the oxford dictionary definition. however, the vein that forms a bow or bridge between the two sides of the gsv is a specific vein. it is very common but not known well. it would be better to give a specific name for it. saphenous bridge or saphenous bow is quite descriptive and defines a venous segment that leaves and re-enters the saphenous compartment in case of segmental hypoplasia or aplasia of the gsv. in the pioneering work on segmental hypoplasia and aplasia with ultrasonography and anatomical investigations,6 segmental hypoplasia was seen in 23% and aplasia in 17.6 of 121 limbs studied. the anatomical study with histological dissections, hypoplasia was seen in 18.8% and aplasia in 15.6% of 32 cadaveric limbs. hypoplasia in the cadaveric limbs was defined as narrowing of the vein. the caliber of the vein could not be measured because of artifacts derived from the postmortem changes. they stated that in 17.4% limbs, the segment of the gsv was so narrow to be visible only by the use of microscopical devices. therefore, one may misdiagnose some of the hypoplasia cases as aplasia with ultrasonography. in the other important study with ultrasonography,5 the authors mentioned on the segmental hypoplasia of the gsv but there was no mention on the segmental aplasia in the population studied. segmental hypoplasia was seen in 12% of patient with varicose disease and 25% of normal population (p>0.001). the authors reported that they used the term hypoplasia to emphasize the point that the vein is present but is very narrow. however, in the same article they reported that segmental hypoplasia was diagnosed when no ascending vein could be clearly identified within the saphenous compartment. segmental hypoplasia and aplasia are confusing on ultrasonography. we need studies with large patient population using high-resolution ultrasonography arrays that aim to define both segmental aplasia and hypoplasia of the gsv at the same study. we believe most of these cases are actually aplasia and not hypoplasia with ultrasonography. levent oguzkurt, md baskent university school of medicine department of radiology, ankara, turkey references 1. bailly m. cartographie chiva. in: encyclopedie medico-chirurgicale. paris: editions techniques; 1993. pp 43-161-b, 1-4. 2. cavezzi a, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs – uip consensus document. part ii. anatomy. eur j vasc endovasc surg 2006;31:288-99.[pubmed] 3. oguzkurt l. ultrasonographic study of the lower extremity superficial veins. diagn interv radiol 2012;18:423-30.[pubmed] 4. ricci s. echo-anatomy of long saphneous vein in the knee region: proposal of a classificaiton in five anatomical pattern. phlebology 2002;16:111-6.[abstract] 5. caggiati a, mendoza e. segmental hypoplasia of the great saphenous vein and varicose disease. eur j vasc endovasc surg 2004;28:257-61.[pubmed] 6. caggiati a, ricci s. the caliber of the human long saphenous vein and its congenital variations. ann anat 2000;182:195-201.[pubmed] [top] hrev_master veins and lymphatics 2013; volume 2:e19 [page 68] [veins and lymphatics 2013; 2:e19] assessment of lower limbs edema in healthy workers who are exposed to long-term gravity mirko tessari, erica menegatti, sergio gianesini, marco pala, michele zuolo, anna maria malagoni, roberto manfredini, paolo zamboni vascular diseases center, university of ferrara, italy abstract the aim of this study is to establish changes in leg volumes in healthy subjects (hs) after prolonged standing and prolonged lying. the study was carried out on two hs groups: the group a (20 subjects) included physicians and nurses who underwent a water plethysmography test, before and after eight hours of standing still in the operating room. the group b (20 subjects) included volunteers who were assessed before and after 10 h of supine resting. group a: baseline leg volume was 1857.5 ml±196.9 on the right and 1850 ml±194.7 on the left limb. after eight hours of hydrostatic pressure action the two lower limbs volume was significantly increased to 1945 ml±209.6, and to 1940 ml±216.2, respectively (p<0.0001). the increased volume is significantly correlated with time (r2=0.95, p<0.0001). group b: baseline leg volume was 1875 ml±175.1 on the right, and 1862.5 ml±166.9 on the left limb. after ten hours of resting supine the volume was 1770 ml±195.6, and to 1757.5 ml±194.2, respectively (p<0.0001). the decreased volume is significantly but inverted correlated with time (r2=−0.98, p<0.0001). this study demonstrates how the hydrostatic pressure is a main determinant for fluid accumulation in the lower extremity. to counteract the gravitational gradient becomes the mandatory prophylactic approach for healthy individuals who are exposed to an increased chronic venous disease risk. introduction echo-color doppler and phlebography, are a diagnostic methods adopted to assess where in the venous tree is present a problem of obstruction or reflux; on the other hand, there are different diagnostic methods used to quantify the venous function.1 still nowadays, the venous pressure measurement during and after walking represents the gold standard for a quantitative reliable and standardized test.2 nevertheless, this is an invasive technique that requires the intravascular pressure measurement while standing. this is a procedure can be uncomfortable, especially for the subject, and that requires a considerable technical effort. therefore, less invasive techniques were developed for patients’ assessment with lower limbs edema. the diagnostic test is based on a volumetric assessment that is able to detect both the leg and foot volumetric changes. the more common methodologies are air3 and/or water plethysmography (wp). the latter is an evolution of all the previous rare investigations about volumetric variation assessments for the venous system evaluation that were limited to a single segment of the calf.4-7 wp allows the total volume determination expressed in milliliters of both the leg and the foot. in literature it is now a validated method for the venous function and edema assessment.8 the wp is able to provide a non-invasively, easily, repeatable and economic measure of the distal portion of the lower limbs edema, reaching an objective measurement that is more precise and simple than the volumetric assessment of the limb circumference in centimeters. aim of the present study is to objectively assess the physiological lower limbs volume changes during an ordinary day of work in subjects exposed or not to the hydrostatic pressure, by the means of wp. materials and methods study population the study took place in a period of six months: the evaluated population was constituted by 40 healthy subjects (hs), who were previously screened for the absence of either chronic venous insufficiency (cvi) or lymphedema by validated clinical and ultrasonography criteria.9 particularly, duplex protocol to assess absence of reflux and/or obstruction in greater and small saphenous vein, as well as in the main deep veins, was used to exclude cvi.10-12 to exclude lymphedema we also used high resolution b-mode imaging of soft tissue to detect enlargement of lymphatic collectors, as well as faded images typical edema of the subcutaneous tissue.13-15 two groups were selected and each one was composed by twenty subjects of both. overall, 480 wp measurements were carried out. the first group (group a) was composed by surgeons and nurses (12 females and 8 males) who voluntarily underwent the test, before and after 8 standing still working hours in the operating room. the mean age was 32.7±7.7 years old. the second group (group b) was composed by volunteers (12 females and 8 males) who underwent the same wp assessment with an interval of at least ten hours between the first (at 7 a.m.) and the second evaluation (at 5 p.m.), while resting supine in the meantime. elastic stockings were forbidden in order to avoid inconsistencies in the measurements. the mean age was 24.1±3.9 years old. leg volume assessment the wp permits the foot, ankle and calf volume measurement. thirteen liters of water are poured into the wp with reference points at every 50 ml. the water temperature ranged between 28-30° c and was monitored by an electrical thermometer. the wp container is filled up to a level of 13 l. subsequently, the 3000 ml transparent container is placed under the draining spout in order to contain the water that will leak once the lower limb will be inserted into the instrument. the patient slowly inserts the foot into the water inside the wp until putting the foot sole on the base of the instrument. the subject has to maintain a sitting posture of 90° between the thigh and the leg so that that the latter is perpendicular to the base of the wp. once the leg has been inserted inside the instrument, the exceeding water discharge is expected at the blowhole spout where inside the 3000 ml transparent container was previously correspondence: mirko tessari, university of ferrara, via aldo moro 8, 44124 cona, ferrara, italy. tel. +39.0532.239498 fax: +39.0532.237443. e-mail: mirko.tessari@unife.it key words: edema, posture, circadian variability, gravity, water plethysmography. contributions: mt, sg, design, data acquisition, analysis and interpretation, manuscript drafting; em, mz, amm, data acquisition; mp, rm, analysis and interpretation; pz, design, analysis and interpretation, manuscript revision. conflict of interests: the authors declare no potential conflict of interests. received for publication: 20 may 2013. revision received: 1 july 2013. accepted for publication: 4 july 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright m. tessari et al., 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e19 doi:10.4081/vl.2013.e19 no nco mm er cia l u se on ly article [veins and lymphatics 2013; 2:e19] [page 69] placed. the collected water volume will give the measurement of the same inserted leg volume and will be expressed in milliliters. these values were reported in a database. the assessments were consecutively repeated for three times for the left limb and three times for the right limb for each subject for reproducibility assessment. during the examination the patient must keep the most absolute immobility in order to allow water level stabilization. the measurements duration is approximately 15 min for each subject. the procedure was equally performed on the two recruited populations. experiment in workers exposed to a prolonged gravitational gradient the first cohort of 20 hs was previously screened for comorbidities. then they underwent leg volume assessment at 7.00 a.m., immediately after their arrival at the hospital. subsequently, they have been working for 8 h in the operatory theatre, in a condition of prolonged standing posture. right after they underwent wp once again at 3.00 p.m. all the measurements were performed right outside the operating room with the same temperature (23°c). experiment in volunteers exposed to prolonged clinostatism in morning hours the second cohort of 20 hs was previously screened for comorbidities. then they underwent leg volume assessment at 7.00 a.m. immediately after their arrival at the hospital. subsequently, they spent 10 h lying in a tilting bed for 10 h, in a condition of prolonged supine posture. at 5 p.m. they underwent a second wp assessment. all the measurements were performed in the same room and temperature (23°c). statistical analysis the data were analyzed with the program instat® version 3.0 (graphpad software inc., �la jolla, ca, usa) for macintosh and are expressed as mean±standard deviation. for the statistical comparison of the 2 different measurements respectively on the 2 groups of subjects the paired t-student test was used. the linear regression analysis between time and leg volume was performed with the pearson test. values p<0.05 were been considered significant. results analysis of the experiment in workers exposed to a prolonged gravitational gradient the right lower limb baseline volume was 1857.5 ml±196.9 and resulted to be totally comparable with the left leg volume (1850 ml±194.7). the volume ranged from 1600 ml to the maximum volume of 2300 ml. in the measurement after eight hours of standing the two limbs volumes were respectively 1945 ml±209.6 for the right leg and 1940 ml±216.2 for the left leg. the minimum volume was 1650 ml and the maximum volume was 2400 ml. the difference between both the right and the left limbs in the morning and the same limb after the prolonged gravitational exposure was respectively of 87.5 ml and of 90 ml. this delta was found to be highly significant to the t-student test (p <0.0001). moreover, the variation of fluids increase in the venous-lymphatic compartment results to linearly and strongly correlate with the time spent under gravity forces for working purpose, with a high significance (r2=0.95, p<0.0001). figures 1 and 2 clearly show the legs volume increase overtime, together with the robust linear correlation respect to the time variable, respectively. analysis of the experiment in volunteers exposed to prolonged lying during morning hours in group b the baseline volume value was 1875 ml±175; 1 on the right and 1862.5 ml±166.9 on the left. the lowest value was 1500 ml while the highest was 2150 ml. after ten hours of lying supine, the right limb volume was 1770 ml±195.61 while the left one was 1757.5 ml±194.2. the lowest volume was 1300 ml while the highest was 2050 ml. even in this cohort the difference between the 2 measurements resulted to be extremely significant (p<0.0001). figure 1. lower limbs (ll) volume significant increase after 8 h of prolonged standing in an operating room without wearing any elastic stocking. figure 2. strong linear correlation among lower limb (ll) volume respect to the time variable in standing conditions. no nco mm er cia l u se on ly article [page 70] [veins and lymphatics 2013; 2:e19] analyzed by a linear regression (pearson index), the leg volume was inversely related to the time that was spent in a supine position (r2=−0.98, p<0.0001). in figure 3 the lower limbs volume reduction overtime is well apparent for the supine position. finally, figure 4 provides this volume reduction inverted and extremely significant correlation overtime. discussion the main outcome of this study is to point out how in human physiology the gravity is responsible for significant increases in lower limbs volume. it is very interesting to note how this increase appears related to the absolute time variable, resulting in a nearly perfect linear correlation when considering the volumetric gains measured before and after exposure to the hydrostatic gradient. the demonstration of leg volume increase by standing was never assessed by plethysmography in healthy subjects but only in cvi patients. to the contrary, in the absence of any hydrostatic overload, the lower limbs tend to shrink significantly in volume. this is likely to be the consequence of the fluid volume redistribution over the other body compartments, in accordance with the communicating vessels law.9 as further confirmation of the pivotal role of the gravity force, there is an inverse correlation between the limb volume reduction and the time spent in absence of the variable hydrostatic pressure exposure. what are the practical implications of our experiment? the first comment is that even a subject with a fully functional phlebo-lymphatic apparatus, to maintain the, fixed orthostatic position, whether sitting or standing, tends to accumulate overtime fluids and macromolecules in the phlebo-lymphatic sector and in the interstitium as well. the pivotal importance of the hydrostatic pressure was confirmed by the volume reduction, which was measured in the supine position. our experimental observation represents an objective assessment of the old postural therapy for the prevention and treatment of the lower limbs edema. our interpretation of the phenomenon is that the absence of hydrostatic pressure tends to equally redistribute the fluid in the other compartments of the body. furthermore, it has been recently hypothesized that the vascular tone can be regulated by new molecules.16,17 however, the experiment in supine seems to exclude the presence of regulatory molecules for the very strong inverted correlation found, suggesting the pivotal role of gravity respect to regulatory molecules. the variation of leg volume along time in workers exposed to long term gravitational gradients is confirmed in medical literature.1821 gravitational exposure for working reasons might facilitate an overload on the vascular walls along days, months and years.22-24 the observed phenomenon, as well as the strong relationship with the time of exposure to a well-known risk factor for cvi, opens new questions for prevention. for instance, in longtime exposed to gravity workers are wearing prophylactic elastic stockings going to significantly change their risk of developing cvi? further studies are warranted. conclusions hydrostatic pressure demonstrated to be a main determinant in lower limbs volumes variations also in healthy subjects. the observed phenomenon is directly related to the time of exposure to the gravitational pressure. thus, a prophylactic counterbalance of a prolonged working time in a standing still position by means of elastic compression results to be mandatory also in healthy lower limbs. references 1. nicolaides an, cardiovascular disease educational and research trust, european society of vascular surgery, et al. investigation of chronic venous insuffifigure 3. lower limbs (ll) volume reduction overtime after a prolonged supine resting. figure 4. lower limbs (ll) volume reduction presenting an inverted and extremely significant correlation with time. no nco mm er cia l u se on ly article [veins and lymphatics 2013; 2:e19] [page 71] ciency: a consensus statement (france, march 5-9, 1997). circulation 2000;102: e126-63. 2. nachbur b. periphere venendruck messungen. zentralbl phlebol 1971;10:224. 3. christopoulos dg, nicolaides an, szendro g, et al. air-plethysmography and the effect of elastic compression on venous hemodynamics of the leg. j vasc surg 1987; 5:148-59. 4. kappert a. zur plethysmographischen erfolgsbeurteilung vn venenoperationen. bern: hans huber verlag; 1971. 5. leu hj. die dehnungsmessstreifenpletysmographie. bern: hans huber verlag; 1971. 6. pauschinger p. die venenkapazität und ihre messung. symp deutsch ges angiol f. stuttgart: heinrich ed. schattauer; 1972. 7. aschberg s. crural venous obstruction or incompetence. acta chir scand suppl 1973;436:1-78. 8. thulesius o, norgren l, gjöres je. footvolumetry, a new method for objective assessment of edema and venous function. vasa 1973;2:4. 9. porter jm, moneta gl. reporting standards in venous disease: an update. international consensus committee on chronic venous disease. j vasc surg 1995;21:635-45. 10. franceschi c, zamboni p. principles of venous haemodynamics. new york: nova publisher; 2009. 11. coleridge-smith p, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs--uip consensus document. part i. basic principles. eur j vasc endovasc surg 2006;31:83-92. 12. cavezzi a, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs--uip consensus document. part ii. anatomy. eur j vasc endovasc surg 2006;31:288-99. 13. szuba a, rockson sg. lymphedema: classification, diagnosis and therapy. vasc med 1998;3:145-56. 14. weissleder h. diagnosis of lymphostatic edema of the extremities. fortschr med 1997;115:32-6. 15. international society of lymphology. the diagnosis and treatment of peripheral lymphedema. 2009 consensus document of the international society of lymphology. lymphology 2009;42:51-60. 16. billaud m, sandilos jk, isakson be. pannexin 1 in the regulation of vascular tone. trends cardiovasc med 2012;22:6872. 17. melikian n, seddon md, casadei b, et al. neuronal nitric oxide synthase and human vascular regulation. trends cardiovasc med 2009;19:256-62. 18. mosti g, partsch h. occupational leg oedema is more reduced by antigraduated than by graduated stockings. eur j vasc endovasc surg 2013;45:523-7. 19. blättler w, kreis n, lun b, et al. leg symptoms of healthy people and their treatment with compression hosiery. phlebology 2008;23:214-21. 20. belczak ce, de godoy jm, ramos rn, et al. is the wearing of elastic stockings for half a day as effective as wearing them for the entire day? br j dermatol 2010;162:42-5. 21. belczak ce, de godoy jm, ramos rn, et al. rate of occupational leg swelling is greater in the morning than in the afternoon. phlebology 2009;24:21-5. 22. maurins u, hoffmann bh, lösch c, et al. distribution and prevalence of reflux in the superficial and deep venous system in the general population – results from the bonn vein study. germany. j vasc surg 2008;48:680-7. no nco mm er cia l u se on ly stefano ricci comment to: plantar vein thrombosis and pulmonary embolism by barros mvl, nascimento is, barros tls, labropoulos n. phlebology [epub 15 january 2014] stefano ricci abstract a 45-year-old female patient with varicose vein disease, assuming hormone therapy for dysmenorrhea treatment and awaiting a hysterectomy, underwent a duplex scanning study. she complained of pain on palpation of the medial plantar region of the left foot associated with fatigue and shortness of breath for approximately five days. she was otherwise healthy and did not have major medical problems or evidence of edema or signs of inflammation. the duplex scan showed no signs of deep venous thrombosis in the femoro-popliteal and calf veins but an acute occlusive thrombus was found in the lateral plantar veins. lung scintigraphy findings revealed pulmonary thromboembolism. the patient was hospitalized for anticoagulant treatment and was discharged after seven days in good clinical condition. after six months duplex scanning showing partial recanalization of the plantar vein thrombosis with associated insufficiency. plantar veins as part of the distal deep venous system have the potential to propagate a thrombus into the infrapopliteal veins. in authors' series of 11 studied patients nine had pain at the foot region, followed by edema in eight. plantar veins were exclusively affected in nine patients, with calf compromise in two, and one with great saphenous vein thrombosis. thrombosis extension occurred in three patients, all of them with calf pain. a high index of suspicion must be maintained for patients presenting with spontaneous unilateral foot pain. the diagnosis is usually simple and easy to make on duplex sonography, but including the plantar veins in the investigative protocol is generally not a routine procedure. patients with symptomatic dvt or chest symptoms should be anticoagulated for three months and evaluated at the end of treatment. comment by stefano ricci this case report confirms the possibility that even distal thrombosis may cause pe. the rarity of the plantar thrombosis and the relatively scarce pulmonary symptomatology could suggest the condition being much more frequent and usually evolving undiscovered. the authors suggest considering these cases as fully dvt cases, by anticoagulation treatment; however, no mention is made about compression treatment of the affected limb, either for pain relief or for edema prevention/reduction. as proximal disruption of the thrombus by repeated compression of the foot determined by the musculovenous foot pump action is hypothesized. do the authors recommend that foot veins thrombosis patients should refrain from walking, in opposition to the current indication in dvt management? [top] hocaoglu c. clozapine-induced rabbit syndrome: a case report the editor’s corner paolo zamboni cerebral venous return is a novel, exciting field of research. as a pioneer, i would say that when i began investigating the intra and extra cranial cerebral veins, very few data were available something about 10-12 years ago. cerebral venous return is very complex from embryological, anatomical and physiological point of view. posture, respiration, atmospheric, hydrostatic, and intracranial pressure are important motor mechanisms. in addition, the venous system is closely related to cerebrospinal fluid dynamics, as well as to the arterial and lymphatic system of the head. in the past 10 years, we began to give some initial explanations of physiology and pathophysiology of venous brain circulation. as usual in science, this contributed to open even more questions. impaired cerebral venous return and the description of chronic cerebrospinal venous insufficiency (ccsvi) could open new perspectives in the understanding of neurodegenerative process, where a powerful regulator of chronic inflammation as the drainage is, was always absent among the pathogenetic mechanisms of this group of diseases. veins and lymphatics look forward to your contribution in this promising field of research either in the form of submission of original articles or by active participation to this section of the journal. you will find the sub-sections hemodynamic corner chaired by clive beggs, as well as the neuro corner organized by ilaria bartolomei. we will also provide you a literature update cured by erica menegatti. dr. paolo zamboni [top] hocaoglu c. clozapine-induced rabbit syndrome: a case report translated from: traitement des varices par la phlébectomie ambulatoire par muller r. méd hyg 1970;28:1424-7. stefano ricci varicose veins treatment by ambulatory phlebectomy some readers could be surprised to find a phlebology technical article in a special issue devoted to dermatology. because of the necessity of looking to the origin of several venous stasis cutaneous complications, every dermatologist is obliged to be involved in varices. many are those practicing intravenous injections called sclerosants and perform subsequently skin incisions for thrombectomies. in any case, either cutaneous local or general allergic reactions, or erosions, or macerations, or other types of cutaneous irritations will highly benefit from dermatologic experience of the practitioner. history still from the beginning of medicine there has been a search for varices elimination, either for esthetical or for clinical reasons. hippocrates’s writings of about 400 years bc report: when in the front of the leg or inside the tissues a varice is present and the front of the leg is black and it seems necessary to pull out some blood, you will not do scarifications, as the most often big ulcers will appear due to the blood flow toward the varices, but you must transfix from time to time the same varice according to the opportunity. then on the raised limb, you will put on the bandage avoiding to leave coagula inside the incisions, after placing a double folded compress and immersed in wine and over it cleen wool soaked in some oil. plutarcus, one century bc, tells that marius, the roman general and consul, submitted to varices operation for cosmetic reasons. each incision being cauterized by red-hot iron, marius refrained from the second limb operation, affirming that the treatment was worst that the disease. aurelius cornelius celsus, a contemporary of christ (he died 7 ad when he was 60 years old), described a very interesting technique: all along the varice, at four transverse fingers regular intervals, small longitudinal incisions are made, the wound is opened (divaricata), red iron cauterization is done, the varice is hooked and extracted the most possible by stripping. no venous ligation is done and no cutaneous suture. a compressive dressing is enough. empirically the good practitioner could obtain an asepsis and antisepsis (cauterization and clean dressing), although partial and ligated to mastery skill. even if patient assumed an alcoholic solution of jusquiame and opium, out of few qualified masters obtaining admirable results, this procedure remained abominable. nowadays, at the opposite, provided the exclusion of the junction and the proximal third of the gsv, in an aseptic way, in local anesthesia, absolutely without red iron cauterization, this technique of ambulatory phlebectomy is easy, radical and extremely cosmetic requiring only a limited skill. all along 2000 years ancestors like claudius galenus (ii century), aetius (vi century), paulus aeginata (vii century) and guy de chauliac (xiv century), all great surgeons involved in varices treatments, could not add any fundamental advancement in treating reticular varices. against the saphenous reflux varices, the progressing knowledge of veins anatomy and physiology induced the elimination of the crural saphenous stem (paolus aeginata around 650) and finally, at the end of xix century, of the gsv junction. celsius’ technique was forgotten or, in any case, none practiced; moreover, in the middle of the past century the so-called sclerosing injections were invented. what i thought would be my method in contrast to the habit, an immodest use of the singular first person will be done. conceiving ambulatory phlebectomy has been a personal and autodidactic adventure lasting about 15 years. all the phlebological knowledge that i acquired from my dermatologic formation in berne hospital was a dogma: never touch to the varices secondary to post thrombotic disease, never touch to all the varices in men after the sixties and in women after the forty fives. i had never performed sclerotherapy; i knew, but had never had experience of it, that the best treatment for superficial thrombophlebitis is local anesthesia, incision, thrombectomy and compression bandaging, the patient being required to walk as much as he can. doing this treatment for the first time to a young delivering lady, at the anterior aspect of the thigh for a superficial thrombophlebitis about 5 cm long, i was astonished for the ease of the operation and the quality of the outcome. before this famous thrombectomy i was involving in those injections called sclerosing, and following dr.blanchod’s and prof. sigg’s experience, i begun to perform some thrombectomies some days after the injection. in fact the endogenous inflammation cause by the agent is nothing else than a thrombophlebitis; we could even say thrombosing injection instead than sclerosing. i employed the blanchod’s method during several years adding to it the compression according to sigg, but i applied a modification that i thought important: local anesthesia. this allowed me to go through varices more and more difficult: very big, very small, and very tortuous, at the knee or the foot. i was however unsatisfied: i observed a recanalization of the varicose tract either after the spontaneous thrombophlebitis or the sclerosis injection. the new varice was at times worst that the previous and the same tract could redo a thrombophlebitis. furthermore, very often a dyschromic pigmentation persisted and, also, a fibrous, sensible cord with irregular recanalisation. i tried to find a solution to this problem; it was simple and la palisse like: take profit of the small thrombectomy incisions to pull out the same varice so performing a phlebectomy. the vein extraction became rapidly the most important and most efficient act. during few years i went on in doing injections previously, but i felt that it was useless as it caused a more difficult extraction without giving any haemostatic advantage; so i eliminated this injection. empirically i defined the details: instruments, incisions numbers, intervals, dimension, longitudinal direction, selective compression, bandaging, etc. what a deception was to discover two years later that i had restored the aurelius cornelius celsus technique described two thousand years ago. ambulatory phlebectomy: description of the present technique general scheme i. preparation a) marking b) disinfection c) anesthesia ii. operation a) incisions b) varice preparation c) extraction iii. bandaging a) cleaning b) incisions closure c) compression iv. convalescence a) first day b) light dressing c) elastic bandage acknowledgement: the employed material is reported with its commercial name unbeknonst of society and representative. it may be replaced by any similar material. the author had never any financial relation with manufacturers. he uses the best items he personally knows. i. preparation a) marking: the patient stands up weight bearing on the treating limb for a good varices filling up. marking is of capital importance and should be precise. cotton rolled tapered buffer, soaked of potassium permanganate 5%. the varice is palpated, perforators are identified; the varice caliber is indicated by the marking width. the good marking will ease the operation. b) disinfection: the patient is lies down. orange merfen. the air is disinfected by ozone during the whole day. since this machine is in use, infection is practically absent (despite the absence of towels and even of sterile gloves). once we had one (benign) infection over 200 incisions, now less than one over 5000. c) anesthesia: it is the painful phase but acceptable. xylocaine 0.5% (16 times less toxic than 2%) with epinephrine, 50 to 90 ml between the skin and the varice all along the segment to treat. wait at least 10 minutes. ii. operation four instruments are sufficient: i) pointed knife, ii) curved toothed small forceps, iii) curved toothed mosquito, and iv) kocher forceps. the small forceps, when closed, is used like a hook for the varice preparation and pulling; when opened it helps to grasp and extract the vein: it works like a fingers prolongation. the mosquito forceps has a similar function but is stronger and less precise: it works like a hand prolongation. finally the kocher forceps allows pulling out the vein avoiding its rupture, doing the heavy job. before starting the patient is positioned in trendelemburgh position to prevent cerebral ischemic syncope (very frequent in case of arterial emotion hypotension) and to avoid any bleeding from emptied varices. it is possible to pull out 140 cm of vein with no more than a spoonful of blood. small caliber shunts (arteriovenous communications) are frequent and bleed shortly. large caliber shunts are exceptional and cause a bit longer bleeding, although not pulsating. it is necessary to compress a while before proceeding waiting for the shunt to spontaneously close. a) incisions: from 10 to 40, longitudinal (occlusion will be eased) as small as possible (0.5-1 mm, rarely bigger) to avoid scars. experience only allows stating the incisions interval. in a young subject, fine skin, thin, with early varices never treated before (an easy case), intervals will be from 5 to 15 cm. at the opposite in an aged subject, thick skin, obese, with old varices especially after a thrombophlebitis or so called sclerosing injections (a difficult case), spaces between incisions will not be longer than 2 to 4 cm as the varice will break down easily and will be encircled by an irregular fibrotic layer, at times (very rare) even calcified. b) varice preparation: in the easy cases it is minimal: you pull the varice, it comes out easily and freely. in difficult cases the varice must be separated from its fibrotic layer rotating by the fingers the small forceps or opening and closing the mosquito. c) extraction: the most satisfying and gratifying part is this one. varicose fragments length varies from 50 cm (easy cases) to 0.5 (very difficult one). when an incompetent perforator is found, bassi’s procedure is employed: the perforator is grasped by the mosquito at the aponeurosis level and the forceps is slowly turned. the varice brakes by torsion with minimal bleeding. iii. bandage a) cleaning: blood and disinfectant are wrapped out with a cotton tampon imbibe by ether passing directly over the incisions that are going to be covered. b) incisions occlusion: every incision is powdered by nèhacetine powder and covered by tricosteril (6 cm in length). no vascular ligation; no skin suture. in subject allergic to the adhesive, over the powder a small piece of copoline is placed (non tissue cellulose compress), fixed by a band-aid or blenderm. this is not done systematically being a bit longer procedure. c) compression: it will be more effective if selectively performed. a thick cellulose cord is build up and applied all along the avulsed varicose tract; it is fixed by band-aid 2.5-3.8 wide. but pay attention! don’t put it with excessive tension, to avoid skin blistering. these blisters and erosions are very painful; they may be treated by terra-cortril gel + a copoline compress + band-aid. at thigh a plastic glue (nobecutane spray) is vaporized to avoid bandage slipping. this glue is well tolerated having observed only 3-4 cases of allergic reaction. a first compression, done by a copoline bandage (12 cm/10 m) adheres to nobecutane and helps for a good pressure distribution, but overall, it protects the skin against the adhesive bandage glue, so avoiding toxic irritations, maceration and contact eczema. popliteal crease must be protected by a cotton pad. compression is repeated by a colored adhesive 8 cm por elast bandage. the adhesive layer is non continuous and thin to allow skin transpiration, particularly appreciated in summer time. the patient must not touch it; he will be able to walk and work without bandage slipping. we will get out the bandage two to eight days apart. finally, we add a strong durelastic colored 10 cm/7.5 m (at thigh) or 8 cm/7.5 m (at leg). this bandage is pulled as much as the patient sustain it; it is taken out at evening and repositioned each morning, crossing in the front and turning in the back of the leg. we recommend the patient to wear it before getting up during the first night only. if he goes to toilet without it and performs a strong valsalva during defecation, a sudden endovenous hypertension will be created and a possible hemorrhage will happen. when doing a phlebectomy at the thigh, the bandage should be started at the thigh root and continued downwards, similarly than for thrombophlebitis, so avoiding to push any thrombus toward the heart. iv. convalescence it starts at the end of the bandaging. the patient gets up and walks without stepping. he gets home and rests in bed the first day (in case of large perforator, big artero-venous shunt, ssv junction, cockett perforator), or simply avoids efforts (in every other cases). the following day on he will restart his normal life and usual job, trying to walk the most he can. some courageous patients even practice sports like ski, horse riding, long walking distances. the only taboo is the treated leg washing. the small incisions heel rapidly; two to eight days after the big bandage is cut out. some nebacetine powder is applied over the still delicate incisions that are covered by band-aid pieces (1.25 cm wide). hematomas will spontaneously disappear, their resolution being enhanced by assuming a protein lythic enzyme. every evening the patient takes off the elastic bandage and every morning he puts it on. convalescence ends at the 21st day by bandage elimination and first washing (bath or shower). results if it was possible to correctly avulse the varice (the most of the cases), there will be no recurrence; at times a nodular recurrence may happen in treating shunt or perforators. from the cosmetic point of view, this method offers the better results achievable nowadays. it is noteworthy that the procedure is a completion of the gsv crossectomy and external stripping (according to mayo); it is not in opposition to surgery. in neuchatel, the surgeon and the phlebologist work in collaboration for the good of the patient. at the opposite, this method excludes the sclerosing injections. the operation is benign and efficient, eliminating the toxic and allergic accidents of sclerosing agents. it avoids residual pigmentations, so unpleasant. very rarely you may observe a small hemorrhage or, exceptionally, a limited infection. treatment is economical: in a series of 3-6 sessions we can eliminate as many varices as in 50-60 sessions (programmed in three years). finally, the aurelius cornelius celsus method is easy, an initiation only being sufficient for achieving good results. through training it is possible to perfectly eliminate big fingers size or string like small varices, from abdomen till below the foot. we can efficiently avulse all varices except the gsv junction and its proximal part, and in particular, the varices secondary to ptd when deep veins are not reanalyzed. i made a detailed movie about this technique and remain at disposition to colleagues for comments. i am pleased to thank prof. delacretaz, director of lousanne dermatologic university clinic for his encouraging, interest and acceptance. [top] stefano ricci part i: history of local anesthesia1 stefano ricci the first clinical application of local anesthesia was officially announced the 15 of september of 1884, 130 years ago. it concerned corneal anesthesia for glaucoma operation. the importance of this event is demonstrated by the fact that between september 1884 and late 1885, 60 publications concerning local anesthesia using cocaine appeared in the united states and canada.2 local anesthesia is, today, one of the most important tools in phlebological practice, not only for the everyday veins operations, actually done mostly as day surgery or office surgery, but also for biopsy, ulcer debridement, scar revision. curiously, as a constant pattern, most the chief characters of this story developed their experience through self-administration of the agents, accepting the risks for satisfying their desire of progress. and the consequences have been quite dramatic in some cases. on october 16, 1846, w.t. morton performed the first total anesthesia, using the letheon (diethylic ether), on a patient having a lateral neck vascular lesion, operated on by j.c. warren.3 in spite of the huge importance of this discovery, which would radically influence the progress of surgery, and its immediate diffusion in the world scientific community (in december 1846 it was already applied in england) the process of inducing unconsciousness was not as simple as it appeared, the first official anesthetic death being reported in england in 1847.4 a system of locally providing agents for pain analgesia in a limited area was still requested. till then acupuncture, hypnotism, refrigeration and nerve compression are known to have been used to alleviate surgical pain, but with limited success. in 1853 a. wood5 invented the hollow metal needle in order to inject morphine directly in the painful area. although it was later realized that the main action of morphine is systemic rather than local, this event opened the possibility of the local administration of those alkaloids that will be discovered three decades later.3 cocaine, an extract of coca leaves, is the first known local anesthetic. for incas people it was a gift of the gods, used as a reward to noblemen. for the mountain people of those great heights chewing of coca leaves provided energy and fatigue insensibility (and mucosal numbness).6 folk physicians in ancient peru chewed coca leaves and employed the saliva for minimizing pain of the injuries they were treating. this was a unique situation in anesthesia: operator and his patient shared the effects of the same drug.6 in 1860 a. niemann,7 an austrian chemist, receiving coca leaves from a friend returning from a tour around the world, isolated the alkaloid that he named cocaine.8 the crystals of this substance had a numbing effect on the tongue. this is the way that still now is in use for testing the purity of the street cocaine.6 the stimulating effect of the drug was the reason for it’s immediate success. the corsican chemist angelo mariano invented the vin mariano by steeping coca leaves in wine, obtaining a huge popularity. coca cola was created in 1886 by the same principle and kept cocaine in its formula till its replacement with caffeine in 1906.6 although the anesthetic properties of cocaine were already signaled by t. moreno,6 a military physician, and in 1879 by von arep,6 who noticed on its own the skin insensibility after the injection of a dilute solution of the drug, the first clinical application of the effect of cocaine is due to carl koller, a surgical intern at vienna university, in 1884.7 koller was interested in ophthalmology and was trying to solve several problems of his field of interest that general anesthesia, although already widespread, could not eliminate. the patients, when anesthetized, could not cooperate, like advisable, with the surgeon. the anesthesiologist’s apparatus interfered with the surgical access area. fine sutures being non available at that time, many surgical incisions on the eye where not closed; in this situation the high incidence of vomiting after anesthesia created the risk of extrusion of the globe internal content with possible irrevocable blindness. the attempts made previously with morphine, chloral hydrate and other drugs appeared useless.3 koller was a colleague of sigmund freud (they worked at the same hospital floor) who was extremely interested about the general effects of cocaine. this seemed an harmless drug, although very interesting as stimulant, therapeutic agent (consumption, asthma, psychosis), drug addition treatments (alcohol, morphine), aphrodisiac, and local use.9 the anecdote tells that freud gave a small amount of cocaine in an envelope to koller, which he placed in his pocket. a leakage of some drug contaminated koller’s fingers. when he casually touched his tongue, he felt the numbing effect.6, 11 for the young doctor the association of this effect with his researches on the eye anesthesia was immediate. after making a solution in water of cocaine crystals, together with his assistant dr. gartner, koller experimented the anesthetic effect on the eyes of a frog, a rabbit, a dog, and finally on it's own. within a minute the eyes became insensible to touch and any kind of trauma.8, 12 the discovery was immediately revealed at the congress of german ophthalmologists in heidelberg,13 but not by poor koller, who could not afford to attend the congress, but by a friend from trieste, j. breattauer, with his agreement.14 it was the 15th of september 1884. references ricci s. history of phlebology (history of local anaesthesia). acta phlebol 2002;3:49-52. matas r. local and regional anesthesia: a retrospect and prospect: i. am j surg 1934;25:189-96. calverley rk. anesthesia as a specialty: past, present, and future. in: barash pg, cullen bf, stoelting rk, eds. clinic anesthesia. 3th ed. philadelphia, pa: lippincott-raven; 1996. pp 3-28. meggison tn. death from chloroform (letter). london medical gazette 1848;6:255-6. wood a. new method of treating neuralgia by the direct application of opiates to the painful points. edinburg j med surg 1855;82:265-81. de jong rh. local anesthetics: from cocaine to xylocaine. in: local anesthetics. st. louis: mosby-year book; 1994. pp 4-5. koller c. on the use of cocaine for producing anaesthesia on the eye. lancet 1884;2:990-2. niemann a. ueber eine neue organische base in den cocablättern. arch pharm 1860;153:129-55, 291-308. calatayud j, gonzález a. history of the development and evolution of local anesthesia since the coca leaf. anesthesiology 2003;98:1503-8.[pubmed] koller k. ueber die verwendung des cocaïn zur anästhesirung am auge. wien med wochenschr 1884;34:1276-8, 1309-11. freud s. über coca. centralblatt für die gesamte therapie. 1884;2:289-314. koller c. historical notes on the beginning of local anesthesia. j am med assoc 1928;90:1742-3. noyes hd. the ophthalmological congress in heidelberg. med rec 1884;26:417-8. fink br. leaves and needles: the introduction of surgical local anesthesia. anesthesiology 1985;63:77-83.[pubmed] [top] hrev_master veins and lymphatics 2017; volume 6:6634 [veins and lymphatics 2017; 6:6634] [page 25] medical interest of 3d reconstructed limb to build a customized multicomponent bandage for the treatment of a lower limb lymphedema with partially amputated calf: a case report frédéric pastouret compression therapy research unit, papignies, belgium introduction multicomponent bandage (mcb) is an essential method in the treatment of lower leg lymphedemas.1,2 however, 2 layers bandages applying methods proposed by manufacturers do not result in selected pressures nor in a digressive pressure gradient and the proposed methods are not adapted for each type of case. for some particular lymphedema’s patients, the therapist has to find a bandage applying method to obtain specific therapeutic criteria as the final stiffness of the assembled bandage, the expected pressure and a specific pressure gradient. objective the aim of this study is to build a customized multicomponent bandage with selected pressures and a digressive pressure gradient for a patient with lymphedema and partially amputated calf (figure 1). the patient underwent a lymphatic system infection of her right lower limb with partial inguinal node dissection, aggravated by a sepsis and a calf subcutaneous tissue infection. she cannot stand high-pressure levels on her limb, usually used during multicomponent bandage treatment for lymphoedema patient. materials and methods this experiment was conducted in 2 phases; first, on the 3d reconstructed lower limb and second on the patient herself. from the simulated limb, a very light foam prosthesis of the partial amputated right calf was customized in order to fill in the loss of the calf tissue under the future bandage. a 2 mm thickness custom silicone pad (medi® silicone for custom made liners, density a-5) was designed to be the protective skin interface layer of the prosthesis (figure 2).3,4 pressure sensors were applied at 10 different selected points (figure 2). multicomponent bandage consists on a first layer of tubular cotton jersey put directly on the skin, a second single layer of mobiderm® (minimal overlap, no tension) and a last single layer of biplast®. biplast® overlap method was adapted with a constant band tension to obtain 20-25 mmhg at dorsal face of the foot (100% of pressure) and a digressive pressure gradient on the rest of the limb (2/3 overlap at the foot, calf and knee distal part; ½ overlap at the tight) (figure 3). the foam prosthesis was placed on the silicone pad which was directly applied on the simulated limb under the multicomponent bandage. bandage applying method was finally tested on the patient (figure 3). pressures were assessed in the same 10 locations on the patient’s own right limb in standing position and during walking. dynamic variation pressure indexes (dvpi) were calculated at each selected points (difference between maximal pressures and minimal pressures during walking), which represent the local massage effect or pump effect under bandage. results on the 3d reconstructed member and on the patient, selected pressures at dorsal face of the foot was respectively 20 mmhg and 23 mmhg. global internal and external digressive pressure gradients (int pg, ext pg) were also obtained with the selected applying method (figure 4). on the patient, dvpi (mmhg) demonstrated high massage/pump effects at the dorsal foot face (16), above the malleoli (86) and under the prosthesis (16), due to the final resistance of the assembled bandage. the customized multicomponent bandage was well tolerated by the patient during experiment. discussion patient was previously treated by another therapist with multicomponent bandage including high pressures. it was a failure because she did not support high pressures (or common pressures used for a lymphoedema patient) especially at the thigh level due to the skin graft. for this reason, the higher tolerated pressure was evaluated on her foot during the first appointment. this low pressure was selected as the pressure reference at the dorsal foot face for her customized multicomponent bandage. having a previous satisfactory experience concerning multicomponent bandages applied with very low pressures and global digressive pressure gradient for lymphoedema patients (leduc’s method), those two pressure paramaters were the solution to build a tolerated bandage for the patient. those pressures were possible to obtain due to the selected applying method, the global conic shape and the circular section all along the limb. in this case, recorded dvpi during walking were not only due to the final stiffness of the assembled bandage, but also to the limb volume change. the patient walking difficulties (inability to bend the knee) and the amputated calf explain the poor” correspondence: frédéric pastouret, compression therapy research unit, papignies, belgium. e-mail: compressiontherapy.researchunit@outlook.com this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright f. pastouret, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6634 doi:10.4081/vl.2017.6634 figure 1. view of the patient lower limbs (left), her partially amputated calf and her thigh and her inguinal node dissection scar. no n c om me rci al us e o nly conference presentation [page 26] [veins and lymphatics 2017; 6:6634] dvpi at the tight level. silicone pad was selected as a safety protective interface between skin graft and the prosthesis to reduce local mechanical stress on the calf skin scars (medical propriety used during scar management)4 but also for two other technical reasons (washable and reusable). the association between mobiderm® (stiff layer) and biplast® (adhesive layer) leads to an adhesive short stretch (inelastic) final assembled multicomponent bandage. mainly, mobiderm® band is used in association with a non-adhesive short stretch band in lymphoedema treatment.5 our kind of adhesive mcb completes the tools range (non-cohesive or cohesive mcb) at the disposal of the therapist. for this patient, staying in the same standing position or walking during a long time was very difficult. working on 3d reconstructed limb was the solution to build a customized multicomponent bandage and offered the possibilities to practice multiple tests (products choice, best applying method). it was like having the patient in our lab. conclusions the use of simulated limb in compression therapy in vitro experiment to assess related pressure parameters is common.6-9 working on 3d reconstructed limb to prepare a customized multicomponent bandage for a specific patient is a new concept in compression therapy that allowed decreasing the patient time’s investment. custom prosthesis with the silicone interface enabled to normalize the leg’s shape, to protect the skin scars and to obtain a high massage/pump effect on the skin graft, which is a very important skin care benefit during the treatment. final pressure, pressure gradients, dvpi and final resistance of assembled bandage are very satisfying and are leading to an optimal bandage tolerance by the patient. references 1. international society of lymphology. the diagnosis and treatment of peripheral lymphedema: 2013 consensus document of the international society of lymphology. lymphology 2013;46:1-11. 2. partsch h, flour m, smith pc. indications for compression therapy in venous and lymphatic disease consensus based on experimental data and scientific evidence. under the auspices of the iup. int angiol 2008;27:193-219. 3. ehrler sc, eveno d. résultats d’une étude multicentrique française concernant la mise en place d’un manchon post opératoire en silicone chez 211 patients amputés du membre inférieur. j orthoped 2009;10:1432-4. 4. monstrey s, middelkoop e, vranckx jj, et al. updated scar management practical guidelines: non-invasive and invasive measures. j plastic reconstr aesth surg 2014;67:1017-25. 5. quere i, presles e, coupe m, et al. prospective multicentre observational study of lymphedema therapy: polit figure 3. multicomponent bandage applying method on the 3d reconstructed limb (left) and on the patient (right). first layer of tubular cotton jersey (a). second single layer of mobiderm®, minimal overlap, no tension (b). last single layer of biplast ®. biplast®, digressive overlap and constant band tension (c). figure 4. recorded pressures (mmhg or %), internal and external pressure gradients (%) and dvpi during walking, according the sensors location. figure 2. pressure sensors locations on the 3d reconstructed limb. c5 is located under the silicone and the prosthesis. c6 on the prosthesis; silicone pad: medi® silicone for custom made liners, density a-5 (blue arrow); light foam prosthesis of the partial amputated right calf (f). no n c om me rci al us e o nly conference presentation [veins and lymphatics 2017; 6:6634] [page 27] study. j malad vasc 2014;39:256-63. 6. stolk r, wegen van der-franken cp, neumann ha. a method for measuring the dynamic behavior of medical compression hosiery during walking. dermatol surg 2004;30:729-36; discussion 36. 7. partsch h, partsch b, braun w. interface pressure and stiffness of ready made compression stockings: comparison of in vivo and in vitro measurements. j vasc surg 2006;44:809-14. 8. gaied i, drapier s, lun b. experimental assessment and analytical 2d predictions of the stocking pressures induced on a model leg by medical compressive stockings. j biomechan 2006;36:3017-25. 9. pastouret f. pressures exerted by circular or flat knitted arm sleeves during simulated muscular contractions. 42nd esl congress, mulhouse, france; 2016. p 67. no n c om me rci al us e o nly hrev_master veins and lymphatics 2017; volume 6:6629 [page 14] [veins and lymphatics 2017; 6:6629] the perikit: an innovative connected portable device with high level of accuracy and reliability in taking circumferential limb measurements joseph harfouche chirec edith cavell clinics, brussels, belgium introduction healthcare professionals, sportsmen and dieticians know how difficult it is to take circumferential limb measurements in a fast, reproducible and accurate way. there is currently no device on the market able to take accurate and fast measurements and being affordable (size and price) at the same time. for instance, in the field of lymphedema management, it is essential to reach the highest level of accuracy in the circumferential measurements in order to answer the healthcare insurances requirements, to follow-up the evolution of the edema, to evaluate and reevaluate the treatment but also to make sure that the compressive garments, (standard or made-to-measure) do fit perfectly the patients. to be considered as accurate, scientists accept that the error can be of maximum a few millimeters. the classical tapeline, which is the most frequently used measurement device, is affordable (size and price) but the measured values are approximate for multiple reasons like the perpendicularity of the tape, the pressure applied by the therapist, and the measurements are not taken each time exactly at the same place (unless we spend a lot of time drawing marks on the patients’ skin, taking the risk to further stigmatize them and irritate or damage their sensitive skin). other devices, such as laser or infrared scanners, can be considered of high level of accuracy but they are very expensive and require space and an adapted infrastructure. the water displacement which is considered as the gold standard is the reference in terms of accuracy. but the weaknesses are: price, time consuming, the water volume, the practicality, the hygiene. since the whole volume is taken, there is no way to know where the change in volume took place on the limb. the new perimeter measurement device and technic is called the perikit. taking measurements is made easy and fast thanks to its patented elements. the perikit consists in a graduated adaptable guide tapeline, installed longitudinally on the limb in order to: i) prevent marking the skin with the ink at the landmarks each 4cm, so it leaves no stigmas after each assessment and it protects the skin from scrubbing and possible damage when cleaning it; ii) to take the measurements on a non-elastic support and not on elastic and unstable skin; iii) to take the measurements faster; iv) to guarantee the exactitude of the place where the circumference are taken during the whole procedure. on the guide tapeline, sliding devices (sld) are installed. on the first sld, a tapeline is fixed to take circumferential measurements and on the second sld, a brake system is fixed to stabilize the mechanism. each sld is equipped with an aperture to read precisely the distance where the measurement is taken. to ensure its stability and accuracy on the limbs, the guide is fixed at its distal part to the joint (wrist or ankle) and will be stuck with bony landmarks (figure 1 : unlar stiloïde for the upper limb; on the malleoli for the lower limb) that are more accurate than skin landmarks. to check the reproducibility and accuracy concerning the reference point positioning and the circumferential measurements, the perikit has been tested on 43 healthy subjects who took part in a study. the choice of healthy subjects can guaranty that no bias of edema variability is possible and that any change in the measurement even of 1 mm is considered as a measurement inaccuracy and not a measurement variability. the measurements were taken on the upper limb each 4 cm beginning with a reference point on the wrist joint. the measurements were retaken independently within 1 hour. results: concerning the circumferential measurements, the interclass correlation (icc) was 0.99 . the bland and altman test confirmed the reproducibility of the system. concerning the reference points taking/retaking, no statistically different changes were noticed between the first and the second assessment. conclusions the perikit shows a high degree of reproducibility and accuracy with major advantages: i) 97% of the measurements taken showed a difference between 0 and 3 mm; ii) high precision in retaking the bony landmark reference point that is fixed on the joint as well as the other landmarks and the mean difference was less than 2 mm; iii) it solved the classic error of inaccuracy accumulations that can occur between each 4 cm, because the perikit stays on the limb during the whole procedure; iv) no tension correspondence: joseph harfouche, chirec edith cavell clinics, brussels, belgium. e-mail: joseph.harfouche@yahoo.com this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright j. harfouche, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6629 doi:10.4081/vl.2017.6629 figure 1. how to measure arm edema. no n c om me rci al us e o nly conference presentation [veins and lymphatics 2017; 6:6629] [page 15] is put on the tapeline by the assessor, so the risk of affecting the accuracy is minimized; v) the perikit can adapt to any shape and length of any limb; vi) no ink marks on fragile skins are used, so the risk of abrasion followed by infection is solved. a connected version of the perikit has also been developed. this consists in a digital and connected perikit (iot), linked to an app. the measurements are taken and instantly displayed simultaneously on the screen of the perikit as well as on any of the following devices where the app can be used: laptops, pads, smartphones, etc. the data can be compared in different charts and communicated to any authorized person (from the patient to the healthcare professionals). this strengthens the features of the analogic version: i) faster measurements: the values are instantly displayed on the screen and in the app; ii) user-friendly: intuitive and easy to use and helps the assessor step by step; iii) faster treatment follow-up and adjustment: thanks to the charts and graphics that show the evolution of the edema at any distance and at any date. as a conclusion, the perikit has been developed in order to facilitate the measurements taking and to improve the reliability of circumferential measurement data, especially in the field of lymphedema. it is no longer, neither time consuming and laborious, nor a privilege for those who can afford it, to take reproducible and accurate measurements. thanks to the perikit and its 2 versions (analogic and connected), almost anyone can easily reach a high level of reliability in taking measurements. no n c om me rci al us e o nly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: laser assisted foam sclerotherapy (lafos): a new approach to the treatment of incompetent saphenous veins by frullini a, fortuna b. phlébologie 2013;66:51-4. stefano ricci abstract for veins exceeding 1 cm of diameter, poorer outcome is expected as the occlusion rate of great or small saphenous veins (gsvs and ssvs, respectively). reducing the diameter of the vein prior to sclerotherapy could improve the results, also requiring a limited volume of foam. a holmium:yag (ho:yag) laser was employed to produce significant shrinkage on the vein media. this laser has been designed to avoid endothelium damaging while inducing coarctation of the vein wall by accumulating heat in the media (5 w, 500 mj, 350 µs max, 10 hz max). the procedure under consideration – laser assisted foam sclerotherapy (lafos) – was applied in 50 patients (38 gsvs, mean diameter 9.17; 12 ssvs, mean diameter 7.91). veins were accessed by a 17 g short catheter with ultrasound (us) assistance. the laser fiber was placed 1-2 cm below the junction and manually retracted applying fluency from 150 to 400 mj without infiltration anesthesia. at the end of the laser phase, sclerosing foam (polidocanol: 3% gsv-5 ml mean; 2% ssv2 ml mean) was injected through the same catheter. one month of compression stockings was prescribed, with a 48-h-thigh eccentric compression by means of a pad. patients were invited to walk daily for at least 1 h. vein shrinkage was constantly achieved and complete occlusion was always observed at 1 month. no patient referred extreme pain during laser procedure, while in 8 cases energy adjustment was required to avoid discomfort. comment by stefano ricci laser is an ever surprising technology. the ability to shrink the vein wall without damaging the endothelium is of particular interest, not only as a way to close veins (the authors’ perspective), but also as a method for saphenous stem caliber restoration (a conservative perspective). as a matter of fact, what happens during this laser action is quite fuzzy, as no data or evidences are reported, the vein shrinkage possibly being due to the simple mechanical stimulation. in the past, the same effect has been studied through the action of radio frequency appliance (the restore research) with inconsistent results. finally, the costs of this combined technique should be analyzed to understand if laser+foam-tumescence is more convenient than laser+tumescence. reply by the authors the most frequent question on holmium laser vein shrinkage is whether this is a true coarctation or simply a vasospasm. in my perspective (and with the experience largely exceeding one hundred lafos), the answer is very simple: it is a true coarctation. vasospasm is an all or nothing phenomenon: when it comes to positioning a needle, the vein disappears and lafos is not feasible as we need an open vein (even if shrinked). during lafos, the vein is commonly shrinked where laser has worked and, immediately below, it has the original diameter. such a gap is not compatibile with a vasospasm, where a quite large segment of vein is affected. obviously, the cost of the procedure will be of the outmost importance in the future of phlebology, but such an common procedure is capable to easily manage the saphenous trunk without the need of anesthesia. moreover, as a laser procedure in some countries it will be reimbursed, with great convenience over simple sclerotherapy. [top] franz schelling a swang song for ccsvi? a commentary to the article: reekers j. a swan song for ccsvi. cardiovasc intervent radiol 2014;37:287-8. franz schelling, md gaissau, austria dr.franz.schelling@gmail.com open letter professor jim reekers, my emails to you seem not to have provoked any reaction. please find below an attempt to render the open letter re your commentary a swan song for ccsvi1 a little more concrete. you declared that ccsvi has been shown, scientifically proven, to not exist. and that the observations of positive responses to its balloon dilatation treatments were just a never lasting placebo effect. all that the internet could show to you were testimonies by disappointed ms patients. what, however, were they disappointed by? failed, or abortive exams for ccsvi? denied, or unsuccessful interventions? unreasonably high expectations, or treatment complications? most importantly, however, how could, or why did you find no access to all the accounts of persistent, at times bewildering benefits following interventions for ccsvi? why is there a call for double blinded trials on a ccsvi that is said not to exist, and found it on an impenetrable clinical ms entity that lacks in any concrete marker for its identification? ought we not focus instead on what is known about the ms lesions’ relationship to the venous pathways which the ccsvi findings relate to? the usual reduction of ccsvi to an appealing abbreviation for the narrowing of the (internal) jugular vein, evident already from your introduction, is one of the reasons for the present impasse in ccsvi research. there exist decidedly more important pieces of evidence on our topic than your statement that some early ms lesions are located around a vein is willing to admit. it was actually with the participation of your institute of radiology at amsterdam that the damaging of the cortical grey matter on the part of venous trunks and branches was made evident in ms for the first time2 and it was your very institute that first revealed in vivo, in seventeen patients with ms, two facts disclosed until then only in general and in separate post mortem specimens: i) the distribution of ms lesions in the brain follows a specific pattern; ii) the lesions’ form and orientation appears determined by the course of veins.3 the unparalleled nature of these features of ms has been pointed out by numerous observers without ever being granted due attention in clinical ms research. instead, in ww ii, there occurred a fatal shift in the way clinical neurology understands ms: its distinctive anatomical pathology came to be equated and ultimately displaced by findings made in an animal model created for unraveling immunization encephalomyelitis: experimental allergic encephalomyelitis or eae. clinical jargon soon referred to ms simply as enc[ephalomyelitis] diss[eminata]. in forgetting about all its well documented venous and scarring findings, charcot’s multilocular sclerosis had thus become an inflammatory myelin/white matter disease whose brain lesions originated in venules and not in veins. as in other ill-understood disease processes, declaring observed inflammatory/immunological reactions as primary, spontaneous, idiopathic, and sufficed for turning them into injurious events. on the other hand, by 1965, charcot’s diagnostic ms triad and any competing ms definition via concrete nervous dysfunctions had come to be replaced by less committal numeric terms. the diagnosis of a clinically definite ms now depended on tracing a dissemination (of as indefinite as unexplainable lesions) in space and time, to be precise in keeping with three temporal cut-off points: i) relapse durations of one day with a relapse interval of one month, respectively a progression of neurodysfunctions over six months became the substratum, the only concrete data to rely on in making a diagnosis, i.e. tracing the demyelinating episodes of ms; ii) neurodysfunctions of a mere day’s duration cannot suffice, however, nor should their progression over half a year be necessary for identifying these demyelinative events: the repair of an area of demyelination takes about three months. in likewise, the need for two relapses, demyelinating episodes, to be separated by a month so as to prove ms is bound to remain inscrutable. what about the much invoked eae ms analogy? as post-infectious/immunization adem (acute disseminated encephalomyelitis) does in man, so also the animal ms of eae extends in the form of narrow perivenular lesion sleeves quite evenly throughout the brain, in particular its white matter. the sleeves are 0,1 to 1,0 mm in diameter and often interspersed with punctate ring-bleedings. in converging towards the lateral ventricles, they may merge to form wider, unevenly outlined lesion pools. reaching far larger dimensions, plaques of human ms proper erupt from subependymal veins. in lining and rising from the lateral ventricles, they form the dawson’s fingers of steiner’s wetterwinkel. plaques which spread farther out resemble ovoids whose lining up on a medullary vein reminds of a string of beads. ultimately, the plaques tend to flatten out into juxtacortical half-moons once they reach the cortical border. the lesions expand from acutely or chronically injured veins, and do so via succeeding, more or less eccentric hits. most plaques attain sizes which are out of any proportion to the size of their vessel of origin. such ranges of a destructive efficacy are known of the work of shock waves of ballistic impacts. and so the pattern of the haloes of the isomorphic fibrillary sclerosis surpassing the plaque borders is hardly to be accounted otherwise than by the spread of sub-destructive concussive effects. the unique co-occurrence of severely destructive (black-holes on mri) besides demyelinated and shadow plaques (subject of neuroradiological ubo, i.e. unidentified bright object counts) finds it explanation by local impacts of differing severity. all these changes, readily evident on longitudinal mri studies, are to be physically accounted for by retrograde venous pressure surges and the momentum of abrupt venous flow reversals alone. for such venous bores to come about, engorged, compliant lengths of the venous pathways involved must be abruptly compressed, and this in the presence of some hindrance to the compressed blood’s momentary escape, be it infratransor intracranially, in other than cerebral veins and eventually to the heart. in the presence of incompetent valves, any sufficiently strong expiratory effort or abrupt trunk compression suffices for driving blood back via the internal jugular vein: ccsvi criterion 1. ccsvi criteria 3 to 5 indicate circumstances that either favor venous flow reversals during the suprastenotic vein compression of, or hinder contralateral collateral reflux drainage via, the internal jugular vein itself. it is ccsvi criterion 2, however, that illustrates the decisive injurious event, the venous flow reversals in the brain. unfortunately this widely neglected parameter has as yet not been evaluated round the clock in everyday’s life and needs to be further improved in its sensitivity. in 1981 varicose dilations of the transition of the sigmoid sinus into the jugular vein seen in cranial radiographs of nearly a hundred patients with ms led to my conjecturing that the retrograde venous damaging of the brain seen in ms might be ended in shunting an incompetent confluence of sinuses or doing a valvuloplasty or even ligature high up in the involved internal jugular veins. the benefits of zamboni et al.’s ballooning of ijv (internal jugular vein) stenosis in ms yet point to the fact that, rather than expiratory efforts, it are compressions of suprastenotically engorged internal jugular veins that underlie the vein-engendered ms lesions’ surging up in the brain.4 as for the cerebral veins being thereby specifically involved, all the pertinent literature, from charcot’s lesion sketches of 1866 to the latest eswan mris, has consistently shown that it is the internal cerebral veins and branches which are primarily at risk. the retrograde overburdening, even rupturing of these veins and their adjacent tissues structures seen in ms is paralleled by a special variant of tbi (traumatic brain injury) alone: both conditions present with dawson’s finger lesions arising from steiner’s wetterwinkel, the outer angle of the lateral ventricles, and in the undersurface of the corpus callosum. these facts are already evident in comparing a few pertinent observations made in ms5,6 with such made in traumatic brain injury.7,8 a comparison of the respiratory, exertional and accidental peak pressures in the venous pathways that relate to cerebral ms lesions with such that do not ought thus to reveal the prime cause of cerebral ms. prominent and exclusive connections of straight and lateral/occipito-marginal sinus appear thereby of special relevance. clinical ms trials, be it for drug or interventional treatments, on the other hand are treble blinded in the following respects: i) blinded as regards the features that specifically characterize the anatomical pathology of ms; ii) blinded for the events which actually underlie the ms specific lesions’ development; iii) blinded in view of what is ultimately required for ending the venous damaging of the brain in ms. learning to see, and duly appreciate, how different eae and ms respectively how close the parallels between ms and certain forms of tbi actually are the condition sine qua non for understanding ms. without understanding the processes which the ms specific venous damages are caused by, it is simply impossible to arrive at a sound evaluation of the different findings of ccsvi and thereby to prepare predictable cures of ms. references reekers j. a swan song for ccsvi. cardiovasc intervent radiol 2014;37:287-8.[abstract] [pubmed] kidd d, barkhof f, mcconnell r, et al. cortical lesions in ms. brain 1999;122:17-26.[full text] [pubmed] tan il, van schijndel ra, pouwels pj, et al. mr venography of multiple sclerosis. ajnr am j neuroradiol 2000;21:1039-42.[full text] [pubmed] schelling f. chronic cerebrospinal venous insufficiency in multiple sclerosis: weighing the findings. sang thrombose vaisseaux 2012;24:394-404.[abstract] adams cwm. a colour atlas of ms etc. london: wolfe; 1989. steiner g. krankheitserreger und gewebsbefund bei ms. berlin: springer; 1931. schacht l, minauf m. [central brain in damage following application of blunt force to the skull. i. lesions of the corpus callosum]. [article in german] arch psychiatr nervenkr 1965;207:416-27.[pubmed] graham di, et al. trauma. in: graham di, lantos pl, eds. greenfield’s neuropathology, 7th ed. vol. 1. london: arnold; 2002. pp 833-898. [top] hrev_master veins and lymphatics 2014; volume 3:4148 [page 52] [veins and lymphatics 2014; 3:4148] the recent clinical trials on use of the novel direct oral anticoagulants in patients with venous thromboembolism: a review gualtiero palareti cardiovascular medicine, university of bologna, italy abstract venous thromboembolism (vte), encompassing deep vein thrombosis and pulmonary embolism, requires an immediate anticoagulation, that has been carried out so far by administering a parenteral anticoagulant drug (heparin or derivatives) overlapped with an oral vitamin k antagonist (vka), more often warfarin. several new direct oral anticoagulants (doacs), with a mechanism of action completely different than vka, have been developed in recent years. recent clinical trials have investigated their use in vte patients showing results at least equal for efficacy and safety, and sometime even better, as the standard anticoagulant treatment. there are differences in the design of the trials. in two cases the involved doac was administered immediately after vte diagnosis as a single drug treatment (rivaroxaban and apixaban), whereas in the other trials (involving dabigatran and edoxaban) the doac was administered after an initial course of approximately 7 days with heparin or derivatives. some clinical trials have also investigated the use of doacs for extended anticoagulant treatment after the acute phase. aim of this article is to review the results of the currently available clinical trials that have compared the use of doacs versus the standard of care in patients with vte. introduction venous thromboembolism (vte), that includes deep vein thrombosis (dvt) and pulmonary embolism (pe), is a frequent disease whose incidence is estimated of about 1.5 per 1,000 inhabitants per year.1 vte is a potentially fatal disease and is associated with late complications such as the post thrombotic syndrome.2 consequently, vte may be regarded as a major cause of morbidity and mortality, being the third cause of death due to cardiovascular diseases after myocardial infarction and stroke.3 in order to prevent thrombus extension and its potential consequences, an immediate anticoagulation is necessary as soon as diagnosis is made, by administering one of the available parenteral fast acting drug, such as unfractionated heparin (ufh), low molecular weight heparin (lmwh) or fondaparinux, and overlapping this therapy by associating an oral vitamin k antagonist (vka, more frequently warfarin), which have a slow onset of action that requires 5 to 10 days before achieving an appropriate anticoagulant effect [i.e., international normalized ratio (inr) between 2.0 and 3.0]. current guidelines recommend giving effective anticoagulation to patients with acute vte for at least 3 months; usually this performed by administering vkas, at the exception of some special populations (such as patients with cancer or during pregnancy) in whom treatment with lmwh is recommended over vka.4 since the risk of recurrence is not negligible, the duration of anticoagulation often lasts longer beyond the first 3 months, as it is suggested for high-risk patients such as those with an unprovoked vte episode. treatment with vka is very effective but is complex to carry out in a correct way. it is associated with noticeable burden for the health systems and demanding for the patients. vka have several limitations, including: slow onset and offset of action, complex genetic control of their effect leading to highly variable individual sensitivity, narrow therapeutic window, and a metabolism affected by many factors, including diet, drugs, hepatic dysfunction, other co-morbid conditions and alcohol intake. the dose/response of vka is unpredictable and frequent coagulation monitoring and doseadjustments are needed to ensure efficacy of treatment and to minimize the risk of bleeding complications. several direct oral anticoagulants (doac) have been developed to overcome some limitations of vkas and to improve the quality of life of patients who need anticoagulation. recent large randomized clinical trials have investigated their use in vte patients (as well as in other clinical indications, e.g. non valvular atrial fibrillation) showing results at least equal for efficacy and safety, and sometimes even better, as the standard anticoagulant treatment. aim of this article is to review the results of the currently available clinical trials that have compared the use of doacs versus the standard of care in patients with vte. the novel direct oral anticoagulants the doacs are different drugs, with different characteristics and mechanisms of action. dabigatran is a direct inhibitor of thrombin (factor iia), while rivaroxaban, apixaban and edoxaban (still not available in our country) are inhibitors of activated factor x (factor xa) (some doac characteristics are shown in table 1).5-8 they do not need routine laboratory monitoring, they can be given in fixed doses once or twice daily per os, and have less food or drug interactions than vka. however, they are not free from drawbacks. their anticoagulant effect weakens quickly in case of poor compliance, and specific antidotes are not yet available. treatment of acute venous thromboembolism all the four mentioned doacs have results of randomized clinical trials in patients with acute vte. all the trials were designed to show a non-inferior efficacy and safety versus the standard treatment. some differences were present among the trials, regarding the studied population (patients with acute vte, or acute dvt only, or acute non-hemodynamic pe), the treatment durations and the blinding. but the most important difference regarded the initial treatment: in the study with dabigatran9 and that with edoxaban10 the initial treatment was performed in all patients with heparin (unfractionated or lmwh) for an average period of 7 days, and then the patients were randomized to receive the investigated drug or the standard treatment (warfarin). in the trial with rivaroxaban (the two einstein studies11,12) and in that with apixaban13 the patients in the experimental arm received that single drug treatment since the beginning. exclusion criteria in all the trials were the presence of contraindications to standard anticoagulation with heparin or vkas, pe with hemodynamic instability, use of thrombectomy or of fibrinolysis, or positioning of a vena cava correspondence: gualtiero palareti, cardiova scular medicine, university of bologna, via massarenti 9, 40138 bologna, italy. e-mail: gualtiero.palareti@unibo.it; gualtiero. palareti@gmail.com key words: venous thromboembolism, anticoagulation, trials, direct oral anticoagulants, warfarin. received for publication: 22 may 2014. revision received: not required. accepted for publication: 9 october 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright g. palareti, 2014 licensee pagepress, italy veins and lymphatics 2014; 3:4148 doi:10.4081/vl.2014.4148 no n c om me rci al us e o nly review [veins and lymphatics 2014; 3:4148] [page 53] filter. for details on results of the trials see table 2.9-15 dabigatran in the randomized, double-blind, recover study,9 were included 2564 patients with acute vte who, after an initial treatment with parenteral anticoagulation therapy with lmwh or ufh (for a median of 9 days), were randomized to receive dabigatran at a dose of 150 mg bis in die (b.i.d.) or dose-adjusted warfarin to achieve an inr of 2.0 to 3.0. duration of treatment was six months. the occurrence of primary outcome for efficacy was of 2.4% in patients treated with dabigatran and 2.1% in those receiving warfarin (time in therapeutic range 60%), confirming the non-inferiority of dabigatran vs warfarin (p<0.001). with regard to the safety, a major bleeding episode occurred in 1.6% and 1.9% of patients in dabigatran and warfarin groups, respectively [hazard ratio (hr) 0.82; 95% confidence interval (ci), 0.45 to 1.48]. the more frequent major bleeding event in the dabigatran group was gastrointestinal (nine events). intracranial hemorrhage occurred in three patients treated with warfarin and in none receiving dabigatran. rivaroxaban the einstein vte program consisted of two randomized trials of rivaroxaban: the einsteindvt11 and the einstein-pe12 studies, that included patients with acute symptomatic dvt or pe, respectively; both studies allowed also different durations of treatment (3, 6 or 12 months), and after the completion of the initial acute treatment, patients could be included in the continued treatment study, a double blind, randomized, superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months. the einstein-dvt study was a randomized, open-label, event-driven, trial that compared oral rivaroxaban alone (15 mg b.i.d. for 3 weeks, followed by 20 mg once daily) with the standard anticoagulation treatment (subcutaneous enoxaparin followed by vka, inr 2.03.0) in 3449 patients with acute, symptomatic dvt and without symptomatic pe. the primary efficacy outcome occurred in 2.1% of patients who received rivaroxaban and in 3.0% of those who received lmwh+vka (overall the time in therapeutic range for warfarin was 57.7%) and the hr was 0.68; 95% ci 0.44 to 1.04; with p<0.001 for non-inferiority. major or clinically relevant non-major bleeds occurred in 8.1% and 8.1% of patients treated with rivaroxaban or standard therapy, respectively (hr with rivaroxaban, 0.97; 95% ci, 0.76-1.22; p=0.77). the einstein-pe study was a randomized, open-label, event-driven, trial that involved 4832 patients with acute symptomatic nonhemodynamic pe with or without dvt. rivaroxaban (at the dose of 15 mg twice daily for 3 weeks, followed by 20 mg once daily) was compared with standard therapy with lmwh followed by an adjusted-dose vka for 3, 6, or 12 months. the primary efficacy outcomes in 2.1% of the rivaroxaban group and 1.8% of the standard therapy group (hr 1.12; 95% ci, 0.751.68; p=0.003 for non-inferiority). the principal safety outcome, that included major or clinically relevant non-major bleeding, occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard therapy group (hr 0.90; 95% ci, 0.76-1.07; p=0.23), with major bleeding events in 1.1% of patients treated with rivaroxaban and 2.2% in those receiving standard therapy apixaban the double blind, double dummy amplify study13 enrolled 5395 patients with acute dvt and/or pe who were randomized to receive apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily) or lmwh + warfarin (2.0-3.0 inr) for 6 months. the primary efficacy outcome, that included recurrent symptomatic vte or death vte-related occurred in 2.3% in the apixaban group and 2.7% in the standard-therapy group (hr, 0.84; 95% ci 0.60-1.18; p<0.001 for non-inferiority). principal safety outcomes included major bleeding alone and major bleeding plus clinically relevant non-major bleeding. major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received standard therapy (hr, 0.31; 95% ci, 0.17-0.55; p<0.001 for superiority). the composite outcome occurred in 4.3% of the patients in the apixaban group and in 9.7% of those in the conventional-therapy group (hr, 0.44; 95% ci, 0.36 to 0.55; p<0.001). edixaban the hokusai study10 was a randomized, double-blind, in which all patients included with acute vte (4921 presented with dvt, and 3319 with pe) initially received heparin (or lmwh) and then were randomized to receive edoxaban at a dose of 60 mg once daily, or 30 mg once daily (e.g., in the case of creatinine clearance of 30-50 ml/min or body weight below 60 kg), or to receive warfarin (time in the therapeutic range was 63.5%) for a duration of treatment of 3 to 12 months. primary efficacy outcome (recurrent symptomatic vte) occurred in 3.2% and in 3.5% of patients in the experimental arm and in the standard treatment group, respectively (hr 0.89; 95% ci, 0.70 to 1.13; p<0.001 for noninferiority). the rate of recurrent vte was particularly low (3.3%) in pe patients with right ventricular dysfunction (assessed by measurement of n-terminal pro-brain natriuretic peptide levels) who received edoxaban group versus those treated with warfarin (6.2%; hr 0.52; 95% ci, 0.28-0.98). table 1. main pharmacological characteristics of the new drugs. dabigatran rivaroxaban apixaban edoxaban mechanism of action direct, selective factor direct, selective direct, selective direct, selective iia inhibitor factor xa inhibitor factor xa inhibitor factor xa inhibitor prodrug yes no no no hours to cmax 25 2-46 1-37 1-28 half-life (hours) 12-145 9-136 8-157 9-118 elimination 80% renal 1/3 renal 25% renal 35% renal 20% biliary 1/3 renal (as inactive metabolites) 75% biliary 65% biliary 1/3 biliary interactions p-glycoprotein p-glycoprotein and cyp3a4 p-glycoprotein (minimal) and cyp3a4 p-glycoprotein food effect absorption delayed absorption delayed not reported not or minimal protein binding (%) 35 90 87 40-59 dosing b.i.d. once daily b.i.d. once daily b.i.d., bis in die. no n c om me rci al us e o nly review [page 54] [veins and lymphatics 2014; 3:4148] t ab le 2 . r at es ( n o ./ 1 0 0 p at ie n tye ar ) o f p ri m ar y o u tc o m es a n d m aj o r b le ed in gs w it h d ir ec t an ti co ag u la n ts o r co m p ar at o rs i n r ec en t tr ia ls i n p at ie n ts t re at ed f o r ve n o u s th ro m b o em b o li sm . tr ia l d o a c a ge nt ; d es ig n; n o. p at ie nt s; i ni ti al t he ra py ; d os in g r at es o f pr im ar y ef fi ca cy o ut co m es r at es o f m aj or b le ed in g ev en ts d o a c c om pa ra to r d o a c c om pa ra to r a cu te p ha se t re at m en t re -c o ve r9 d ab ig at ra n; tr ea tm en t o f a cu te d vt o r pe ; 2 56 4; 1 .8 1. 3% 1 .6 % 1 .9 % in iti al tr ea tm en t w ith l m w h ( m ed ia n 9 d) ; 1 50 m g b. i.d . x 6 m on th s h r= 1. 44 ( 0. 78 -2 .6 4) h r= 0. 82 ( 0. 45 -1 .4 8) p< 0. 01 * l m w h + w ei ns te in -d vt 11 r iv ar ox ab an ; a cu te a nd e xt en de d tr ea tm en t o f d vt p at ie nt s; 2 .1 % 3 .0 % 0 .8 % 1 .2 % 3 44 9, s in gl e dr ug tr ea tm en t s in ce th e be gi nn in g (3 , 6 o r 12 m on th s) ; h r= 0. 68 ( 0. 44 -1 .0 4) h r= 0. 65 ( 0. 33 -1 -3 0) l m w h + w 1 5 m g b. i.d . x 2 1 d th en 2 0 m g o. i.d . p < 0. 00 1* ei ns te in -p e1 2 ri va ro xa ba n; a cu te a nd e xt en de d tr ea tm en t o f p e pa tie nt s; 4 83 3; 2 .1 % 1 .8 % 1 .1 % 2 .2 % s in gl e dr ug tr ea tm en t s in ce th e be gi nn in g (3 , 6 o r 12 m on th s) ; h r= 1. 12 ( 0. 75 -1 .6 8) h r= 0. 49 ( 0. 31 -0 .7 9; 0 .0 03 ) l m w h + w 1 5 m g b. i.d . x 2 1 d th en 2 0 m g o. i.d . p = 0. 00 3* am pl ify 13 ap ix ab an ; t re at m en t o f a cu te d vt o r pe ; 2 60 9; s in gl e dr ug tr ea tm en t 2. 3% 2 .7 % 0. 6 1 .8 % s in ce th e be gi nn in g; 1 0 m g b. i.d . x 7 d th en 5 m g b. i.d . x 6 m on th s h r= 0. 84 ( 0. 60 -1 .1 8) r r= 0. 31 ( 0. 17 -0 .5 5) l m w h + w p < 0. 00 1* p< 0. 00 1° h ok us ai 10 e do xa ba n; a cu te a nd e xt en de d tr ea tm en t o f d vt o r pe ; 8 24 0; 3. 2% 3 .5 % 1 .4 % 1 .6 % in iti al tr ea tm en t w ith l m w h ( m ed ia n 7 d) ; 6 0 m g o. i.d . h r = 0 .8 9 (0 .7 01. 13 ) h r= 0. 84 ( 0. 59 -1 .2 1) l m w h + w p < 0. 00 1* e xt en de d tr ea tm en t re -m ed y d ab ig at ra n; e xt en de d tr ea tm en t a ft er th e fir st 3 m on th s; 1 50 m g b. i.d . re -s o n at e1 4 re -m ed y: 2 86 6; c om pa ra to r w 1 .8 % 1 .3 % 0 .9 % 1 .8 % h r= 1. 44 ( 0. 78 -2 .6 4) w h r= 0. 52 ( 0. 27 -1 .0 2) w p< 0. 01 * p = 0. 06 ° r eso n at e: 1 36 3; c om pa ra to r pl ac eb o 0. 4 5 .6 0. 3% 0 h r= 0. 08 ( 0. 02 -0 .2 5) p la ce bo p la ce bo p < 0. 00 1° am pl ify e xt en si on 15 a pi xa ba n; e xt en de d tr ea tm en t w ith 2 d iff er en t d os es : 2 .5 m g b. i.d .= 3. 8 2 .5 m g b. i.d .= 0. 2% 2 .5 m g b. i.d . o r 5 m g b. i.d .; 24 82 ; c om pa ra to r pl ac eb o h r= 0. 33 ( 0. 22 -0 .4 8) h r= 0. 49 ( 0. 09 -2 .6 4) 5 m g b. i.d .= 4. 2 1 1. 6 0 .5 % h r= 0. 36 ( 0. 25 -0 .5 3) p la ce bo 5 m g b. i.d .= 0. 1% p la ce bo p < 0. 00 1° h r= 0. 25 ( 0. 03 -2 .2 4) f or b ot h co m pa ri so ns d o ac , d ir ec t o ra l a nt ic oa gu la nt s; d vt , d ee p ve in th ro m bo si s; p e, p ul m on ar y em bo lis m ; l m w h , l ow m ol ec ul ar w ei gh t h ep ar in ; b .i. d. , b is in d ie ; h r, h az ar d ra tio ; o .i. d. , o pt im al im m un om od ul at in g do se ; r r, r el at iv e ri sk . * st at is tic al s ig ni fic an ce fo r no nin fe ri or ity ; ° st at is tic al s ig ni fic an ce fo r su pe ri or ity . no n c om me rci al us e o nly review [veins and lymphatics 2014; 3:4148] [page 55] the principal safety outcomes (major or clinically relevant non-major bleeding) occurred in 8.5% of patients in the edoxaban group and in 10.3% of those treated with warfarin (hr 0.81; 95% ci, 0.71 to 0.94; p=0.004 for superiority). studies on extended treatment some clinical trials have investigated the effects of doacs in vte patients treated for extended therapy after an initial therapy of at least 3 months from the index event. among these studies, only the re-medy (dabigatran) study14 had warfarin as comparator, while the others [einstein-dvt extended treatment (rivaroxaban),11 the re-sonate (dabigatran)14 and amplify extension (apixaban)15 had placebo as comparator (table 2).9-15 the einstein-dvt continued-treatment study (rivaroxaban) in the einstein-dvt it was carried out, in parallel, a double-blind superiority study that included 1196 patients who had completed 6 to 12 months of therapy after the index vte event.11 they were randomized to receive rivaroxaban (20 mg once daily) or placebo for an additional 6 or 12 months. recurrent events occurred in 1.3% of patients treated with rivaroxaban and in 7.1% of those receiving placebo (hr 0.18; 95% ci, 0.09-0.39; p<0.001). the principal safety outcome of major bleeding occurred in 4 patients (0.7%) in the rivaroxaban group and in none in the placebo group (p=0.11). however, major or clinically relevant non-major bleeds occurred in 6.0% and 1.2% in the rivaroxaban and placebo groups, respectively (p<0.001) the re-medy and re-sonate study (dabigatran) in the re-medy study14 2866 patients, who had received 3 to 12 months of anticoagulant therapy after a vte episode, were randomized to treatment with dabigatran 150 mg twice daily or with warfarin (inr 2.0 to 3.0) for an additional period of 6 to 36 months. recurrent symptomatic vte occurred in 1.8% and 1.3% of patients treated with dabigatran and warfarin, respectively (hr 1.44; 95% ci 0.78 to 2.64; p=0.01 for non-inferiority). major bleeds occurred in 0.9% and 1.8% in dabigatranand warfarin-treated patients, respectively (hr 0.52; 95% ci, 0.27 to 1.02). major or clinically relevant bleeding was less frequent with dabigatran (hr 0.54; 95% ci, 0.41 to 0.71). more acute coronary syndromes occurred in the dabigatran (0.9%) than in the warfarin group (0.2%) (p=0.02). the authors concluded that dabigatran was as effective as warfarin in the extended treatment of vte; it was associated with a reduced risk for bleeding but an increased incidence of acute coronary events. in the double-blind, placebo-controlled resonate study14 1363 patients with vte who had completed 6-18 months of anticoagulant therapy were randomized to receive dabigatran 150 mg b.i.d. daily or placebo for 6 more months. recurrent vte occurred in 0.4% of patients in the dabigatran group and in 5.6% in the placebo group (hr 0.08; 95% ci, 0.02-0.25; p<0.001 for superiority). major bleeding occurred in 2 patients (gastrointestinal bleeding in both cases) in the dabigatran group (0.3%) and 0 patients in the placebo group. major or clinically relevant bleeding occurred in 5.3% of patients in the dabigatran group (5.3%) and in 1.8% in the placebo group (hr 2.92; 95% ci, 1.52-5.60). one patient each in the dabigatran and placebo groups had an acute coronary syndrome. the authors concluded that an extended treatment with dabigatran was highly effective in reducing the rate of vte recurrences as compared with placebo, and was associated with only a low risk for major bleeding. the amplify-ext study (apixaban) this was a randomized, double-blind study that compared the effects during one year of treatment with two doses of apixaban (2.5 mg and 5 mg, twice daily) or placebo in 2486 patients with vte who had already received anticoagulation for 6-12 months. primary efficacy outcomes occurred in 11.6% of patients treated with placebo, and in 3.8% who received 2.5 mg b.i.d. of apixaban and in 4.2 % of those who were treated with 5 mg b.i.d. of apixaban; with both apixaban doses the reduction of events was highly statistically significant (p<0.001). the rates of major bleeding were not different in the placebo group (0.5%), than in the 2.5-mg apixaban group (0.2%), and in the 5-mg apixaban group (0.1%). the authors concluded that the extended anticoagulation with apixaban at both adopted doses reduced the risk of recurrent vte without increasing the rate of major bleeding. conclusions the clinical trials on the use of doacs in patients with acute vte have all shown that the efficacy of these drugs on prevention of thrombotic complications was non-inferior to the standard treatment, consisting of initial administration heparin (or derivatives) followed by warfarin. moreover, all the treatments with doacs proved at least as safe and sometimes even better than the comparator treatment. as regards the long-term therapy, it should be pointed-out that only one study (remedy14) was performed versus warfarin as comparator, while in all the others the comparator was placebo. while the one doac (dabigatran) that was compared with warfarin proved similarly effective and with less major bleeding complications (though not reaching the statistical significance), the other doacs compared to placebo proved more effective and with no higher rates of major bleeding. it is of interest to notice that altogether the results of these trials showed substantially lower bleeding rates in vte patients compared with results in recent clinical trials on doacs use in patients with non valvular atrial fibrillation, a finding that could be due to the usually older age of the latter versus vte patients (with more chronic medical conditions and concurrent medications) and the shorter duration of the studies in vte patients. references 1. cushman m, tsai aw, white rh, et al. deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. am j med 2004;117:19-25. 2. prandoni p, lensing awa, cogo a, et al. the long-term clinical course of acute deep venous thrombosis. ann intern med 1996;125:1-7. 3. heit ja, silverstein md, mohr dn, et al. predictors of survival after deep vein thrombosis and pulmonary embolism a population-based, cohort study. arch intern med 1999;159:445-53. 4. kearon c, akl ea, comerota aj, et al. antithrombotic therapy for vte disease: antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. chest 2012;141:e419s-94s. 5. stangier j, rathgen k, staehle h, et al. the pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. br j clin pharmacol 2007;64:292-303. 6. kubitza d, becka m, voith b, et al. safety, pharmacodynamics, and pharmacokinetics of single doses of bay 59-7939, an oral, direct factor xa inhibitor. clin pharmacol ther 2005;78:412-21. 7. raghavan n, frost ce, yu z, et al. apixaban metabolism and pharmacokinetics after oral administration to humans. drug metab dispos 2009;37:74-81. 8. camm aj, bounameaux h. edoxaban: a new oral direct factor xa inhibitor. drugs 2011;71:1503-26. no n c om me rci al us e o nly review [page 56] [veins and lymphatics 2014; 3:4148] 9. schulman s, kearon c, kakkar ak, et al. dabigatran versus warfarin in the treatment of acute venous thromboembolism. n engl j med 2009;361:2342-52. 10. buller hr, decousus h, grosso ma, et al. edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. n engl j med 2013;369:1406-15. 11. bauersachs r, berkowitz sd, brenner b, et al. oral rivaroxaban for symptomatic venous thromboembolism. n engl j med 2010;363:2499-510. 12. buller hr, prins mh, lensin aw, et al. oral rivaroxaban for the treatment of symptomatic pulmonary embolism. n engl j med 2012;366:1287-97. 13. agnelli g, buller hr, cohen a, et al. oral apixaban for the treatment of acute venous thromboembolism. n engl j med 2013;369:799-808. 14. schulman s, kearon c, kakkar ak, et al. extended use of dabigatran, warfarin, or placebo in venous thromboembolism. n engl j med 2013;368:709-18. 15. agnelli g, buller hr, cohen a, et al. apixaban for extended treatment of venous thromboembolism. n engl j med 2013;368:699-708. no n c om me rci al us e o nly hocaoglu c. clozapine-induced rabbit syndrome: a case report intelligent textiles nick morrison abstract investigators of venous disorders have long lamented the inability to measure compression dosage of both graduated compression hose and more especially compression bandaging in order to assure accurate and consistent therapeutic intervention. new intelligent or smart fabrics are being developed that may well serve this purpose. these textiles are manufactured to function as a sensor capable of monitoring such things as pressure, temperature, cardiopulmonary functions, and athletic performance, and could be used to aid in detection and treatment of diabetic, venous and decubitus ulcer. one company, footfalls and heartbeats, ltd (auckland, nz) has developed technology that combines mathematically determined textile structures using electrically conductive yarn to form a repeatable and sensitive sensor network…. [and] through…conductive fibre technology and micro power sources, electrical signals are produced that can be filtered, amplified and analysed in real-time to produce multiple data sets relating to physiological output, limb movement, proprioception and either tensile or compressive force detection within or upon organic or man-made structures. in essence this process allows a compression bandage, for example, to electronically monitor itself and potentially the tissue beneath it without internal wiring. the information obtained is wirelessly transmitted to a monitor that can then store or pass it along to the patient and/or caregiver allowing for real-time calculation of the dosage of the treatment modality, that is, the compression applied to specific treatment areas. because this entire process is wireless from the fabric itself to the monitor, patient comfort and the durability of the bandage is preserved. the footfalls and heartbeats product, smart sock, used to measure the degree of compression from overlying compression bandages was displayed at the advamed meeting in washington, dc, usa in september, 2013. other applications of smart textiles can include medical monitoring during testing such as ecg and further developments are expected to allow the textiles to monitor active and passive muscular and vascular function with the potential, for example, to allow for ambulatory testing of venous functions (plethysmography, etc). i extend my appreciation to dean bender (president, circaid by medi) for his expertise. a partial list of companies developing smart textiles/products appears below. footfalls and heartbeats: http://www.footfallsandheartbeats.com/index.cfm/discovery/our-science/ dr. scholl's pressure monitor devices: http://www.footmapping.com/footmapping/home/index.jspa heapsylon (us): http://www.heapsylon.com/sensoria-healthcare/ [top] stefano ricci comment to: acute and chronic consequences of polidocanol foam injection in the lung in experimental animals by grandi l, grandi ra, tomasi cd, da rocha jl, cardoso v, dal-pizzol f. phlebology 2013;28:441-4. stefano ricci abstract to assess the occurrence of pulmonary embolism and long-term inflammatory activation after polidocanol foam injection, domestic rabbits, of both sexes, weighing around 2 kg were used: a control group (injection of saline solution, n = 4) and an experimental group (injection of polidocanol foam 1 and 3 mg/kg, n = 4 each dose), administered in the lateral superficial auricular vein as a slow bolus over 1 min. foam (1 ml polidocanol 3%+ 4 ml air) 0.3 ml and 1.0 ml was injected respectively for the 1 mg/kg and the 3 mg/kg group. technetium (tc99m) lung scintigraphy was realized 15 min after injection, then the rabbits were killed and the lungs were removed for histopathological evaluation. a separated group of animals was reserved for histopathological evaluation 30 days after injection. the pulmonary perfusion showed an important reduction of pulmonary perfusion in all injected cases; while in the control group no alterations were found. the pathological exam at earlier times shows the presence of platelet-fibrin clots mainly in the small pulmonary veins, independent of the dose administered and occasional presence of droplets corresponding to fat embolism, and an acute inflammatory response. in later times it was observed chronic thrombus in small veins with mixed chronic inflammatory response, sparse or more limited. this work shows that the injection of polidocanol foam in experimental animals leads to acute and chronic alterations in pulmonary perfusion and lung inflammation. if few amounts of polidocanol foam can be deposited into the lung (in low quantity, not causing significant pulmonary embolism) it can induce inflammation in the pulmonary parenchyma. the use of rabbits does not allow using maneuvers that can reduce the incidence of embolism (leg elevation, immobility). in addition, the veins used to in the rabbits cannot reflect the veins used in humans, with a shorter time than the time needed to inactivate polidocanol. comment by stefano ricci opposed opinions are always welcome, when useful to understand open problems. however, in this case study limitations are very important. so evident lung lesions after foam injection, extremely rare in humans, may indicate that the right experiment animal has not been employed yet. it would have been interesting also to test if liquid polidocanol injection would cause some lung lesions due to this particular reaction in rabbits. furthermore, 1 ml of foam in a 2 kg (=0.5 ml × kg) animal is a very high dosage if compared to the human suggested use (6 ml = 0.1 ml × kg). same even for the lower dosage (0.15 ml × kg). comment by lorenzo tessari the paper deals with a top priority matter in foam sclerotherapy: the safety profile. for this reason its conclusions are to be considered extremely important and to be taken into account with caution because potentially influencing a really delicate topic. with these premises, some major bias must be pointed out. 1. it is obvious and already demonstrated that the bubbles reaches the lungs, but this doesn’t mean they are going to create harm in there. this was already demonstrated (morrison, parsi, tessari) in papers and worldwide meeting lectures. 2. scintigraphy only demonstrated the bubble hemodynamics pathway, not the possible induced damage. 3. conversely, the histological report of sclerotherapy-induced thrombosis/embolism is strongly biased by the excessive dosage used in the animal model described in the grandi paper. in everyday clinical practice pol maximum dosage is 0.4 mg/kg. the paper deals with dosages even 6-7 times higher! 4. materials and methods strongly influence the foam sclerotherapy performance: a more detailed description of the used methods would have been necessary in the authors’ description. 5. moreover, the rabbit ear vein is more assimilable to a reticular vein: consequently an excessive sclerosing agent dosage together with the different hemodynamics when compared with the human lower limbs one, could explain the histological findings of the authors. 6. in the results the authors claim a reduction in the pulmonary perfusion after the foam injection. as demonstrated by watkins the drug is fastly and easily inactivated by the plasma protein. the vasospasm is more probably due to an endothelial release of cathabolytes (endothelin like). 7. in the discussion the authors use a totally personal opinion when claiming that the acute alterations observed in theses animals can only be the normal dynamic of polidocanol foam bubbles… as the bubble emboli entered the heart early after foam injections. before such statement, the author should demonstrate the biocompatible gasses bubbles could, independently from the drug, cause lung damage (the same thing could happen when linked to the albumin if not). as already demonstrated by grigolato and tessari works, no pulmonary damage follow after foam sclerotherapy in humans. [top] hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: pulmonary gas exchange after foam sclerotherapy (research letter) by moro l, rossi bartoli i, cesari m, scarlata s, serino f-m, antonelli incalzi r. jama dermatol 2014;150:207-9. lorenzo tessari abstract a venous gas microembolization should lead to some loss of gas exchange surface, with consequent gas exchange abnormalities and reduction in the transfer factor of the lung for carbon monoxide (tlco). aim of this proof-of-concept study was to verify whether tlco worsens after foam sclerotherapy (fs) treatment. eleven consecutive voluntary patients [7 women and 4 men, mean age of 64 (sd=12) years], scheduled to undergo fs for varicose veins, were enrolled in the study. the patients (7 women and 4 men) had mean age of 64 (sd=12) years. respiratory function tests (rft) were performed after an overnight fasting and 24 h smoke-free using a baires computerized system. the following parameter were obtained and adjusted for hemoglobin concentration: tlco, co diffusion index (through alveolus-capillary barrier), and kco (i.e., tlco adjusted for alveolar volume). fs was performed mixing 1% polidocanol with physiological gas (70% co2, 30% o2). the mean volume of injected foam was 6 cc (standard deviation, sd=2.82) in ssv (2 cases) and 6.25 cc (sd=1.67) in gsv (9 cases). the timetable of the study was: general clinical assessment; after 10 min, rft (time 0, t0); after 10 min, sclerotherapy; after 20 min, rft (time 1, t1); after 7 days, rft (time 2, t2). none of the patients reported adverse events of the fs. no statistically significant difference across study time-points was reported for rft (all p values >0.05). lung bubble microembolism seems unlikely to complicate fs, at least if a co2/o2-based mixture (less emboligen than an air-based mixture) is used. it is possible that gas exchange modifications may occur in case of major respiratory alterations. however, the tlco parameter we adopted, is highly sensitive even to clinically silent modifications. in conclusion, bubble microembolism either is not a typical effect of fs or only minimally impact on gas exchanges. other mechanisms may be accounted for fs-related respiratory adverse effects. comment by lorenzo tessari all my congrats to the authors for the excellent work and for the objectives they gained. it was time that someone pointed out the difference among sclerotherapy adverse events that are linked to the drug and those linked to the carrier (the gas bubble) or to the release of endothelial cathabolites deriving from the drug itself (endothelin1, histamin, serotonin, etc.). in the paper the authors demonstrate that there is no link with the biocompatible soluble (co2, o2) gas for some adverse events that, even if rarely, can happen (bronchospasm, stroke, etc.) after foam sclerotherapy. nevertheless, it would have been useful to compare biocompatible gases with air. concerning the drug, australian, english and italian authors (parsi,watkins, tessari, izzo ) (1,2,3) have already demonstrated the drug inactivation as soon as it is bound by the blood proteins, a binding that occurs as soon as the sclerosing agent gets into the blood stream. surely, the sclerotherapy adverse effects can derive from the endothelial cathabolites release, as suggested by the authors, in an amount that is proportional to the endothelial treated area, as derived from the major frequency of complications following spider veins rather than saphenous trunk treatments. references 1. watkins mr. deactivation of sodium tetradecyl sulphate injection by blood proteins. eur j vasc endovasc surg 2011;41:521-5.[abstract][pubmed] 2. parsi k, exner t, low j, et al. in vitro effects of detergent sclerosants on antithrombotic mechanism. eur j vasc endovasc surg 2009;38:220-8.[abstract][pubmed] 3. tessari l, cavezzi a, izzo m, et al. in vivo demonstration of sodiumtetradecysulphate sclerosant foam binding with blood proteins. (abstract 13th annual meeting of the european venous forum, thursday 28 june–saturday 30 june 2012, florence, italy). phlebology 2012;27:307-26.[abstract] [top] hrev_master veins and lymphatics 2017; volume 6:6637 [veins and lymphatics 2017; 6:6637] [page 33] control of lower extremity edema in patients with diabetes: double blind randomized controlled trial assessing the efficacy of mild compression diabetic socks stephanie c. wu,1 ryan t. crews,1 melissa skratsky,1 julia overstreet,2 sai v. yalla,1 michelle winder,1 jacquelyn ortiz,1 charles a. andersen2 1center for lower extremity ambulatory research (clear), dr. william m. scholl college of podiatric medicine at rosalind franklin university of medicine and science, north chicago, il; 2madigan army medical center, tacoma, wa, usa introduction lower extremity edema is often an early sign of significant fluid retention that could result in cardiac overload and conditions such as heart failure and is a common clinical finding in persons with diabetes.1-3 persons with type-2 diabetes mellitus especially, have a higher prevalence of peripheral edema than healthy subjects.4,5 however, the lack of reliable measures to objectively quantify peripheral edema makes it difficult to assess the true prevalence in this population.6 once systemic pathology has been managed or ruled out, peripheral edema is most often treated with graduated compression therapy.7-9 however, patients with diabetes have a 2-5 times greater risk for developing peripheral arterial disease (pad)10-12 as compared to those without diabetes, and compression therapy has long been considered risky practice in patients with diabetes because of the fear of compromising vascularity.13-15 as a result, foot elevation as opposed to graduated compression has generally been recommended to reduce lower extremity edema in diabetic patients, and the diabetic socks currently advocated by healthcare professionals offer either no compression or minimal compression, no greater than 8-15 mmhg, to preemptively guard against exacerbating symptoms of lower extremity pad. a four-week open label pilot study involving 20 subjects with diabetes and lower extremity edema suggested diabetic socks designed to provide mild compression (18-25 mmhg) (sigvaris inc, peachtree city, ga, usa) can be used to decrease lower leg edema without compromising vascular flow.16 the primary objective of this five week, multi-center, double blind randomized controlled trial was to assess the effectiveness of a diabetic sock that provides mild compression (18-25 mmhg) as compared to a non-compression diabetic sock in patients with both diabetes and lower extremity edema. the secondary objective was to assess the effect of the mild compression diabetic sock versus the noncompression diabetic sock on lower extremity macro and microcirculation. materials and methods 80 subjects with le edema and diabetes were randomized to receive either mildcompression knee high diabetic socks (1825 mmhg) or non-compression knee high diabetic socks. subjects were instructed to wear the socks during all waking hours. follow-up visits occurred weekly for four consecutive weeks. edema was quantified through midfoot, ankle, and calf circumferences and cutaneous fluid measurements. vascular status was tracked via ankle brachial index (abi), toe brachial index (tbi), and skin perfusion pressure (spp). results 77 subjects (39 controls and 38 mildcompression subjects) successfully completed the study. there were no statistical differences between the two groups in terms of age, body mass index, gender, and ethnicity. repeated measures analysis of variance and sidak corrections for multiple comparisons were used for data analyses. subjects randomized to mild-compression diabetic socks demonstrated significant decreases in calf and ankle circumferences at the end of treatment as compared to baseline. le circulation did not diminish throughout the study with no significant decreases in abi, tbi or spp for either group. conclusions results of this rct suggest that mild compression diabetic socks may be effectively and safely used in patients with diabetes and le edema. references 1. eberth-willershausen w, marshall m [prevalence, risk factors and complications of peripheral venous diseases in the munich population]. hautarzt 1984;35:68-77. 2. yu gv, schubert ek, khoury we. the jones compression bandage. review and clinical applications. j am podiatr med assoc 2002;92:221-31. 3. chantelau e. [symptom veiled by polyneuropathy. swollen foot in diabetes mellitus]. mmw fortschr med 2006;148:46-7. 4. messerli fh. vasodilatory edema: a common side effect of antihypertensive therapy. am j hypertens 2001;14:9789. 5. mudaliar s, chang ar, henry rr. thiazolidinediones, peripheral edema, and type 2 diabetes: incidence, pathophysiology, and clinical implications. endocr pract 2003;9:406-16. 6. brodovicz kg, mcnaughton k, uemura n, et al. reliability and feasibility of methods to quantitatively assess peripheral edema. clin med res correspondence: stephanie c. wu, center for lower extremity ambulatory research (clear), dr. william m. scholl college of podiatric medicine at rosalind franklin university of medicine and science, north chicago, il, usa. e-mail: stephanie.wu@rosalindfranklin.edu acknowledgments: the study was also partially supported by grant number 2t35dk074390 from the national institute of diabetes and digestive and kidney disease. the content is solely the responsibility of the authors and does not represent the official views of the national institute of diabetes and digestive and kidney diseases of the national institutes of health. funding: the study was funded by a grant from sigvaris inc (peachtree city, ga) the manufacturer of the mild-compression socks. the sponsor played no role in the conduct of the study, the analysis of the data, nor the drafting of this manuscript. conflict of interest: the authors declare no potential conflict of interest. conference presentation: results from the study were previously published in abstract form in: diabetes 2015;64(s1):a37. doi: 10.2337/db15-1-38. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright s.c. wu et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6637 doi:10.4081/vl.2017.6637 no n c om me rci al us e o nly conference presentation [page 34] [veins and lymphatics 2017; 6:6637] 2009;7:21-31. 7. armstrong dg, nguyen hc. improvement in healing with aggressive edema reduction after debridement of foot infection in persons with diabetes. arch surg 2000;135:1405-9. 8. gardner amn, fox rh. the return of blood to the heart: venous pumps in health and disease. london: john libbey; 1989. 9. gaskell p, parrott jcw. the effect of a mechanical venous pump on the circulation of the feet in the presence of arterial obstruction. surg gyn obst 1978;146:583-92. 10. akbari cm, logerfo fw. diabetes and peripheral vascular disease. j vasc surg 1999;30:373-84. 11. banga jd. lower extremity arterial disease in diabetes mellitus. diab rev int 1994;3:6-11. 12. dinh t, scovell s, veves a. peripheral arterial disease and diabetes: a clinical update. int j low extrem wounds 2009;8:75-81. 13. eneroth m, persson bm. amputation for occlusive arterial disease, a propsective multicenter study of 177 amputees. int orthop 1992;16:383-7. 14. pawlaczyk k, gabriel m, urbanek t, et al. effects of intermittent pneumatic compression on reduction of postoperative lower extremity edema and normalization of foot microcirculation flow in patients undergoing arterial revascularization. med sci monit 2015;21:398692. 15. park dj, han sk, kim wk. is the foot elevation the optimal position for wound healing of a diabetic foot? j plast reconstr aesthet surg 2010;63:561-4. 16. wu sc, crews rt, najafi b, et al. safety and efficacy of mild compression (18-25 mm hg) therapy in patients with diabetes and lower extremity edema. j diabetes sci technol 2012;6:641-7. no n c om me rci al us e o nly hrev_master veins and lymphatics 2014; volume 3:4632 [veins and lymphatics 2014; 3:4632] [page 89] internal jugular vein narrowing and body mass index in healthy individuals and multiple sclerosis patients christopher magnano,1,2 pavel belov,1 jacqueline krawiecki,1 jesper hagemeier,1 robert zivadinov1,2 1department of neurology, buffalo neuroimaging analysis center, school of medicine and biomedical sciences, university at buffalo, buffalo, ny; 2mri clinical and translational research center, school of medicine and biomedical sciences, university at buffalo, buffalo, ny, usa abstract internal jugular vein (ijv) narrowing has been implicated in central nervous system (cns) disorders. body mass index (bmi) is a cardiovascular risk factor that has been also linked to cns diseases, however it is unknown whether a relationship exists between ijv narrowing and bmi. the objectives were to assess the relationship between ijv cross-sectional areas (csa) and bmi in healthy individuals (hi) and multiple sclerosis (ms) patients. a total of 388 subjects (194 ageand sexmatched hi and ms patients) received magnetic resonance venography and structural brain magnetic resonance imaging at 3t. region of interest analysis was performed using a semiautomated contouring-thresholding technique to determine the minimum csa of the ijvs at c2/c3, c5/c6, and c7/t1 cervical levels. partial correlation analyses were used to determine the associations. increased bmi was related to increased ijv csa at lower cervical levels (r=0.240, p<0.0001 at c5/c6 and r=0.293, p<0.0001 at c7/t1) in both ms patients and hi. both ms and hi, showed associations between increased bmi and ijv csa measures, particularly at lower cervical locations, in individual group analyses. no differences in association between bmi and ijv csa were observed between hi and ms patients. relationship between ijv csa and bmi were not significant at upper cervical locations in the studied groups. increased bmi is associated with ijv csa widening, rather than narrowing, at lower cervical levels in both ms patients and hi. this finding warrants further investigation, but indicates that bmi can obscure interpretation of ijv csa narrowing. introduction blood is supplied to the brain and spinal cord by two sets of branches from the dorsal aorta.1 the vertebral arteries arise from the subclavian arteries, while the internal carotid arteries branch from the common carotid arteries.1 deoxygenated blood is drained from the brain and spinal cord by the venous system, particularly the internal jugular veins (ijvs), which connect the sinuses to the vena cava.2,3 the cerebral venous system is considered most important contributor for maintenance of adequate brain perfusion, in order to meet the metabolic needs necessary for normal cerebral function.2 venous drainage from the cerebral hemispheres consists of two systems: the superficial, which drains blood from the cortex and superficial white matter by cortical veins, and is collected by the dural sinuses;4 and the deep venous system, which contains approximately 70% of the total blood volume, and incorporates small veins and venules for the majority of its composition.4 in contrast to the symmetric arterial system, the venous system is asymmetric and highly heterogeneous.4 ijv morphology has previously been investigated with respect to aging and gender differences in healthy individuals (hi),5,6 in addition to a number of central nervous system (cns) diseases, including multiple sclerosis (ms), alzheimer’s disease and parkinson’s disease.4 numerous recent studies have focused on morphological and hemodynamic venous jugular flow abnormalities in ms patients and his.4,7-11 however, it is unknown at this time whether the ijv narrowing has any pathological significance, or is just a normal physiologic variant. body mass index (bmi) is a standard measure of degree of obesity. it is also a cardiovascular risk factor that has been linked to cns diseases.12-15 we hypothesized that, as a result of obesity, we would find a reduced ijv crosssectional area (csa) due to venous constriction in subjects with large bmis. venous narrowing can be caused either directly due to intraluminal defects or hypoplasia, or as a result of blockages such as venous thrombosis.13,16 as bmi is linked with increased risk of cns diseases, we expected to find more pronounced narrowing in a cohort of ms patients when compared with his. we were also interested to explore the cervical level at which csa reduction would impact these associations. therefore, we examined the relationship between the ijv csa at three different cervical levels in healthy and diseased subjects with a spectrum of body mass indices. materials and methods subjects this prospective, single-center, cross-sectional study included 388 subjects, with 194 consecutive his with no evidence of neurological disease and 194 consecutive relapsing remitting (rr) ms patients being enrolled (matching 1:1). inclusion criteria included completion of magnetic resonance imaging (mri) screening to ensure no mri-prohibitive medical history. cardiovascular risk factors were collected from all participants in-person by a trained interviewer with cross-examination of medical records. all participants were assessed with a structured environmental questionnaire containing information about medical history (illnesses, surgeries, medications, etc.), as well as cardiovascular risks, including history of hypertension, smoking, or heart disease (which was defined to include congestive heart failure, heart attack, arrhythmia, valvular disease, heart murmurs, enlarged heart, heart surgeries, palpitations, or any other category that would necessitate medical therapy). height and weight were assessed to determine bmi. physical and neurological examination were obtained in all study particpants. all subjects were required to meet the health screen requirements on physical examination and history of known vascular abnormalities also precluded enrollment in correspondence: robert zivadinov, department of neurology, school of medicine and biomedical sciences, buffalo neuroimaging analysis center, 100 high st., buffalo, ny 14203, usa. tel. 716.859.3579 fax: 716.859.4005. e-mail: rzivadinov@bnac.net key words: healthy individuals, multiple sclerosis, internal jugular veins, cross-sectional area, body mass index, magnetic resonance imaging, magnetic resonance venography. conflict of interests: the authors declare no potential conflict of interests. funding: rz received funding for consultancy from teva pharmaceuticals, biogen idec., emd serono, novartis, sanofi-genzyme. received for publication: 29 july 2014. revision received: 28 october 2014. accepted for publication: 20 november 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright c. magnano et al., 2014 licensee pagepress, italy veins and lymphatics 2014; 3:4632 doi:10.4081/vl.2014.4632 no n c om me rci al us e o nly article [page 90] [veins and lymphatics 2014; 3:4632] the study. his were recruited among hospital personnel and local advertisement respondents, while the ms patients were enrolled at the center specialized for demyelinating diseases. all study experiments were performed in accordance with the relevant guidelines and regulations. the study was approved by the local institutional review board, and informed consent was obtained from all subjects. image acquisition all subjects were examined on a ge 3.0t signa excite hd 12.0 twin speed 8-channel scanner (general electric, ge, milwaukee, wi, usa) with a maximum slew rate of 150t/m/s and maximum gradient amplitude in each orthogonal plane. a 2-dimensional magnetic resonance venography (mrv) sequence was acquired for all ijv csa measurements. the mrv was acquired with 150, 1.5mm-thick slices using a 320¥192 matrix (frequency x phase) with a 22.0 cm field of view (fov) and a phase field of view (pfov) of 75% for a resolution of .69¥1.15¥1.5 mm3. additional imaging parameters included echo time (te)/repetition time (tr)/flip angle (fa) of 4.3 ms/14 ms/70°, and a bandwidth (bw) of 31.25 khz, for a total acquisition time of 5:19 min. mrv was acquired in a true (non-obliqued) axial orientation with one average, and no parallel imaging techniques were employed. a 2-dimensional fluid-attenuated inversion-recovery (flair) sequence was acquired for assessment of t2 hyperintense lesion pathology. flair scans were 3-mm thick slices with no gap, te/ti/tr=120/2100/ 8500 ms, flip angle=90°; with a 256¥256 matrix and a 25.6 cm fov for an in-plane resolution of 1x1 mm2 with a phase fov of 75% and one average. image analyses cross-sectional area analyses ijv assessment was performed using csa region of interest (roi) analysis on the 2d mrv with the java image manipulation tool (jim) version 5.0 (http://www.xinapse.com) at specific cervical locations blinded to the subjects’ status. briefly, the sequence was viewed orthogonally to assess which slices corresponded to the desired anatomical coverage, namely c2-c3, c4, c5-c6, and c7-t1. within each of these locations, the operator determined the slice on which the ijv came to a minimum, and then used the roi toolkit to select the right and left ijvs. most commonly, this was accomplished using the contour roi tool, using the automated preview contours tool to best select its edges. when necessary, the operator manually adjusted the roi boundary. reproducibility was assessed using two operators performing csa analysis on a set of 25 mrvs twice, with analyses a minimum of 2 weeks apart. operators were blinded to each other’s roi assessments, as well as to their own prior set of rois. intraand inter-operator reproducibility was assessed using the intra-class correlation (icc), with corresponding pand q-values. t2 hyperintense lesion determination t2-weighted hyperintense lesion number and volume were assessed using a semiautomated edge detection contouring/thresholding technique on flair images.17 statistical analysis statistical analyses were performed using the statistical package for social sciences (ibm inc, version 21.0). the demographic and clinical differences between genders were tested using student’s t-test and chi-square tests. bmi and csa measures were compared using partial correlation analyses. group comparisons were calculated using student’s ttest. due to multiple comparisons, only a nominal p-value<0.01, was considered statistically significant using two-tailed tests. table 1. demographic and clinical characteristics of healthy individuals and multiple sclerosis patients. total (n=388) hi (n=194) ms (n=194) p-value age° 42.6 (15.8) 44 43.0 (17.5) 46 42.2 (13.9) 43 0.629** sex (m/f) 126/262 63/131 63/131 1.00** bmi 26.8 (5.7) 25.8 26.8 (5.7) 25.8 26.8 (5.8) 25.8 0.938** heart disease 51/264 (16.2%) 20/142 (12.3) 31/122 (20.3) 0.074** hypertension 57/263 (17.8%) 19/150 (11.2) 38/113 (25.2) 0.001* smoking 132/205 (39.2%) 58/122 (32.2) 74/83 (47.1) 0.006* number of subjects with 246/121 (67) 65/119 (35.3) 181/2 (98.9) <0.0001* t2° hyperintense lesions number of t2° 15.4 (20.5) 7 2.8 (7.1) 0 28.1 (21.8) 22 <0.0001* hyperintense lesions volume of t2° 5.79 (11.5) 0.581 0.248 (1.13) 0 11.4 (14.2) 5.84 <0.0001* hyperintense lesions (ml) age° at onset n/a n/a 31.0 (12.8) 30.0 n/a disease duration in years n/a n/a 12.0 (9.4) 10.0 n/a edss n/a n/a 2.5 (1.3) 2.0 n/a hi, healthy individuals; ms, multiple sclerosis; bmi, body mass index; edssexpanded disability status scale. p-values were calculated using student’s t-test and chi-square tests: *p-values less than 0.01 considered significant; **p-values less than 0.05 were considered trends. °age and t2 lesion characteristics are presented as mean (standard deviation) median. categorical variables (cardiovascular risk factors) are #yes/total # (%). table 2. internal jugular vein cross-sectional area values and standard deviations in healthy individuals and multiple sclerosis patients across multiple cervical locations. all subjects hi ms p-value c7/t1 115.9 (73.2) 118.0 (79.3) 113.8 (66.6) 0.575 c5/c6 95.3 (58.5) 97.4 (60.2) 93.2 (56.7) 0.473 c2/c3 66.1 (29.4) 66.7 (31.4) 65.5 (27.2) 0.691 hi, healthy individuals; ms, multiple sclerosis. the cross-sectional area is expressed in millimeter square. values reported are mean (standard deviation). p-values were calculated using student’s t-test and chi-square tests. table 3. association of internal jugular vein cross-sectional area and body mass index in healthy individuals and multiple sclerosis patients across multiple cervical locations. all subjects hi ms age vs bmi 0.169 (0.002)* 0.062 (0.416)** 0.262 (0.001)* c7/t1 0.293 (0.000)* 0.294 (0.000)* 0.296 (0.000)* c5/c6 0.240 (0.000)* 0.247 (0.001)* 0.234 (0.002)* c2/c3 0.045 (0.411)** 0.078 (0.324)** 0.009 (0.909)** hi, healthy individuals; ms, multiple sclerosis; bmi, body mass index. values reported are partial correlations (p-value). *p-values less than 0.01 considered significant; **p-values less than 0.05 were considered trends. no n c om me rci al us e o nly article [veins and lymphatics 2014; 3:4632] [page 91] results demographic characteristics demographic characteristics are presented in table 1. hi and ms subjects were ageand sex-matched. as expected, significant differences were found between his and ms subjects in terms of cardiovascular risk factors, smoking, and number and volume of t2 hyperintense lesions. bmi was not significantly different between the study groups. the ms patients were on disease-modifying treatment including interferon b 1a, glatiramer acetate and natalizumab. reproducibility of the crosssectional area measurement interand intra-operator reproducibility was found to be highly significant with strong icc values and corresponding p-values (icc>0.69 for inter-operator with p<0.001, and icc>0.84 for intra-operator, with p<0.001 at all levels and for all operators). internal jugular vein cross-sectional area morphology ijv csas was greater at lower cervical levels, ranging from a mean of 66.1 mm2 at c2/c3 to115.9 mm2 at c7/t1. breakdown at each level is shown in table 2. cross-sectional area correlations with body-mass index as shown in table 3, greater ijv csa was strongly correlated with increased bmi (r≥0.234, p≤0.002 for all) at lower cervical levels (c5/c6 and c7/t1), whereas this association was not detected at upper cervical levels (c2/c3 nor c4). the association was significant in all subjects, as well as individually in hi and ms patients groups. there were no differences between the study groups, as the associations were similar in terms of strength and significance, irrespective of disease status (tables 2 and 3; figure 1). age interaction with cross-sectional area association with body-mass index as shown in table 3, bmi was associated with age in all subjects (r=0.169, p=0.002) and in ms patients (r=0.262, p=0.001). bmi was not associated with age in hi (r=0.062, p=0.416). however, the bmi and ijv csa association was found to be age independent in partial correlation analysis, across all groups (data not shown). figure 1. associations between body mass index (bmi) and cross-sectional area at levels c7/t1 (a, b, c), c5/c6 (d, e, f), and c2/c3 (g, h, i). no n c om me rci al us e o nly article [page 92] [veins and lymphatics 2014; 3:4632] discussion we investigated the association of ijv csa on mrv with bmi in ms patients and his, and found a relationship between the two at the lower cervical levels, independent of any age effects. findings were similar in both his and ms patients, suggesting that this relationship is independent of the disease state. while our initial hypothesis was that ijv narrowing would be associated with increased bmi, actually the results showed the opposite; namely, that as the bmi increased, so did the ijv csa. these findings suggest that the more obese a subject is, rather than narrowing, their ijv csa is actually enlarging. this could be due to the fact that, assuming a constant volume of blood to pump, that more obese subjects will thus have lower flow rates, although our study was limited to only structural and did not include functional outcomes. as subjects with larger bmis tend to be more sedentary and less mobile, their oxygen demand will decrease, and thus both their oxygen supply via arterial blood, as well as deoxygenated clearance via the venous system, will decrease, leading to reduced flow rates. while our hypothesis was that the location of vascular assessment would play a role in ijv csa, this was only true to a point: c5/c6 and c7/t1 had a similar relationship with bmi, whereas c2/c3 did not. we suspect that this may be due to the fact that there is a high degree of heterogeneity at upper cervical levels (c2-c3), as evidenced by the increased prevalence of collaterals. since the correlations between ijv csa and bmi seem to be indicative of total flow at lower levels (where the vast majority of venous flow is drained through the ijvs), it is possible that the exclusion of additional venous collateral assessment could be confounding our results at upper cervical levels. therefore further exploration is warranted regarding this issue. age and bmi were associated across the entire cohort and in the ms patients, but not in the his. however, we speculate that the fact that bmi and csa relationship was age independent in hi, suggests that the age dependence of bmi in ms patients may be due to decreased level of activity, rather than strictly age, and would warrant further study. while we also investigated differences in association between ijv csa and bmi between ms patients and hi, none was observed, consistent with other groups’ findings.18-20 this suggests that csa and bmi measures are unrelated to the disease status. any differences are most likely functional (i.e. flow-related) rather than structural (i.e. due to morphology). this study was limited in scope to structural assessment of the ijvs; flow quantification can provide additional information, as other groups are currently investigating. additionally, our study had several other limitations. the focus on the ijv csa neglected any collateral flow; future work should examine collateral vein measures, particularly at upper cervical locations. it would be also interesting to examine the level of activity, in order to explore how this affects the relationship between ijv csa and bmi in ms and his. this work only examined the minimum csa at each cervical location, and an automated analysis of the csa at each slice would offer a more volumetric approach. moreover, only rr ms patients were enrolled in the study, in order to allow agematching with hi. it could be that secondaryprogressive ms patients show different relationship between ijv csa and bmi. even within only examining structural involvement, the mrv technique we used is beneficial for detecting venous compression, but intra-luminal restrictions may be concealed; use of doppler technique may be useful in this direction. conclusions increased bmi is associated with ijv csa widening, rather than narrowing, at lower cervical levels in both ms patients and hi. this finding warrants further investigation, but indicates that bmi can obscure interpretation of ijv csa narrowing. references 1. purves d, williams sm. neuroscience, 2nd ed. sunderland, ma: sinauer associates; 2001. 2. schaller b. physiology of cerebral venous blood flow: from experimental data in animals to normal function in humans. brain res brain res rev 2004;46:243-60. 3. ciuti g, righi d, forzoni l, et al. differences between internal jugular vein and vertebral vein flow examined in real time with the use of multigate ultrasound color doppler. ajnr am j neuroradiol 2013;34:2000-4. 4. zivadinov r, chung cp. potential involvement of the extracranial venous system in central nervous system disorders and aging. bmc med 2013;11:260. 5. gur rc, mozley pd, resnick sm, et al. gender differences in age effect on brain atrophy measured by magnetic resonance imaging. proc natl acad sci usa 1991;88:2845-9. 6. resnick sm, pham dl, kraut ma, et al. longitudinal magnetic resonance imaging studies of older adults: a shrinking brain. j neurosci 2003;23:3295-301. 7. zivadinov r, marr k, cutter g, et al. prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in ms. neurology 2011;77:138-44. 8. zamboni p, galeotti r. the chronic cerebrospinal venous insufficiency syndrome. phlebology 2010;25:269-79. 9. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:392-9. 10. zamboni p, menegatti e, occhionorelli s, salvi f. the controversy on chronic cerebrospinal venous insufficiency. veins and lymphatics 2013;2:e14. 11. sisini f, gianesini s, menegatti e, et al. on the consistency of flow rate color doppler assessment for the internal jugular vein. veins and lymphatics 2014;3:1863. 12. kim ay, rhim h, park m, et al. venous thrombosis after radiofrequency ablation for hepatocellular carcinoma. ajr am j roentgenol 2011;197:1474-80. 13. stam j. thrombosis of the cerebral veins and sinuses. n engl j med 2005;352:1791-8. 14. stambo gw, grauer l. transhepatic portal venous power-pulse spray rheolytic thrombectomy for acute portal vein thrombosis after ct-guided pancreas biopsy. ajr am j roentgenol 2005;184:s118-9. 15. kim sa, lim sy. a case of stent thrombosis occurred at 5 years after sirolimus-eluting stent implantation. chonnam med j 2011;47:124-6. 16. lim bg, kim ym, kim h, et al. internal jugular vein thrombosis associated with venous hypoplasia and protein s deficiency revealed by ultrasonography. j anesth 2011;25:930-4. 17. zivadinov r, heininen-brown m, schirda cv, et al. abnormal subcortical deep-gray matter susceptibility-weighted imaging filtered phase measurements in patients with multiple sclerosis: a case-control study. neuroimage 2012;59:331-9. 18. zaniewski m, kostecki j, kuczmik w, et al. neck duplex doppler ultrasound evaluation for assessing chronic cerebrospinal venous insufficiency in multiple sclerosis patients. phlebology 2013;28:24-31. 19. farina m, novelli e, pagani r. cross-sectional area variations of internal jugular veins during supine head rotation in multiple sclerosis patients with chronic cerebrospinal venous insufficiency: a prospective diagnostic controlled study with duplex ultrasound investigation. bmc neurol 2013;13:162. 20. krsmanovic z, zivkovic m, lepic t, et al. small internal jugular veins with restricted outflow are associated with severe multiple sclerosis: a sonographer-blinded, case-control ultrasound study. bmc neurol 2013;13:90. no n c om me rci al us e o nly hrev_master veins and lymphatics 2014; volume 3:1867 [veins and lymphatics 2014; 3:1867] [page 81] cerebral venous outflow and cerebrospinal fluid dynamics clive b. beggs medical biophysics laboratory, university of bradford, uk abstract in this review, the impact of restricted cerebral venous outflow on the biomechanics of the intracranial fluid system is investigated. the cerebral venous drainage system is often viewed simply as a series of collecting vessels channeling blood back to the heart. however there is growing evidence that it plays an important role in regulating the intracranial fluid system. in particular, there appears to be a link between increased cerebrospinal fluid (csf) pulsatility in the aqueduct of sylvius and constricted venous outflow. constricted venous outflow also appears to inhibit absorption of csf into the superior sagittal sinus. the compliance of the cortical bridging veins appears to be critical to the behaviour of the intracranial fluid system, with abnormalities at this location implicated in normal pressure hydrocephalus. the compliance associated with these vessels appears to be functional in nature and dependent on the free egress of blood out of the cranium via the extracranial venous drainage pathways. because constricted venous outflow appears to be linked with increased aqueductal csf pulsatility, it suggests that inhibited venous blood outflow may be altering the compliance of the cortical bridging veins. introduction traditionally, the cerebral venous drainage system has been viewed simply as a network of collecting vessels channeling blood from the brain to the heart; with the result its regulatory role has tended to be over-looked. however, in recent years there has been renewed interest in the cerebral venous drainage system, because of the discovery of the vascular syndrome chronic cerebrospinal venous insufficiency (ccsvi),1 which is characterized by restricted cerebral venous outflow and increased hydraulic resistance to blood flow back to the heart.2 although the subject of ccsvi has been mired with controversy,3 with many disputing the validity of the syndrome,4-6 there is increasing evidence that venous drainage anomalies may be associated with physiological changes in the intracranial space.7,8 this has precipitated renewed interest in the role that venous anomalies might play in neurological disease,9 something which has highlighted the close link between the venous drainage system and the dynamics of the cerebrospinal fluid (csf) system.10 in this review we investigate the link between restricted cerebral venous outflow and the biomechanics of the csf system. intracranial fluid volume regulatory mechanism being encased in a rigid enclosure, the brain employs a complex intracranial fluid regulatory mechanism to control the pulsatility of blood flow through the cerebral vascular bed.11-13 this system utilizes a sophisticated windkessel mechanism to compensate for the transient increases in arterial blood volume that occur during systole, by displacing an approximately equal volume of csf out of the cranium into the spinal column14 (figure 1). as such, the system maintains monro-kellie homeostasis and ensures that the flow of blood through the cerebral capillary bed is smooth and non-pulsatile in healthy young adults.11,15 the whole system is driven by volumetric changes in the arterial pulse, which are transferred to the csf, causing it to pulse backwards and forwards across the foramen magnum (fm). although in healthy young adults blood flow through the cerebral capillary bed is normally free of any pulse, by the time it reaches the dural sinuses it once again exhibits pulsatile characteristics.11,16 this suggests that the csf pulse interacts with the venous flow somewhere in the cranium to regulate blood outflow. while this mechanism has generally been thought to be a passive interaction,10 recent evidence has emerged to suggest that active venoconstriction of the large extracranial veins may also play a part in the regulatory process.17 deeper insights into the dynamics of the intracranial fluid system can be gained by considering how the fluid flows in and out of the cranium vary over the cardiac cycle. transient arterial, venous, and csf flows in and out of the cranium are illustrated in figure 2, which shows the cervical pulses for a typical healthy individual.16 from this it can be seen that the system is driven by the arterial pulse, which as it enters the cranium during systole greatly increases the volume of blood in the pial arteries.18 this peaks at about 0.23 of the cardiac cycle and is closely followed by the peak in csf flow through the fm, which occurs at 0.28 of the cardiac cycle. finally, in late systole at about 0.35 of the cardiac cycle, there is a peak in the venous blood flow leaving the cranium. figure 2 also shows the csf pulse in the aqueduct of sylvius (aos), which in comparison to the cervical csf pulse, exhibits a much smaller amplitude and is out of phase. from figure 2 it can be seen that during diastole there is a decrease in the venous blood flow rate leaving the cranium. given that blood flow through the cerebral capillary bed remains relatively constant throughout the cardiac cycle, this implies that during diastole, venous blood is being stored somewhere in the cranium, only to be rapidly ejected during systole. while the physiological mechanisms associated with this strange phenomenon are poorly understood, it is known that approximately 70% of intracranial blood volume is located within the venous compartments,19 many of which are thin-walled veins that can readily expand and collapse with small changes in transmural pressure.20,21 it is therefore likely that blood is stored in these vessels during diastole. a number of researchers have reported the presence of regulatory sphincters,22,23 which control the discharge from these veins into the superior sagittal sinus (sss), and it has been postulated that constriction of these sphincters causes the cortical veins to engorge and puff out, before periodically discharging into the sss.23 evidence supporting this hypothesis comes from greitz24 and nakagawa et al.,25 who both observed the pulsatile compression of cortical bridging veins by the sub-arachnoid csf. correspondence: clive b. beggs, medical biophysics laboratory, school of engineering, university of bradford, bradford, west yorkshire bd7 1dp, united kingdom. tel.: +44.0.1274.233679 fax: +44.0.1274.234124. e-mail: c.b.beggs@bradford.ac.uk key words: cerebral venous drainage, cerebrospinal fluid, chronic cerebrospinal venous insufficiency, intracranial pressure, normal pressure hydrocephalus, multiple sclerosis. acknowledgments: clive beggs received a travel grant from the annette funicello research fund for neurological diseases. received for publication: 7 august 2013. revision received: 27 october 2014. accepted for publication: 4 november 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright c.b. beggs, 2014 licensee pagepress, italy veins and lymphatics 2014; 3:1867 doi:10.4081/vl.2014.1867 no n c om me rci al us e o nly review [page 82] [veins and lymphatics 2014; 3:1867] cerebrospinal fluid bulk flow in addition to the csf pulse, there is a slow bulk flow of csf from the choroid plexus (cp) to the sss, via the arachnoid villi (av), driven by the pressure gradient between the two. while it used to be assumed that all the csf was absorbed through the av into the sss,26-28 it is now thought that some csf drains to the lymph nodes via nasal lymphatics.29 in animals, as much as 50% of csf drains to the lymph nodes,30,31 whereas in adult humans a greater proportion appears to drain directly into the venous blood via the av,29,31 with lymphatic drainage playing only a minor role.29 the sss acts as a collecting vessel for csf from the sub-arachnoid space (sas). csf absorption into the sss via the av, which has been measured in the range 4.5-9.4 mm3/s in healthy individuals,26 is very susceptible to changes in the pressure difference between the sas and sss.26-28 in a study involving 100 healthy adults, ekstedt26 demonstrated that there is a linear relationship between this pressure difference and csf absorption through the av, with the average rate of absorption being 2.397 mm3/s/mmhg. they measured the mean csf pressure in the sas [i.e. the intracranial pressure (icp)] as being 10.35 mmhg when supine, and calculated that the mean pressure in the sss was 7.57 mmhg, which equates to a mean pressure drop of 2.78 mmhg across the av. csf is produced in the cp, which are located in the walls of the third, fourth and lateral ventricles. the endothelium of the cp is leaky, with no tight junctions, allowing the transfer of fluid (water) between the blood vessels and the csf.32 a number of researchers have attempted to quantify csf production rates in humans. cutler et al.27 in a study involving children with sclerosing panencephalitis and pontine glioma, measured the mean rate of formation of csf to be 5.83 mm3/s. in a similar study, lorenzo et al.33 found the mean csf production rate in healthy children to be 6.00 mm3/s. it is possible to obtain a rough estimate of the csf production rate by monitoring the flow of csf through the aos and calculating the difference between the net negative csf flow (nnf) in the caudal direction and the net positive flow (npf) towards the third ventricle. using this methodology, magnano et al.34 found the bulk aqueductal csf flow in healthy adults to be 7.1 mm3/beat (approximately 8.28 mm3/s), whereas beggs et al.7 and gorucu et al.35 in similar studies found mean flow to be 4.0 mm3/beat (approximately 4.65 mm3/s) and 2.17 mm3/s, respectively. given that measured csf production rates appear to be of similar magnitude to absorption rates through the av, it suggests that lymphatic drainage of csf plays only a relatively minor role in humans. link between venous outflow and cerebrospinal fluid dynamics a number of studies have linked constricted venous outflow with changes in the dynamics of the cerebrospinal fluid system.7,8,36 under normal circumstances, in healthy individuals the csf npf per heartbeat is slightly less than the csf nnf, with the mathematical difference between nnf and npf representing the bulk flow percolating through the ventricles. in a magnetic resonance imaging (mri) study involving 67 multiple sclerosis (ms) patients and 35 healthy controls, magnano et al.36 observed a significant 48% mean decrease in bulk csf flow in the patients with ms and a 45% increase in mean npf. mean nnf was also increased in the ms patients, although this was not significant. similar results were obtained by gorucu et al.,35 who also investigated ms patients. however, although these studies associated altered csf dynamics with ms, they did not observe the venous characteristics of the subjects. by contrast, zamboni et al.8 investigated ms patients who were diagnosed with ccsvi. as with the other studies, they observed a large reduction in bulk csf flow and a tendency towards increased aqueductal pulsatility in ms patients compared with healthy controls. this suggested that in ms patients retrograde venous hypertension in the dural sinuses may be inhibiting absorption of csf into the sss, reducing bulk flow and altering aqueductal pulsatility.10 this opinion is reinforced by the findings of an interventional study in which venous angioplasty was performed on ms patients with ccsvi.37 prior to the intervention, these patients exhibited increased csf pulsatility in the aos, which was lessened when the restricted venous outflow pathways were opened up. if altered csf dynamics in patients with ms is due to constricted venous outflow, then one might expect the same phenomenon to be observed in healthy individuals diagnosed with ccsvi. in order to test this hypothesis, beggs et al.7 performed a study on healthy individuals not related to ms patients. the findings of this study were similar to those of magnano et al.,36 figure 1. hydrodynamic model of the intracranial space, showing the interactions between the arterial and venous blood flows and the cerebrospinal fluid (csf). sss, superior sagittal sinus; sts, straight sinus; sas, sub-arachnoid space; av, arachnoid villi; cp, choroid plexus; fm, foramen magnum; wm, windkessel mechanism; sr, staling resistor; vl, lateral ventricle; v3, third ventricle; v4, fourth ventricle; aos, aqueduct of sylvius; ijvs, internal jugular veins; vvs, vertebral veins. (courtesy of biomed central, the original publisher10). no n c om me rci al us e o nly review [veins and lymphatics 2014; 3:1867] [page 83] and revealed a statistically significant 32% increase in csf npf in the ccsvi positive subjects, compared with the ccsvi negative individuals, with a tendency towards reduced csf bulk flow. as such, they suggested that ccsvi is associated with altered csf dynamics, irrespective of whether on not ms is present, reinforcing the opinion that increased aqueductal csf pulsatility is primarily a biomechanical phenomenon associated with restricted venous outflow from the cranium. increased cerebral blood flow pulsatility has been linked with microstructural white matter (wm) damage.38-40 increased pulsatility in the cerebral vascular bed is indicative of decreased arterial compliance, and is associated with arteriosclerosis41 and hypertension.42 hyper ten sion, a known risk factor for small vessel disease43 and leukoaraiosis (la),44 is thought to be associated with changes in vascular mechanics.38,42 it has been suggested15 that increased vascular pulsatility might cause wm damage indicative of early stage la.39 bateman11 found blood flow through the wm to be highly pulsatile in individuals with la and concluded that this would increase endothelial shear stress, which in turn would cause wm damage.15 jolly et al.39 found both increased blood flow pulsatility and increased aqueductal csf pulse volume to be associated with microstructural wm changes in elderly subjects. daouk et al.45 found apparent diffusion coefficient, an early indicator of microstructural changes, to be strongly correlated with aqueductal stroke volume in alzheimer’s disease (ad) patients. furthermore, magnano et al.34 found increased aqueductal pulse to be associated with more severe t1 and t2 lesion volumes in ms patients. this raises intriguing questions about the relationship between vascular pulsatility and aqueductal csf pulsatility. greitz46 postulated a link between increased pulsation in the cerebral vascular bed and csf pulsatility in the aos, arguing that pulsations in the cerebral capillaries were transmitted through the parenchyma to the lateral ventricles. however, beggs et al.7 demonstrated that increased aqueductal pulsatility is associated with constricted cerebral venous outflow in healthy adults, suggesting that other mechanisms may be at work. contrary to greitz, beggs argued that impairment of cerebral venous outflow would induce retrograde hypertension in the dural sinuses, reducing intracranial compliance and resulting in altered csf dynamics.10 there is evidence that occlusion of the venous drainage pathways can cause blood to accumulate within the cranium, something that theoretically could alter intracranial compliance. in an experiment involving healthy subjects, kitano et al.47 showed that compression of the internal jugular veins (ijvs) resulted in a 5-20% increase intracranial blood volume. frydrychowski et al.18 also performed bilateral compression of the ijvs on healthy individuals and found that it caused a reduction in the width of the sas a finding consistent with the storage of blood in the cortical veins. furthermore, in a recent study involving ad patients, beggs et al.48 found jugular venous reflux to be strongly associated with increased brain parenchyma volume, something that they postulated was possibly due to blood retention within the brain. because csf is incompressible, any reduction in the compliance of the cortical bridging veins due to blood retention should, in theory, impact on the windkessel mechanism smoothing blood flow to the cerebral vascular bed. evidence to support this, comes from the study by frydrychowski et al.18 who observed that during compression of the ijvs, pulsatility in the pial arteries traversing the sas increased by 107%. collectively, this suggests that venous drainage anomalies are associated with blood retention in the cerebral veins, and that this in turn is associated with altered biomechanical characteristics within the intracranial space. intracranial compliance and venous drainage intracranial compliance is generally characterized by the arteriovenous delay (avd) between the arterial pulse entering the cranium and the venous pulse leaving it.49 one of the major paradoxes of the intracranial fluid system is associated with the avd. how is this possible, in a system where all the fluids involved are incompressible and the cranium is apparently a rigid container, to have a time lag between the blood flow signals entering and leaving the cranium? the brain parenchyma tissue contains no gaseous material and is generally thought to be incompressible,50 due to its very high water content.51 one possible explanation to this apparent paradox lies in the cortical bridging veins, which are coupled via the dural sinuses to the extracranial venous drainage system. these collapsible thin walled vessels are thought to play an influential role in regulating intracranial compliance.20,21,52 the ability of the cortical veins to store venous blood and delay outflow is dependent on their compliance, with more compliant veins storing greater volumes of blood than incompliant ones.20 as a result, compliant veins exhibit greater pulsatility in blood flow. indeed, bateman20 eloquently showed that in patients with normal pressure hydrocephalus (nph), cortical vein pulsatility was 60% less than in the sss, suggesting that the disease is characterized by a reduction in the compliance of the veins that bridge the sas. bateman found that cortical vein compliance was significantly increased following shunt surgery, indicating that the compliance attributed to these vessels is primarily functional, not structural, and dependent on the transmural pressure difference between the venous blood and the sub-arachnoid csf. this figure 2. transient intracranial blood and cerebrospinal fluid (csf) flow rates over the cardiac cycle in a healthy individual (the figure is based on data published in ambarki et al., 200716). no n c om me rci al us e o nly review [page 84] [veins and lymphatics 2014; 3:1867] implies that the compliance of cortical bridging veins is dependent both on the craniospinal compliance 20 and the ability of any venous blood stored in them to freely exit the cranium via the extracranial veins. therefore, any constriction of the extracranial venous drainage pathways could, in theory, influence the compliant behaviour of the cortical veins. a strong correlation has been demonstrated between intracranial pressure (icp) and venous pressure in the dural sinuses,53 and it has been shown that venous sinus stenting in patients with idiopathic intracranial hypertension (iih) can rapidly normalize icp.54 while this relationship is poorly understood, there is evidence that the cortical bridging veins play an influential role.20 some have likened the action of the cortical bridging veins to a starling resistor, which collapses, occluding the blood flow, when the transmural pressure reaches a certain threshold.55 the fluid flow through the bridging veins appears not to be regulated by the pressure difference between the two ends of the vessels, but rather by the pressure difference between the blood in the veins and the sub-arachnoid csf. the cortical bridging veins are very sensitive to small changes in transmural pressure. because they are required to open and close to regulate blood flow from the cortex, the cortical venous pressure is only about 2 to 5 mmhg higher than the icp.55 this means that small changes in icp or venous pressure can greatly influence the behavior of blood flow from the cortex. indeed, it has been estimated that a change of as little as 1.5 mmhg in the difference between icp and the pressure in the bridging veins could be responsible for the difference between severe hyperemia (cbf=1000 ml/min) to serve ischemia (cbf=300 ml/min).55 postural changes body position is known to have a profound effect on the fluids in the cranium. when upright the pressure in the ijvs becomes subatmospheric, with the result that they collapse. this causes the cerebral venous drainage pathways to be diverted through the vertebral and epidural veins.56 also, when upright the venous pressure at the confluens sinuum in the dural sinuses becomes sub-atmospheric, in adults dropping from a mean of 8.5 mmhg when supine, to –8.6 mmhg when upright.57 the icp, which is normally in the range 7-15 mmhg when supine,58 also falls when upright. alperin et al.59 in an mri study involving healthy young adults, found that in the upright position there was a reduction in icp, which fell from a mean of 10.6 mmhg when supine, to 4.5 mmhg when upright. however, others disagree with this finding and instead believe that icp becomes sub-atmospheric when in the upright position. for example, based on the work of chapman et al.,60 czosnyka and pickard61 concluded that icp in adults in the vertical position is negative, with a mean of around –10 mmhg. given the magnitude of the pressure changes involved in moving from the supine to upright positions, there is reason to believe that this might alter the functional behaviour of the cortical bridging veins and also overall intracranial compliance. alperin et al.59 found that in adults in the upright position, venous outflow became considerably less pulsatile (a 43% reduction in the venous pulsatility index), with flow occurring predominately through the vertebral plexus, rather than the ijvs, which were the principle drainage pathway when supine. as such, their findings appear to corroborate those of valdueza et al.56 importantly, alperin et al also observed a 2.8-fold increase in intracranial compliance when in the upright position compared with supine position, which was associated with 2.4-fold decrease in oscillatory volume of the cervical csf flow. they also found changing posture to the upright position resulted in a 12% reduction in cbf. alperin et al.’s findings are supported by those of ragauskas et al.62 who also observed increased intracranial compliance when in the upright position. while the precise physiological mechanisms involved in the posture-related regulatory process are not understood, these findings appear to be consistent with greatly reduced pressure in the dural sinuses when in the upright position.63 normal pressure hydrocephalus because increased aqueductal csf pulsatility appears to be associated with constricted venous outflow,7 it is perhaps worth considering nph in more detail, a disease that is thought by some 21,49,52,64 to be associated with venous anomalies and which is characterized by increased aqueductal pulsatility.65-70 normal pressure hydrocephalus occurs when there is an abnormal accumulation of csf in the ventricles, causing them to become enlarged,71 but with little or no increase in icp.72,73 nph is associated with significantly reduced csf absorption through the av into the sss.74,75 given that icp does not substantially increase in individuals with nph, this suggests that csf is being resorbed elsewhere.76 bateman49 postulated that csf resorption is likely to occur in the subependymal brain parenchyma and some have identified ventricular reflux in nph patients,77,78 leading to oedema and neuronal degeneration.76 tracer studies have shown that csf can pass through the ependymal wall of the ventricles and enter the brain parenchyma.29 tight junctions are absent from most of the ependyma lining the ventricles, making it relatively permeable to the retrograde transport of water, particularly when the csf pressure is raised.32 trypan blue injected into the csf in the ventricles readily spreads into the brain,79 and tracers injected into the ventricles are taken up by perivascular macrophages,80 suggesting that csf can permeate the perivascular spaces. in hydrocephalus patients, due to impaired drainage of csf from the ventricles, csf can pass into the periventricular wm as ventricular reflux causing interstitial edema.81-84 bateman49 found the avd to be 53% shorter in nph patients compared with healthy controls. a similar reduction in avd in nph patients was observed in a subsequent study,52 and mase et al.85 independently confirmed this finding, showing a 64% reduction in intracranial compliance in nph patients compared with healthy controls. this suggests that nhp is characterized by reduced intracranial compliance. bateman20 showed that in nph patients cortical vein pulsatility was 60% less than in the sss, indicating a reduction in the compliance of the bridging veins. however, following shunt insertion this situation was reversed and there was a 186% increase in cortical vein compliance within 3-5 days of the intervention. using direct cannulation of the cortical veins, venous sinuses and the sas in dogs with hydrocephalus, portnoy et al.86 was able to show that the cortical vein-to-csf pressure difference in hydrocephalic animals was much greater than that in the normal animals. in the hydrocephalic dogs the cortical vein pressure was 21.54 mmhg when the csf pressure was 16.37 mmhg and the sss pressure was 8.43 mmhg, compared with respective values of 11.72, 10.46 and 5.15 mmhg in the normal animals. interestingly, while the hydrocephalic dogs exhibited an increase of only 3.28 mmhg in sss pressure, this was accompanied by a 9.82 mmhg increase in cortical vein pressure, indicating that hydrocephalus profoundly altered the functional relationship between these two vessels. this suggests that in hydrocephalic patients, the sub-arachnoid csf may be interacting with cortical bridging veins at their junction with the sss,20 compressing them so that the up-stream venous pressure is greatly increased. bateman20 hypothesized that this increase in cortical venous pressure would be transmitted up-stream to the capillaries resulting in increased production of interstitial fluid. this, together with reduced csf absorption through the av, would result in an over production of fluid, which as bateman demonstrated using nuclear cisternography, might result in retrograde csf flow in the aos and ventricular reflux.20 no n c om me rci al us e o nly review [veins and lymphatics 2014; 3:1867] [page 85] hypothesis and perspectives from the descusion above it can be seen that while understanding of the intracranial fluid system has improved over the years, much still remains unknown. there is no unifying model which adequately explains the dynamic behaviour of all the component fluids in the intracranial space, and the role of the intracranial fluid system in either preventing, or promoting, neurological disease is poorly understood. in particular, the regulatory role of the cerebral venous system is not well understood. while the contribution of venous anomalies to various neurological pathologies is becoming clearer,10,87 much remains to be discovered. for example, there is a need to understand the extent to which venous drainage influences intracranial compliance. if one considers the timing of the peaks in the respective pulses shown in figure 2, it can be seen that arterial flow into the cranium peaks first, followed closely by the cervical csf peak in the caudal direction, which is then followed by the peak in venous flow out of the cranium. this indicates that volumetric changes are being rapidly transferred from one fluid to another, which is what one would expect from a system containing non-compressible materials. having said this, the presence of an avd indicates that compliance must exist somewhere in the system. while the mechanisms involved are poorly understood, the time delay between the arterial and venous peak flows is likely to be due to a combination of spinal column compliance and the ability of the cortical bridging veins to freely expel stored blood from the cranium via the dural sinuses and extracranial venous pathways. however, while this is a plausible explanation, there is paucity of good quality data on the subject and there is need to better characterize the functional behaviour of the cortical bridging veins both in healthy individuals and patients with neurological conditions. a better understanding of the interaction between the csf, the bridging veins and the sss should enable new insights to be gained into the pathophysiology of conditions such as nph and iih. from figure 2 it can be seen that when the cervical csf flow reverses during diastole and starts to flow back into the cranium, two things happen: firstly, the volume of arterial blood entering the cranium starts to fall, reducing the volume of blood in the pial arteries; and secondly, the volume of venous blood exiting the cranium also starts to fall, indicating that venous blood is being stored in somewhere in the cranium, presumably in the compliant cortical veins. given that positive aqueductal flow, towards the lateral ventricles, occurs late in diastole, this suggests that the venous pulse is likely to influence the dynamics of the csf flow in the aos. although, the mechanics of this relationship are not understood, there is good reason to believe that the two pulses might be connected. nakagawa et al.25 and others22,23 all observed the pulsatile compression of cortical bridging veins by the sub-arachnoid csf, suggesting that the venous signal strongly reflects transient volumetric changes in the cortical bridging veins and thus the overall volume and compliance of the sas.21,49,64 given that the sas is a relatively large volume, with low resistance to csf flow,26 it is therefore reasonable to assume that the csf returning to the cranium during diastole will first tend to fill the sas, before forcing its way up the relatively high resistance aos towards the third ventricle. this can be clearly seen in the lag between the cervical and aqueductal csf signals in figure 2. the fact that the aqueductal csf pulse lags the cervical csf pulse by 0.2 to 0.3 of a cardiac cycle suggests that its dynamic is influence by the compliance of the sas. evidence supporting this opinion comes beggs et al.,7 who found that constricted venous outflow was strongly associated with increased aqueductal pulsatility healthy adults. the hydraulic resistance of the extracranial venous drainage system has been shown to be on average 63.5% greater in ms patients diagnosed with ccsvi compared with ccsvi negative healthy controls.2 if constriction of the venous drainage pathways inhibits free egress of blood transiently stored in the cortical bridging veins, then this is likely to reduce the compliance of the whole sas. this would mean that there would be less room to accommodate the returning csf in the sas, with the result that more of the fluid would be forced up the aos towards the third ventricle, which is exactly what beggs et al. observed. similar, results have also been observed in ms patients8,35,36. furthermore, zivadinov et al.,37 who performed venous angioplasty on ms patients diagnosed with ccsvi, found that the procedure normalized the csf pulsatility in the aos, adding weight to the argument that the functional compliance of the cortical bridging veins profoundly influences the dynamics of the aqueductal csf pulse. the degree to which constriction of the extracranial venous pathways produces retrograde venous hypertension in the dural sinuses is also not well understood. given that the pressure drop through the extracranial venous system is normally of the order 3-5 mmhg,88 an increase of 63% in the resistance of these vessels (as calculated by beggs et al.2) would equate to a pressure increase in the region 1.89-3.15 mmhg, assuming that the blood flow rate remains constant. although only a rough estimation, this calculation is consistent with the 2.21 mmhg mean increase in venous pressure measured in ccsvi positive ms patients by zamboni et al.89 as such, it suggests that ccsvi is associated with mild venous hypertension (<5 mmhg) in the dural sinuses; something that would tend to reduce absorption of csf by the av26,27 and inhibit the bulk flow of csf.7,8 body position is known to be an important factor affecting icp. mavrocordatos et al.90 showed that in anaesthetized neurosurgical patients lying on a flat surface, the icp could be raised (mean increase) by 2.8-3.1 mmhg through simply flexion of the head to left or right, while rotating the head resulted in an mean increase of 4.1-4.8 mmhg. while the reasons for these changes are not fully understood, there is evidence that rotation of the head can compress both the jugular veins and the vertebral veins,91 inhibiting the cerebral venous drainage. iwabuchi et al.57 investigated changes in venous pressure in the confluens sinuum associated with neck rotation and found that in the supine position, a mean increase of 30.3% was observed on a rightward rotation, whereas only a mean elevation of 1.1% was observed for a leftward rotation. however rather surprisingly, in the sitting position, right and left rotations of the neck resulted in increases in pressure of 85.5% and 18.2% respectively. collectively, these findings suggest that the cerebral venous drainage system plays an influential role in regulating icp. furthermore, they indicate that the functional behaviour of the cerebral venous drainage system is greatly influenced by postural changes. it is therefore surprising that relatively little is known about how changes in posture (e.g. supine to upright) affect the intracranial fluid system, particularly in healthy individuals, who for ethical reasons are rarely studied. the mri work by alperin et al.59 revealed marked changes in the behaviour of the intracranial fluid system when healthy subjects move from the supine to upright position. these changes were particularly obvious in the behaviour of the venous system, which became much less pulsatile when upright, something that appears to be associated with greater intracranial compliance in this position. clinical relevance the issue of cerebral venous drainage has for many years been overlooked and it is only recently that the subject has received much attention. the mystery surrounding its apparent connection with the csf system, only serves to highlight that relatively little is known about the physiological mechanisms that regulate the intracranial fluid system. in particular, the way in which the intracranial fluid system adapts when changing from supine to the upright position is poorly understood. however, there is evidence that no n c om me rci al us e o nly review [page 86] [veins and lymphatics 2014; 3:1867] impaired cerebral venous outflow can markedly alter the dynamics of the intracranial fluid system. a better understanding of the physiology associated with cerebral venous outflow may therefore be of great benefit in understanding the progression of neurological conditions such as nph and iih. conclusions there is growing evidence that the cerebral venous drainage plays an influential role in regulating the dynamics of the intracranial fluid system. in particular, the compliance of the cortical bridging veins appears to be critical to the behaviour of the system, with abnormalities at this location implicated in nph. the compliance associated with these vessels appears to be functional in nature and dependent on the free egress of blood out of the cranium via the extracranial venous drainage pathways. constricted venous outflow appears to be linked to increased csf pulsatility in the aos, suggesting that inhibited venous blood flow may be altering the compliance of the cortical bridging veins. references 1. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:3929. 2. beggs c, shepherd s, zamboni p. cerebral venous outflow resistance and interpretation of cervical plethysmography data with respect to the diagnosis of chronic cerebrospinal venous insufficiency. phlebology 2014;29:191-9. 3. zamboni p, menegatti e, occhionorelli s, salvi f. the controversy on chronic cerebrospinal venous insufficiency. veins and lymphatics 2013;2:e14. 4. doepp f, paul f, valdueza jm, et al. no cerebrocervical venous congestion in patients with multiple sclerosis. ann neurol 2010;68:173-83. 5. beggs c. multiple sclerosis appears to be associated with cerebral venous abnormalities. ann neurol 2010;68:560-1; author reply 561-2. 6. khan o, filippi m, freedman ms, et al. chronic cerebrospinal venous insufficiency and multiple sclerosis. ann neurol 2010;67:286-90. 7. beggs cb, magnano c, shepherd sj, et al. aqueductal cerebrospinal fluid pulsatility in healthy individuals is affected by impaired cerebral venous outflow. j magn reson imaging 2014;40:1215-22. 8. zamboni p, menegatti e, weinstockguttman b, et al. the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis is related to altered cerebrospinal fluid dynamics. funct neurol 2009;24:133-8. 9. zivadinov r, weinstock-guttman b. funding ccsvi research is/was a waste of valuable time, money and intellectual energy: no. mult scler 2013;19:858-60. 10. beggs cb. venous hemodynamics in neurological disorders: an analytical review with hydrodynamic analysis. bmc med 2013;11:142. 11. bateman ga. pulse-wave encephalopathy: a comparative study of the hydrodynamics of leukoaraiosis and normal-pressure hydrocephalus. neuroradiology 2002;44:740-8. 12. egnor m, rosiello a, zheng l. a model of intracranial pulsations. pediatr neurosurg 2001;35:284-98. 13. wagshul me, eide pk, madsen jr. the pulsating brain: a review of experimental and clinical studies of intracranial pulsatility. fluids barriers cns 2011;8:5. 14. egnor m, zheng l, rosiello a, et al. a model of pulsations in communicating hydrocephalus. pediatr neurosurg 2002;36:281303. 15. bateman ga, levi cr, schofield p, et al. the venous manifestations of pulse wave encephalopathy: windkessel dysfunction in normal aging and senile dementia. neuroradiology 2008;50:491-7. 16. ambarki k, baledent o, kongolo g, et al. a new lumped-parameter model of cerebrospinal hydrodynamics during the cardiac cycle in healthy volunteers. ieee trans biomed eng 2007;54:483-91. 17. ivanov ay, petrov ae, vershinina ea, et al. evidence of active regulation of cerebral venous tone in individuals undergoing embolization of brain arteriovenous malformations. j appl physiol (1985) 2013;115:1666-71. 18. frydrychowski af, winklewski pj, guminski w. influence of acute jugular vein compression on the cerebral blood flow velocity, pial artery pulsation and width of subarachnoid space in humans. plos one 2012;7:e48245. 19. an h, lin w. cerebral venous and arterial blood volumes can be estimated separately in humans using magnetic resonance imaging. magn reson med 2002;48:583-8. 20. bateman ga. the reversibility of reduced cortical vein compliance in normal-pressure hydrocephalus following shunt insertion. neuroradiology 2003;45:65-70. 21. williams h. a unifying hypothesis for hydrocephalus, chiari malformation, syringomyelia, anencephaly and spina bifida. cerebrospinal fluid res 2008;5:7. 22. luce jm, huseby js, kirk w, butler j. a starling resistor regulates cerebral venous outflow in dogs. j appl physiol 1982;53:1496-503. 23. vignes jr, dagain a, guerin j, liguoro d. a hypothesis of cerebral venous system regulation based on a study of the junction between the cortical bridging veins and the superior sagittal sinus. laboratory investigation. j neurosurg 2007;107:1205-10. 24. greitz d. cerebrospinal fluid circulation and associated intracranial dynamics. a radiologic investigation using mr imaging and radionuclide cisternography. acta radiol suppl 1993;386:1-23. 25. nakagawa y, tsuru m, yada k. site and mechanism for compression of the venous system during experimental intracranial hypertension. j neurosurg 1974;41:427-34. 26. ekstedt j. csf hydrodynamic studies in man. 2. normal hydrodynamic variables related to csf pressure and flow. j neurol neurosurg psychiatry 1978;41:345-53. 27. cutler rw, page l, galicich j, watters gv. formation and absorption of cerebrospinal fluid in man. brain 1968;91:707-20. 28. ekstedt j. csf hydrodynamic studies in man. 1. method of constant pressure csf infusion. j neurol neurosurg psychiatry 1977;40:105-19. 29. weller ro, djuanda e, yow hy, carare ro. lymphatic drainage of the brain and the pathophysiology of neurological disease. acta neuropathol 2009;117:1-14. 30. cserr hf, knopf pm. cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view. immunol today 1992;13:507-12. 31. johanson ce, duncan ja 3rd, klinge pm, et al. multiplicity of cerebrospinal fluid functions: new challenges in health and disease. cerebrospinal fluid res 2008;5 :10. 32. abbott nj. evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. neurochem int 2004;45:545-52. 33. lorenzo av, page lk, watters gv. relationship between cerebrospinal fluid formation, absorption and pressure in human hydrocephalus. brain 1970;93:67992. 34. magnano c, schirda c, weinstock-guttman b, et al. cine cerebrospinal fluid imaging in multiple sclerosis. j magn reson imaging 2012;36:825-34. 35. gorucu y, albayram s, balci b, et al. cerebrospinal fluid flow dynamics in patients with multiple sclerosis: a phase contrast magnetic resonance study. funct neurol 2011;26:215-22. 36. magnano c, schirda c, weinstock-guttman b, et al. cine cerebrospinal fluid imaging in multiple sclerosis. j magn reson imaging 2012;36:825-34. no n c om me rci al us e o nly review [veins and lymphatics 2014; 3:1867] [page 87] 37. zivadinov r, magnano c, galeotti r, et al. changes of cine cerebrospinal fluid dynamics in patients with multiple sclerosis treated with percutaneous transluminal angioplasty: case-control study. j vasc interv radiol 2013;24:829-38. 38. mitchell gf, van buchem ma, sigurdsson s, et al. arterial stiffness, pressure and flow pulsatility and brain structure and function: the age, gene/environment susceptibility reykjavik study. brain 2011;134: 3398-407. 39. jolly ta, bateman ga, levi cr, et al. early detection of microstructural white matter changes associated with arterial pulsatility. front hum neurosci 2013;7:782. 40. wahlin a, ambarki k, birgander r, et al. intracranial pulsatility is associated with regional brain volume in elderly individuals. neurobiol aging 2014;35:365-72. 41. henry-feugeas mc. intracranial mr dynamics in clinically diagnosed alzheimer’s disease: the emerging concept of “pulse wave encephalopathy”. curr alzheimer res 2009;6:488-502. 42. safar me, levy bi, struijker-boudier h. current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. circulation 2003;107:2864-9. 43. gons ra, de laat kf, van norden ag, et al. hypertension and cerebral diffusion tensor imaging in small vessel disease. stroke 2010;41:2801-6. 44. van gijn j. leukoaraiosis and vascular dementia. neurology 1998;51:s3-8. 45. daouk j, chaarani b, zmudka j, et al. relationship between cerebrospinal fluid flow, ventricles morphology, and dti properties in internal capsules: differences between alzheimer’s disease and normalpressure hydrocephalus. acta radiol 2013. [epub ahead of print]. 46. greitz d. radiological assessment of hydrocephalus: new theories and implications for therapy. neurosurg rev 2004;27:14565; discussion 166-7. 47. kitano m, oldendorf wh, cassen b. the elasticity of the cranial blood pool. j nucl med 1964;5:613-25. 48. beggs c, chung cp, bergsland n, et al. jugular venous reflux and brain parenchyma volumes in elderly patients with mild cognitive impairment and alzheimer’s disease. bmc neurol 2013;13:157. 49. bateman ga. vascular compliance in normal pressure hydrocephalus. ajnr am j neuroradiol 2000;21:1574-85. 50. miller k, chinzei k. constitutive modelling of brain tissue: experiment and theory. j biomechanics 1997;30:1115-21. 51. bilston le. brain tissue mechanical properties. in: miller k, ed. biomechanics of the brain. new york: springer; 2011. pp 69-89. 52. bateman ga. the pathophysiology of idiopathic normal pressure hydrocephalus: cerebral ischemia or altered venous hemodynamics? ajnr am j neuroradiol 2008;29:198-203. 53. pickard jd, czosnyka z, czosnyka m, et al. coupling of sagittal sinus pressure and cerebrospinal fluid pressure in idiopathic intracranial hypertension-a preliminary report. acta neurochir suppl 2008;102: 283-5. 54. fargen km, velat gj, lewis sb, et al. concomitant intracranial pressure monitoring during venous sinus stenting for intracranial hypertension secondary to venous sinus stenosis. j neurointerv surg 2013;5:e22. 55. schaller b. physiology of cerebral venous blood flow: from experimental data in animals to normal function in humans. brain res brain res rev 2004;46:243-60. 56. valdueza jm, von munster t, hoffman o, et al.postural dependency of the cerebral venous outflow. lancet 2000;355:200-1. 57. iwabuchi t, sobata e, ebina k, et al. dural sinus pressure: various aspects in human brain surgery in children and adults. am j physiol 1986;250:h389-96. 58. albeck mj, borgesen se, gjerris f, et al. intracranial pressure and cerebrospinal fluid outflow conductance in healthy subjects. j neurosurg 1991;74:597-600. 59. alperin n, lee sh, sivaramakrishnan a, hushek sg. quantifying the effect of posture on intracranial physiology in humans by mri flow studies. j magn reson imaging 2005;22:591-6. 60. chapman ph, cosman er, arnold ma. the relationship between ventricular fluid pressure and body position in normal subjects and subjects with shunts: a telemetric study. neurosurgery 1990;26:181-9. 61. czosnyka m, pickard jd. monitoring and interpretation of intracranial pressure. j neurol neurosurg psychiatry 2004;75:81321. 62. ragauskas a, daubaris g, petkus v, et al. clinical study of craniospinal compliance non-invasive monitoring method. acta neurochir suppl 2008;102:165-9. 63. hicks jw, munis jr. the siphon controversy counterpoint: the brain need not be “baffling”. am j physiol regul integr comp physiol 2005;289:r629-32. 64. williams h. the venous hypothesis of hydrocephalus. med hypotheses 2008;70: 743-7. 65. luetmer ph, huston j, friedman ja, et al. measurement of cerebrospinal fluid flow at the cerebral aqueduct by use of phasecontrast magnetic resonance imaging: technique validation and utility in diagnosing idiopathic normal pressure hydrocephalus. neurosurgery 2002;50:534-43; discussion 543-4. 66. schroth g, klose u. cerebrospinal fluid flow. iii. pathological cerebrospinal fluid pulsations. neuroradiology 1992;35:16-24. 67. gideon p, stahlberg f, thomsen c, et al. cerebrospinal fluid flow and production in patients with normal pressure hydrocephalus studied by mri. neuroradiology 1994;36:210-5. 68. kim ds, choi ju, huh r, et al. quantitative assessment of cerebrospinal fluid hydrodynamics using a phase-contrast cine mr image in hydrocephalus. childs nerv syst 1999;15:461-7. 69. el sankari s, gondry-jouet c, fichten a, et al. cerebrospinal fluid and blood flow in mild cognitive impairment and alzheimer’s disease: a differential diagnosis from idiopathic normal pressure hydrocephalus. fluids barriers cns 2011;8:12. 70. bradley wg jr, scalzo d, queralt j, et al. normal-pressure hydrocephalus: evaluation with cerebrospinal fluid flow measurements at mr imaging. radiology 1996;198:523-9. 71. kitagaki h, mori e, ishii k, et al. csf spaces in idiopathic normal pressure hydrocephalus: morphology and volumetry. ajnr am j neuroradiol 1998;19:1277-84. 72. kiefer m, unterberg a. the differential diagnosis and treatment of normal-pressure hydrocephalus. dtsch arztebl int;109:15-25; quiz 26. 73. tsunoda a, mitsuoka h, bandai h, et al. intracranial cerebrospinal fluid measurement studies in suspected idiopathic normal pressure hydrocephalus, secondary normal pressure hydrocephalus, and brain atrophy. j neurol neurosurg psychiatry 2002;73:552-5. 74. tullberg m, mansson je, fredman p, et al. csf sulfatide distinguishes between normal pressure hydrocephalus and subcortical arteriosclerotic encephalopathy. j neurol neurosurg psychiatry 2000;69:7481. 75. bradley wg. normal pressure hydrocephalus: new concepts on etiology and diagnosis. ajnr am j neuroradiol 2000; 21:1586-90. 76. tullberg m, jensen c, ekholm s, wikkelso c. normal pressure hydrocephalus: vascular white matter changes on mr images must not exclude patients from shunt surgery. ajnr am j neuroradiol 2001;22: 1665-73. 77. brumback ra, yoder fw, andrews ad, et al. normal pressure hydrocephalus. recognition and relationship to neurological abnormalities in cockayne’s syndrome. arch neurol 1978;35:337-45. 78. algin o, hakyemez b, ocakoglu g, parlak m. mr cisternography: is it useful in the diagnosis of normal-pressure hydrono n c om me rci al us e o nly review [page 88] [veins and lymphatics 2014; 3:1867] cephalus and the selection of “good shunt responders”? diagn interv radiol 2011;17:105-11. 79. goldman ee. vitalfarbung am zentralnervensystem. abh preuss akad wiss phys math k1 1913;1:1-60. 80. bechmann i, kwidzinski e, kovac ad, et al. turnover of rat brain perivascular cells. exp neurol 2001;168:242-9. 81. weller ro, massey a, newman ta, et al. cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in alzheimer’s disease. am j pathol 1998;153:725-33. 82. weller ro, wisniewski h. histological and ultrastructural changes with experimental hydrocephalus in adult rabbits. brain 1969;92:819-28. 83. wisniewski h, weller ro, terry rd. experimental hydrocephalus produced by the subarachnoid infusion of silicone oil. j neurosurg 1969;31:10-4. 84. weller ro, wisniewski h, shulman k, terry rd. experimental hydrocephalus in young dogs: histological and ultrastructural study of the brain tissue damage. j neuropathol exp neurol 1971;30:613-26. 85. mase m, miyati t, kasai h, et al. noninvasive estimation of intracranial compliance in idiopathic nph using mri. acta neurochir suppl 2008;102:115-8. 86. portnoy hd, branch c, castro me. the relationship of intracranial venous pressure to hydrocephalus. childs nerv syst 1994;10: 29-35. 87. haacke em, beggs cb, habib c. the role of venous abnormalities in neurological disease. rev recent clin trials 2012;7:100-16. 88. dawson ea, secher nh, dalsgaard mk, et al. standing up to the challenge of standing: a siphon does not support cerebral blood flow in humans. am j physiol regul integr comp physiol 2004;287:r911-4. 89. zamboni p, galeotti r, menegatti e, et al. a prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. j vasc surg 2009;50: 1348-58e1-3. 90. mavrocordatos p, bissonnette b, ravussin p. effects of neck position and head elevation on intracranial pressure in anaesthetized neurosurgical patients: preliminary results. j neurosurg anesthesiol 2000;12:10-4. 91. hulme a, cooper r. the effect of head position and jugular vein compression on icp. a clinical study. intracranail pressure iii. berlin: springer-verlag; 1976. pp 259263. no n c om me rci al us e o nly hrev_master veins and lymphatics 2013; volume 2:e20 [page 72] [veins and lymphatics 2013; 2:e20] elastic or inelastic compression in patients with leg ulcer and restricted mobility? giovanni mosti angiology department, clinica md barbantini, lucca, italy abstract in patients with leg ulcer and restricted mobility, compression with elastic material is often preferred based on the concept that it is more effective as it exerts a sustained higher resting pressure while inelastic material is believed to exert a very low resting pressure and to work only during movement. the aim of this study is to demonstrate that elastic and inelastic material can exert similar pressure at rest and that inelastic material can produce a much higher pressure during sitting and light exercise in ulcer patients with restricted mobility. in 30 patients (12 men, 18 women mean age 76.3±9.1 years, range 63-80) with leg ulcers and severely reduced mobility we applied consecutively elastic and inelastic bandages with the same resting pressure of 40 mmhg. pressure changes were measured while the patient was sitting and standing and during active and passive muscle contractions. the pressure differences between standing and supine and sitting and supine position were calculated as well as between muscle systole and diastole during active and passive contractions. starting with the same resting pressure inelastic bandages produce significantly higher pressure peaks in the sitting and standing position and during the muscular systole both during active and passive exercise compared to elastic bandages (p<0.001). the results show that inelastic bandages, applied with the same pressure as elastic bandages at rest, will exert much higher pressures even during minimal or passively induced muscle contractions. the concept that elastic compression should be used in patients with reduced mobility needs to be reconsidered. introduction immobility or severely impaired mobility represent an indication for compression therapy in order to prevent venous thromboembolism1-4 and to reduce edema that will develop5-11 when the patient spends his life mainly in a sitting position or is unable to move correctly for any other reason. these conditions are frequently considered as an indication for elastic compression12-13 based on the concept that it can exert a high, sustained, resting pressure in contrast to inelastic compression which would produce a low resting pressure and would be effective only in the standing position and, especially, during muscle contraction. the aim of this study is to show that, in patients with leg ulcers who are immobile or with restricted mobility, inelastic bandages can exert a pressure at least as high as elastic material at rest but much higher even during minimal movements, and, as a consequence, much more effective to counteract the venous hemodynamic impairment. materials and methods thirty patients (12 men, 18 women mean age 70.3±10.1 years, range 59-80) with leg venous ulcers and severely impaired mobility who spent most of the day either sitting in an armchair with limited ambulation or in bed were enrolled. all of them were fully informed and gave their written consent to participate in the study. ethical committee approval is not requested in italy for studies comparing ce (european community) marked products and not requiring randomization in different groups (they are considered as observational studies). inclusion criteria: patients of both sexes, age from 20 to 80 years, suffering from venous leg ulcers and with restricted mobility [patients who, for different health problems (orthopedic, cardio-respiratory, overweight) spend their life lying in bed or sitting in an armchair but able to move for their simple needs]. exclusion criteria: patients with arterial impairment and an ankle-brachial pressure index <0.8 or with complete block of ankle, knee, hip joints were excluded from the study. in all patients the same experienced bandager successively applied an elastic and inelastic bandage from the base of the toes to the popliteal fossa in the supine position, in a randomized sequence. the time interval between the two applications was 30 min during which the patient stayed resting in bed. as elastic bandage we used dauerbinde k® (lohmann & rauscher, rengsdorf, germany) stretched by 50-60% and overlapped by 50-60%; the inelastic bandage was made up of cotton padding layer and a cohesive inelastic bandage (cellona®, mollelast haft®; lohmann & raucher) applied with full stretch and superimposed by 50%. in the lying position the bandager adjusted the pressure of each bandage to 40 mmhg recorded by a validated14,15 pneumatic device with an air filled probe (picopress® microlab, padua, italy). the probe was placed at point b1 on the medial aspect of the calf where the tendinous part of the gastrocnemius turns in muscular part according to the recommendations of a consensus document on sub-bandage pressure measurements in vivo.16 the patients were then asked to do maximal dorsiflexions end extension of the foot which were followed by maximal passive dorsiflexions and extension carried out by a physiotherapist. finally patients were asked to move the toes actively as much as possible. the patients were then moved from the bed to the armchair where series of active and passive foot dorsiflexions (therapist-assisted) were carried out again. after that the patients were asked to stand, and to walk briefly with assistance if needed. the exerted pressure was continuously measured in the supine, sitting and standing position and during active and passive ankle and toe movements. the following pressure differences were calculated: sitting minus supine position, standing minus supine position, the active systolic-diastolic difference and passive systolic-diastolic difference, the toe systolic-diastolic difference and the walking systolic-diastolic difference. statistical analysis the results underwent statistical analysis using student’s t-test for paired data to compare the different maneuvers under the same bandage and the student’s t-test to compare elastic vs inelastic bandages. differences with p<0.05 were considered statistically significant. the graphs were created with graph pad, version 5 (graph pad, san diego, ca, usa). correspondence: giovanni mosti, angiology department, clinica md barbantini, via del calcio, 55100 lucca, italy. e-mail: jmosti@tin.it key words: elastic compression, inelastic compression, leg ulcers, reduced mobility, immobility. received for publication: 30 july 2013. revision received: 1 october 2013. accepted for publication: 17 october 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright g. mosti, 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e20 doi:10.4081/vl.2013.e20 no nco mm er cia l u se on ly article [veins and lymphatics 2013; 2:e20] [page 73] results the resting pressure increases significantly both with elastic and inelastic material during active and passive dorsiflexion, both in supine and sitting position, with the very small toe movements, in the sitting and standing position and during walking. the pressure increase produced by the inelastic material is significantly higher when compared with elastic (p<0.001) (figures 1 and 2). as a consequence all the pressure differences (between sitting and supine position, standing and supine position, systolic and diastolic pressure during active and passive movements of ankle and toes and during walking) were significantly higher with inelastic compared with elastic material (p<0.001) (figure 3) as can be seen in the pressure recordings (figures 4 and 5). discussion the pressure of a bandage does not depend on the elastic property of the material used17 but on the strength exerted by the bandager during wrapping. in this study elastic and inelastic bandages have been applied with exactly the same initial resting pressure in the lying position. by standing up and by different active or passive leg movements the pressure increase was always significantly higher with inelastic than with elastic material. this finding is in disagreement with the concept that inelastic bandages produce a low resting pressure and achieve effective pressures only during movement. this is the reason why many clinicians believe that patients who are unable to move should better be treated by elastic material. elastic would be an active compression in the resting position while inelastic would be a passive or restraining compression, that produces low or no resting pressure, and would only be effective during muscular contraction. it is also thought that since a patient with restricted mobility has little or no muscular activity this passive inelastic material would not be suitable to develop enough compression pressure. several experimental studies have clearly shown that inelastic compression can exert a significantly higher pressure compared with elastic both in supine and standing position and during work.18-20 by a general physics definition, elastic material tends to return to its original length once stretched; therefore it will not be tolerated if highly stretched to exert high pressure (which could be termed the squeezing effect). inelastic material doesn’t have any elastic return property and can exert a high resting pressure without causing any pain. this is the rationale for recommending the application of inelastic material with full stretch while elastic material should be applied with a stretch of 50-60% in order not to be painful. the resulting resting pressure of an inelastic bandage applied under full stretch will be higher than that of an elastic bandage and will be in the range indicated in a recent consensus document as strong (40-60 mm hg) or very strong (>60 mmhg) while the pressure exerted by an elastic bandage properly applies should not exceed 40-45 mmhg (mediumstrong)21 in order to be well tolerated. since the figure 1. pressure difference between elastic and inelastic material moving from supine to standing position (a), and from supine to sitting position (b). the pressure in the standing and in the sitting position is significantly higher (p<0.001) with inelastic material compared with elastic. ***p<0.001; n.s., not significant. figure 2. pressure difference between elastic and inelastic material in muscular diastole and systole during active dorsiflexion (a), passive dorsiflexions (b), toe movements (c) and exercise (d). with inelastic material the pressure peaks are always significantly higher (p<0.001). **p<0.01; ***p<0.001. no nco mm er cia l u se on ly article [page 74] [veins and lymphatics 2013; 2:e20] patients in this study spend most of the time in bed or in an armchair we intentionally did not use very strong pressure but choose to start with a resting pressure of 40 mmhg that is able to narrow/occlude the vein both in the supine and sitting position.22 according to their elastic properties, elastic bandages give way to the muscle volume increase during contraction while inelastic material tends to form a stiff shell around the leg and does not give way. it is the leg which gives way with active or passive ankle-or toe movement. our results show that just with small muscular activity (foot dorsiflections, toes movements) inelastic material produces significantly higher pressure peaks than elastic material (figures 3-5). it could be demonstrated that higher sitting and standing compression pressure is positively correlated with a reduction of venous reflux even when the pressure at application of the different materials is the same.23,24 the high pressure amplitudes during active or passive movements correlate with a higher increase of venous pumping function.25 measuring the ejection fraction of the calf pump it could be demonstrated that inelastic bandages revealed a significantly higher increase of venous pumping function compared with elastic bandages applied with the same resting pressure. this effect has been proved both in normal subjects26 and patients with venous insufficiency25 and was more pronounced in higher 60 mmhg than in lower pressure ranges (20 and 40 mmhg).27 even small and passive foot dorsiflexions or toe movements are able to produce amazing pressure amplitudes with inelastic compression (figure 5). such exercises can be carried out also passively by healthcare professionals or even trained relatives. one disadvantage of inelastic compression is its rapid pressure loss. in a previous study we were able to show that, in spite of a consistent pressure loss, the inelastic bandage continues to be very effective in improving the calf muscle pump function even after a week, maintaining a significantly higher efficacy compared to elastic compression with a negligible pressure loss.28 the pressure loss can mainly be explained by edema reduction and material fatigue and makes the bandage more comfortable. a weakness of our study is that only pressure values are reported. comparing different compression materials functional parameters like ejection fraction or venous reflux would have been interesting outcome parameters but cannot reliably measured in our immobile population. nevertheless the positive correlation between standing pressure or massage effect and venous reflux and ejection fraction has been widely proved.23-28 it can be reasonably assumed that it exists also in patients with restricted mobility provided they have some opportunities to move actively or even passively both in the bed and in the armchair. conclusions the recommendation to use only elastic compression in immobile patients must be reconsidered. a skilled bandager will apply inelastic compression at least with the same pressure exerted by the elastic bandage. inelastic bandages produce higher pressure peaks than elastic material even during simple active or passive movements being able to increase the venous pump. it may be assumed that the stronger massaging effect produced by inelastic material may have positive effects not only on venous hemodynamics but also on the microcirculation and on lymph-drainage. if this positive effects on venous hemodyfigure 3. pressure difference with different exercise or body position. ***p<0.001. ssi, standing minus supine position; asdd, active systolic-diastolic difference; psdd, passive systolic-diastolic difference; ssd, sitting minus supine position. figure 4. pressure recordings with elastic compression: pressure peaks during active and passive dorsiflexions, toe movements, standing and walking are low. no nco mm er cia l u se on ly article [veins and lymphatics 2013; 2:e20] [page 75] namic reflect in a better outcome of leg ulcers in this group of patients is not an aim of our study and should be proved by future trials. references 1. amaragiri sv, lees ta. elastic compression stockings for prevention of deep vein thrombosis. cochrane database syst rev 2000;(3):cd001484. 2. nicolaides an, fareed j, kakkar ak, et al. prevention and treatment of venous thromboembolism, international consensus statement (guidelines according to scientific evidence). int angiol 2006;25:101-61. 3. roderick p, ferris g, wilson k, et al. towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anesthesia as thromboprophylaxis. health technol assess 2005;9:1-78. 4. handoll hh, farrar mj, mcbirnie j, et al. heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures. cochrane database syst rev 2000;27: cd000305. 5. jonker mj, deboer em, adèr hj, bezemer pd. the oedema-protective effect of lycra support stockings. dermatology 2001;203:294-8. 6. partsch h, winiger j, lun b. compression stockings reduce occupational swelling. j derm surg 2004;30:737-43. 7. clarke m, hopewell s, juszczak e, et al. compression stockings for preventing deep vein thrombosis in airline passengers. cochrane database syst rev 2006; (2):cd004002. 8. gniadecka m. dermal oedema in lipodermatosclerosis: distribution, effects of posture and compressive therapy evaluated by high frequency ultrasonography. acta derm venereol 1995;75:120-4. 9. krijnen rm, de boer em, ader hj, et al. compression stockings and rubber floor mats: do they benefit workers with chronic venous insufficiency and a standing profession j occup environ med 1997;39:889-94. 10. diehm c, trampisch hj, lange s, schmidt c. comparison of leg compression stocking and oral horse-chestnut seed extract therapy in patients with chronic venous insufficiency. lancet 1996,347:292-4. 11. van geest aj, veraart jc, nelemans p, neumann ha. the effect of medical elastic compression stockings with different slope values on edema. measurements underneath three different types of stockings. dermatol surg 2000;26:244-7. 12. wuwhs. principles of best practice: compression in venous leg ulcers. a consensus document. london: mep ltd, 2008. 13. ewma. understanding compression therapy. ewma position document. london: mep ltd, 2003. pp 13-14. 14. partsch h, mosti g. comparison of three portable instruments to measure compression pressure. int angiol. 2010;29:426-30. 15. mosti g, rossari s. l’importanza della misurazione della pressione sottobendaggio e presentazione di un nuovo strumento di misura. acta vulnol 2008;6:31-6. 16. partsch h, clark m, bassez s, et al. measurement of lower leg compression in vivo: recommendations for the performance of measurements of interface pressure and stiffness. a consensus statement. dermatol surg 2006;32:229-38. 17. british standard. the elastic properties of flat, non-adhesive, extensible fabric bandages. bs 705 1995. london: bsi-british standards institution; 1995. 18. mosti g, mattaliano v. simultaneous changes of leg circumference and interface pressure under different compression bandages. ejves 2007;33:476-82. 19. partsch h. the static stiffness index: a simple method to assess the elastic property of compression material in vivo. derm surg 2005;31:625-30. 20. partsch h. the use of pressure change on standing as a surrogate measure of the stiffness of a compression bandage. eur j vasc endovasc surg 2005;30:415-21. 21. partsch h, clark m, mosti g, et al. classification of compression bandages: practical aspects. dermatol surg 2008; 34:600-9. 22. partsch b, partsch h. calf compression pressure required to achieve venous closure from supine to standing position. j vasc surg 2005;42:734-8. 23. mosti g, partsch h. duplex scanning to evaluate the effect of compression on venous reflux. int angiol 2010;29:416-20. 24. partsch h, menzinger g, mostbeck a. inelastic leg compression is more effective to reduce deep venous refluxes than elastic bandages. dermatol surg 1999;25:695700. 25. mosti g, mattaliano v, partsch h. inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous reflux. phlebology 2008;23:287-94. 26. poelkens f, thijssen dhj, kersten b, et al. counteracting venous stasis during acute lower leg immobilization. acta physiol 2006;186:111-8. 27. mosti g, partsch h. is low compression pressure able to improve venous pumping function in patients with venous insufficiency? phlebology 2010;25:145-50. 28. mosti g, partsch h. inelastic bandages maintain their hemodynamic effectiveness over time despite significant pressure loss. j vasc surg 2010;52:925-31. figure 5. pressure recordings with inelastic compression: pressure peaks during active and passive dorsiflexions, toe movements, standing and walking are very high and much higher compared with elastic compression starting from the same resting pressure. no nco mm er cia l u se on ly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: catheter-directed foam sclerotherapy for insufficiency of the great saphenous vein: occlusion rates and patient satisfaction after one year by williamsson c, danielsson p, smith l. phlebology 2012:1-6. stefano ricci abstract between november 2007 and october 2008, 100 consecutive symptomatic patients with verified axial reflux in the gsv were treated with a catheter-directed foam sclerosation technique (cds). cds delivers the foam during a short period of time directly to the intended site, along the length of the gsv, with less impact from surrounding factors. the catheter induces a vasospasm which might further enhance drug interaction with the vein wall. median age was 52.5 years (range 18–92), 28 men and 72 women. all patients had visible varicose veins. twenty-three had recurrent varicose veins. the treatment was performed in the outpatient clinic by a team consisting of two vascular surgeons and two nurses. exclusion criteria were allergy to polidocanol, a very tortuous vein (which could make the catheters impossible to advance) or a gsv diameter exceeding 10 mm at the terminal valve. the skin was infiltrated with local anesthesia. the vein was accessed by a micro-puncture introducer set and a 0.35 fr guide wire was advanced proximally under us surveillance and positioned at the sfj. a catheter was introduced over the guide wire and positioned approximately 2 cm distal to the sfj and the guide wire was removed. the table was slightly tilted to elevate the leg to empty the gsv. ten ml sclerosing foam (sf) was made by mixing 2 ml chilled 3% polidocanol and 8 ml air. the sfj and site of puncture was compressed for five minutes and the thigh massaged to fill superficial varicosites with foam. no additional local injection of foam was given. all patients wore two-layer short stretch compression bandages for one to five days after treatment. evaluation with us was performed at two weeks and at one year after treatment. foam delivery along the gsv was technically successful in 94 of the 100 patients. the median time for the procedure was 22 (8–90) min. the complete treatment exceeded 30 min in 20 patients, but only in two patients following the 50th patient. at the us control two weeks after treatment, the gsv was completely occluded in 92 of the 94 successfully treated patients. at the one-year follow-up, 84% (79/94) were satisfied with the result. the one-year us showed that 70% (64/91) of the gsvs were completely occluded, 15% (14/91) of the gsvs were recanalized and 14% (13/91) were partly occluded. no major complications occurred such as visual disturbance, pulmonary embolism, dvt or infection. two patients had superficial thrombophlebitis; at the one-year follow-up 26 patients had pigmentations to some extent. the cost for the drugs and the single-use medical material was calculated to be 106 eur. comment by stefano ricci catheter-direct foam sclerotherapy is interesting because, as demonstrated by the authors, it is safe, cheap and easy to perform. in particular it do not need high technology or a dedicated setting, so can be also performed in unfavorable social and economical conditions. about 70% occlusion rate is not an ideal outcome even if could be largely ameliorated by further subsequent sclerotherapy. unfortunately no specific data about us pre-treatment findings (terminal valve competence, calibers, aasv, extension of varicosities, isolated dilatations, pelvic reflux, recurrence of gsv incompetence?? etc.) are reported, all situations mixed up. us was performed in a 60° upright position, which could have different results compared to 90° standing position. also the concept of satisfaction is questionable, no distinction being made, for example, between cosmetic and clinical state. over a 24% incidence of pigmentation, only 6 cases were displeased: what an advantage to live and work in sweden!! in mediterranean countries this result would be accepted with lower compliance. interestingly, post treatment compression was very limited (1-5 days) indicating a very good sclerotherapy technique, however it is surprising that also c4 (19) patients, as c5 (8) and c6 (4) were left without hosiery with still good outcome. reply by the authors thank you for commenting the article. an important aim of the study was to show the simplicity of this minimally invasive technique. with an increasing elderly population it is important to find a safe and easy method to address superficial venous insufficiency. in studies, ultrasound detected recanalization, totally or segmentally, is usually evaluated and defined as success or failure. however, the clinical result is more relevant and most treated patients experience relief of symptoms, probably due to less reflux compared to pre-treatment. our experience is that only patients with totally recanalized saphenous veins are in need of a new treatment. this makes the result better than the figures presented in the study. the low rate of displeased patients although some had pigmentations might be explained by relief of symptoms. none were treated due to cosmetic complaints alone. it is though very true that bruising is a problem. previously we did not take any cosmetic consideration. in public healthcare this may be an acceptable strategy but not in a private practice. we have learned that the patients skin type must be considered, a very light skin is unfavorable for foam. the depth of the saphenous vein is important. low amount of subcutaneous fat and a distance from the saphenous vein less the 10 mm is not recommended due to risk for permanent bruising. it is also possible to resect superficial tributaries by mini phlebotomies in local anesthesia in a combined session with cds. the bottom line is that there are ways to avoid bruising and a very good cosmetic result can be achieved in most cases. for this, experience is needed and is probably more important in private clinics dealing with patients suffering cosmetically from their varicose veins. [top] hrev_master veins and lymphatics 2014; volume 3:4037 [veins and lymphatics 2014; 3:4037] [page 47] scintigraphy-based analysis of possible pulmonary lesions after foam sclerotherapy: a pilot study lorenzo tessari,1 marcello izzo,2 attilio cavezzi,3 francesco zini,4 mirko tessari,5 daniela grigolato6 1glauco bassi foundation, trieste; 2mathematics for technology, medicine & biosciences research center, university of ferrara; 3eurocenter venalinfa, san benedetto del tronto (ap); 4casa di cura città di parma, parma; 5vascular disease center, university of ferrara; 6uoc of nuclear medicine, university hospital of verona, italy abstract the aims of this study were to assess extemporaneous in vivo binding between 99mtco4 and two sclerosant detergents in foam sclerotherapy, and subsequently to control any possible damage in lungs and other organs related to sclerosant foam passage. a prospective comparative pilot study was performed on two male patients (62 and 56 years old) affected by varicose veins; each of them underwent scintigraphy investigations with free radiotracer and a scintigraphy investigation after each of the four sessions of sclerotherapy of varicose tributaries of the lower limbs with labeled sclerosant foam. one of the two patients underwent two further scintigraphic investigations, with free radiotracer and with labeled sclerosant foam, at a later stage. four ml of 2% polidocanol (pol) foam, or four ml of 1% sodiumtetradecylsulfate (sts) foam for session were injected. the sclerosant foam was labeled with the radioactive tracer technetium pertechnetate, 99mtco4(120 mbq per exam). two scintigraphy assessments for free tracer (basal) and five scintigraphy investigations of bound-tosclerosant tracer uptake/transit were obtained. no relevant variations in time/activity curves of the lungs and other organs were documented between the basal and post-sclerotherapy findings, also at the later stage. free radiotracer mean region-of-interest data were: 336 counts (heart), 208 counts (lungs) and 371 counts (thyroid). mean values extrapolated from each curve at each step for labeled co2o2-based sclerosant foam were respectively: 351 counts (pol) and 328 counts (sts) for heart, 202 counts (pol) and 188 counts (sts) for lungs, 335 (pol) and 263 (sts) for thyroid. no pulmonary damage by sclerosant foam was caused. neither immediately after treatments, nor at short-term follow-up. introduction foam sclerotherapy was introduced more than 60 years ago, and cabrera and monfreux’s innovative methods in the late 1990s gave a new impulse to using sclerosant foam (sf).1 the extended use of this treatment was achieved after the introduction of the tessari method.2,3 foam sclerotherapy has proved to be a validated, effective and safe method to treat varicose veins of the lower limbs,4 and possibilities and limitations for this technique have been elucidated in several publications.5,6 more recently, issues have been raised and discussed as to potential risks, side effects and complications of sf.7 distal embolization of sf bubbles to lungs and possible lung capillary/parenchyma inflammation has been postulated in the past8 and recent9 literature. furthermore, especially in the presence of a right-to left shunt such as a patent foramen ovale, isolated cases of neurological complications have been reported.4 the authors aimed to assess any possible change in the tissues of various organs, particularly the lungs, which may be affected by possible passage/impact of sf bubbles. furthermore, any difference between airbased sf and co2o2-based sf was investigated in order to assess a possible higher safety profile of biocompatible gases vs room air. finally, the clinical and experimental trial aimed at assessing any difference between the two commonly used detergent sclerosant drugs [sodiumtetradecysulfate (sts) and polidocanol (pol)] as to the above-mentioned issues. in order to get a reproducible and quantifiable method for detecting possible tissue changes in the target/transit organs after sclerosant foam injections, scintigraphy was employed in a qualitative and semi-quantitative way. on the basis of the chemical/physical properties of pertechnetate ion (99mtco4-), a protocol to assess extemporaneous in vivo binding between 99mtco4and pol/sts foam during various steps was designed. p 99mtco4shows a stable chemical structure not easily suited to bind other molecules. the study aimed at assessing the possibility of linkage between this radiotracer and the sf to check the presumed possibility of tracing the pathway and accumulation of sf bubbles by means of 99mtco4-, as reported in a previous publication.8 in fact, in the vascular stream pertechnetate ions remain in equilibrium, partially in free form and partially bound to serum proteins. more specifically, free ions leave the vascular compartment and migrate to interstitial fluids as a result of their small size, so as to decrease the pertechnetate blood concentration this leads to an equivalent release of 99mtco4that is bound to the proteins as an unavoidable result of its elimination.10 the pertechnetate ion is removed by various organs and systems into the interstitial liquid, as seen in the stomach, thyroid, salivary glands, bowel, choroid plexus, kidneys, vascular structures and mucosae.11 interestingly, the pertechnetate ion is strongly taken up by the thyroid gland only in its free form and not bound to other molecules.12 noticeably, lungs represent a transit organ for 99mtco4and its temporal concentration peak declines along the 30 min of the scintigraphic observation and this pattern is very similar also for other various organs.13 finally and more importantly, the increased capillary permeability leads to an increased 99mtco4uptake in inflamed tissues. therefore, in the case of possible drug-induced lung damage following foam sclerotherapy, there would be an increased 99mtco4persistence into the lungs after its injection during the post-treatment period. materials and methods a prospective comparative pilot study was performed on two male patients (56 and 62 years old) affected by primary varicose veins (c2 of ceap clinical-etiology-anatomicpathophysiologic classification) related to correspondence: lorenzo tessari, via giovanni falcone 24/b, peschiera del garda (vr), 37019 italy. tel.: +39.0456401681. e-mail: lorenzo@tessaristudi.it key words: foam sclerotherapy, scintigraphy. contributions: lt, study design, data collection, data analysis, critical review, final approval; mi, data analysis, critical review, final approval; ac, data collection, data analysis, writing, critical review, final approval; fz, data collection, data analysis, final approval; mt, data collection, final approval; dg, data analysis, critical review, writing, final approval. conflict of interests: the authors declare no potential conflict of interests. received for publication: 24 april 2014. revision received: 23 september 2014. accepted for publication: 24 september 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright l. tessari et al., 2014 licensee pagepress, italy veins and lymphatics 2014; 3:4037 doi:10.4081/vl.2014.4037 no n c om me rci al us e o nly article [page 48] [veins and lymphatics 2014; 3:4037] great saphenous vein (gsv) reflux. the patients were treated with sf which was labeled with a radionuclide (99mtco4-) and they gave informed written consent to the procedures; no ethical committee approval was required, as per any observational study in italy. basal scintigraphy was performed immediately after injection of 4 ml of saline solution with the radiotracer (rt) 99mtco4in a varicose tributary of the lower leg. subsequently, scintigraphy was performed after each of the four sessions of foam sclerotherapy which were performed on each patient. an overall imaging of the outcomes is reported in figure 1. injections were performed into the tributaries and the gsv stems, tailoring each session according to the outcomes achieved, using 4 ml of 2% pol foam or 4 ml of 1% sts foam per session with the patient in the supine position. sclerosant foam was obtained through tessari’s method2 with one part of sclerosant drug (pol or sts) and four parts of gas (air or co270%+o230%). prior to foam formation, the sclerosant drug was mixed with 99mtco4(120 mbq per exam): more specifically 1 cc of pol 2%, or 1 cc of sts 1% were mixed with 0.2 cc of rt. in more detail, the flow chart of the protocol for each patient was as follows: step 1, basal scintigraphy examination after injection of free 99mtco4(figure 2). step 2 at day 7, scintigraphy examination 10 min after pol 2% + air radiolabelled sclerosant foam injection (figure 3a). step 3 at day 14, scintigraphy examination 10 min after pol 2% + co2o2 radiolabeled sclerosant foam injection (figure 3b). step 4 at day 21, scintigraphy examination 10 min after sts 1% + co2o2 radiolabeled sclerosant foam injection (figure 3c). step 5 at day 28, scintigraphy examination 10 min after sts 1% + air radiolabeled sclerosant foam injection (figure 3d). step 6 at day 42, scintigraphy examination for one of the two patients during the 90 min following free rt injection and 90 min after sts 1% + air radiolabeled sclerosant foam injection (figure 4). this final step was undertaken to assess any possible late lung (and thyroid) tissue change due to several/repeated foam sclerotherapy sessions, as in the previous steps. radiation exposition was controlled in each patient after every step and no limitexceeding figure was recorded. uptake and transit of free rt and of sclerosant-bound rt were assessed in transit organs (lungs and heart) and in target organs (thyroid, salivary glands, stomach) with semiquantitative scintigraphy by means of a double-head gamma camera and region-of-interest (roi) investigation. all scans lasted 30 min except for the step 6 scan (90 min). all dynamic evaluations were focused on the chest and neck, in anterior and posterior projections. ninety photograms (1800 s in total) were taken at intervals of 20 s every frame (matrix 128¥128 pixel). the count per second in rois were plotted against time and the curves were fitted (counting out the initial transient phase). activity in the site of sclerosant injection was measured at different interval times (see above) and the total count was divided by the background activity registered in the contralateral leg. results at step 1 after injection of pertechnetate ion, the two patients showed a typical pattern of rt distribution in all transit and target organs and more specifically the semi-quantitative calculations resulted in a mean half time of 57.26 s in the lung, 57.35 s in the heart and -138.68 s in the thyroid. the integrated areas between 9th and 30th min were 336 (heart), 208 (lung) and 371 (thyroid). for each patient at step 1, step 2, step 3 and step 4, step 5 the various roi images (same size) and relative figure 1. curves and images of various regions-of-interest of different organ uptake afterfree radiotracer injection (step 1). figure 2. organ uptake at step 1 for one patient. no n c om me rci al us e o nly article [veins and lymphatics 2014; 3:4037] [page 49] curves of uptake have been summarized in table 1 where mean figures for each organ and each session are summarized. the mean figures have been calculated for each organ after summation of all resulting values for each step and from both patients. comparison between step 1 and steps 2, 3, 4 and 5 showed overlapping time/activity curves related to lung transit. assessment of overall amplitude of the curves showed a minimal difference in comparison to free rt curve related to the radioactivity which has remained trapped in the vessels of the leg which was the site of the sclerosant foam injection. the only relevant difference between the basal step 1 and all other foam sclerotherapy steps (2 to 5) concerned the delayed transit time and a small reduction in amplitude in all samples, which is a consequence of peripheral vein uptake of the rt mixed with sclerosant foam. in fact, spasm of the treated vein and sclerosant foam stagnation in the treated veins (varicose tributary and consequently gsv trunk) contributed to the delayed arrival of rt to the lungs. imaging of the varicose tributary and saphenous veins (figure 5a) clearly depicted rt stagnation in these peripheral vein territories and gradual 99mtco4release over time (figure 5). the activity/time curves related to the main up taking organs (thyroid and stomach in step 2,3,4 and 5 showed a pattern distribution which was overlapping the free rt curve of step 1. data on these dose uptakes are summarized in figure 1 and lung/thyroid/heart values are reported in table 1. as thyroid normally takes up 99mtco4in its free form, the findings above highlight how rt in thyroid circulation is neither bound to the sclerosant bubbles nor to the sclerosant drug. examination of any possible difference in the patterns and curves for the two sclerosant drugs sts and pol at the four different sclerotherapy steps (2 to 5) in comparison to step 1 (free rt) showed overall similar results. conversely, air-based sf showed a more prolonged delay in time overall to reach the maximum radioactivity in the curves (time to max) in comparison to co2+o2-based sf (table 2). we can speculate that bubbles of co2+o2 sclerosant foam tend to break up earlier than airbased sf so that rt release is accelerated. data analysis of the procedures of step 6 in one of the two investigated patients showed free 99mtco4curves at the pulmonary and thyroid levels which overlap the step 1 activity/time curves (figure 4). as no signifitable 1. figures deriving from total counts in the different regions-of-interest between the 9th and the 30th min in each curve. heart lung difference between thyroid basal (step 1) and sclerosant foam in lungs at step 2, 3, 4, 5 99mtco4–(basal) 336.02 208.49 371.64 pol air 293.00 191.74 −9% 292.42 pol co2 o2 351.36 202.04 −4% 335.08 sts co2 o2 328.51 188.29 −10% 263.23 sts air 265.61 191.29 −9% 324.43 pol, polidocanol; sts, sodiumtetradecylsulfate. figure 3. a) organ uptake at step 2 for one patient; b) organ uptake at step 3 for one patient; c) organ uptake at step 4 for one patient; d) organ uptake at step 5 for one patient. figure 4. a) step 6 images and curves of lungs after free radiotracer (rt) injection (left) and after last labeled sodiumtetradecylsulfate (sts) injection (right); b) step 6 images and curves of thyroid after free rt (left) and last labeled sts foam. no n c om me rci al us e o nly article [page 50] [veins and lymphatics 2014; 3:4037] cant difference in uptake was highlighted, these data confirm that at 42 days after four sclerotherapy sessions, no relevant changes in lung and thyroid circulation/tissues occurred. furthermore, the second part of step 6 consisted in one last foam sclerotherapy session with sts 1% sclerosant foam and subsequent scintigraphic assessment of rt uptake in the lungs and thyroid again showed no relevant changes in the curves in comparison to curves originating from free rt injection performed at the first part of step 6 (figure 4). as a consequence of these findings, no lung circulation changes due to sclerosant foam can be postulated. the lack of important variations in the time/activity curves of the lungs between the first and the last foam sclerotherapy session indicates that sclerosant foam does not reach or does not induce any lung lesion. discussion this observational experimental study was carried out to assess sclerosant foam effect on a few organs that may potentially receive a tissue lesion following sclerotherapy sessions. after a preliminary investigation on technetium pertechnetate chemical-physical proprieties and on the possible binding interactions with sf, the authors finalized a clinical and scintigraphy protocol. the aim was to assess the pathway of sf bubbles/drug through the blood stream and the binding/effect of sf on target and transit organ tissues. in a previous study,8 99mtco4was used to assess pulmonary patterns and bubble accumulation during foam sclerotherapy. in our study, the use of 99mtco4proved to be unreliable to demonstrate the sclerosant drug pathway along the blood stream and within the transit organs (e.g. lungs), as the radiotracer flows independently. in fact, to bind the sclerosant drug to the 99mtc we would need an adequate procedure of reduction 99mtco4-+ sn2+ + sts or pol and hence the extemporaneous way to combine sclerosant drug with rt proved to be of no utility. from the chemical and scintigraphy point of view, it is recognized that radionuclide 99mtc is obtained in physiologic solution as pertechnetate ion, and it has a coordination compound among technetium and oxygen. the metal atom is bound to four binding oxygen (0-2) thus forming a very compact tethraedron-like structure, with four identical faces of triangular shape. technetium oxidation state in ion is +7. this constitutes the most stable oxidation state and represents one of the most stable pertechnetate chemical species in watery solutions. in order to prepare a radiolabelled drug from the 99mtco4-, with coordinated bindings to give particular biological properties to the complex, it would be necessary to remove, partially or totally, the oxygen atoms that are bound to the metal. finally substitution of these o2 atoms with the coordinated atoms of new binders cannot happen with a simple extemporaneous mixing. hence tracing sf pathway by means of this radiolabelled ion would require a more complex process to overcome the chemical/physical difficulties as to above. contrasting evidence from a few studies highlighted the possible alterations induced by the sclerosant foam on the lung capillaries/tissues. after a preliminary non-conclusive scintigraphic study from milleret,8 on one side grandi9 and collaborators showed lung parenchyma lesions in rats after foam sclerotherapy, on the other side moro14 and coworkers recently showed no significant changes in pulmonary ventilation parameters after sclerosant foam injection. one of the objective limitation of grandi’s study9 subsides in the injected dose of sf in the rats which was by far much higher than the maximum permitted dose in humans; similarly the very short time/pathway between ears (the injected site) and lungs may have influenced their conclusions as well. notwithstanding the very small sample size, the variability of the methodology (gas, table 2. time to maximal radioactivity in each curve. lungs heart thyroid background (vs contralateral limb) 99mtco4 60 s 60 s 27 min 15 min co2o2-based sf 120 s 120 s 17 min 19 min air-based sf 5 min 4 min 26 min 26 min sf, sclerosant foam. figure 5. a) lung and great saphenous vein imaging and lung uptake curves (for the first five steps); b) heart imaging and relative uptake curves (for the five steps); c) thyroid imaging and uptake curves (for the five steps); d) stomach imaging and uptake curves (for the five steps). no n c om me rci al us e o nly article [veins and lymphatics 2014; 3:4037] [page 51] agents) and the limited pathology treated, this preliminary study confirms the overall safety of foam sclerotherapy as to the possible chemical lesion to transit/target organs. the invariable and total neutralization of sts or pol drug by blood components (proteins firstly) was demonstrated by parsi15-17 and watkins.18 similarly tessari and collaborators showed no free sts in the blood of common femoral vein (at short/mid/long term time intervals) after injecting sts-based sclerosant foam in the great saphenous vein/tributaries of the lower leg.19 due to the very small sample size no statistical analysis was performed, though all data seem to be coherent with the conclusions on the safety of foam sclerotherapy as to the possible chemical lesion in distal transit/target organs. similarly no specific speculation on the possible foam bubbles accumulation in the lungs is possibly drawn from this study, as the mechanical passage of the sf bubbles was not quantified with this methodology; conversely the clinical/experimental study was addressed to investigate any possible residual lesion on the pulmonary capillaries/tissues after sf passage. though our investigations were aimed mainly at pulmonary circulation and no specific scintigraphic examination was carried out for brain/ocular circulation, the final total body scintigraphy of the second patient (step 6) did not show any residual lesion in any organs, including cerebral parenchyma. the data from this observational study reinforce the concept of the absence of any direct chemical activity of sf within lungs and other central organs, which is coherent with the results of our scintigraphic study and with the results of other studies.15-19 conversely all scintigraphic investigations showed a clear increase of rt accumulation in the injected areas of the lower limbs, where inflammation and sclerothrombosis obviously occurred. conclusions a few conclusions may be drawn from the data collected through this scintigraphy-based preliminary study: i) definitely no damage of the sclerosant foam on the pulmonary tissues was demonstrated; ii) extemoraneous mixing of a sclerosant drug with pertechnetate ion is not a correct procedure to highlight the drug pathways in foam sclerotherapy, differently from what was shown in the past; new, alternative procedures for a stable binding between sts/pol and rt would be required if the sclerosant drug tracing within the blood stream is targeted; iii) little delayed uptake differences were shown as to the time/curves between free rt and sf, due to the sclerosant foam transient persistence in the peripheral vein where it was injected; iv) air-based sclerosant foam top radioactivity was reached later than co2+o2 based sf, due to the early release of the rt from the bubbles in the second case; v) no significant differences were highlighted between pol and sts curves. references 1. wollman jc. the history of sclerosing foams. derml surg 2004;30:694-703. 2. tessari l. nouvelle technique d’obtention de la sclero-mousse. phlébologie 2000; 53:129. 3. tessari l, cavezzi a, frullini a. preliminary experience with a new sclerosing foam in the treatment of varicose veins. derm surg 2001;27:58-60. 4. rabe e, breu f, cavezzi a, et al. european guidelines for sclerotherapy in chronic venous disorders. phlebology 2013;29:33854. 5. coleridge-smith p. chronic venous disease treated by ultrasound guided foam sclerotherapy. ejves 2006;32:577-83. 6. myers ka, jolley d, clough a, kirwan j. outcome of ultrasound-guided sclerotherapy for varicose veins: medium-term results assessed by ultrasound surveillance. eur j vasc endovasc surg 2007;33:116-21. 7. cavezzi a, parsi k. complications of foam sclerotherapy. phlebology 2012;27:46-51. 8. milleret r, mehier h. sclerosing foam and lung: a scintigraphic study. abstract presented at: 21st annual congress of the american college of phlebology. phlebology 2008;23:9. 9. grandi l, grandi ra, tomasi cd, et al. acute and chronic consequences of polidocanol foam injection in the lung in experimental animals. phlebology 2013;28:441. 10. saha gb. fundamentals of nuclear pharmacy. 5th ed. new york: springer verlag; 2004. 11. harden r, alexander wd. isotope uptake and scanning of stomach in man with 99mtc-pertechnetate. lancet 1967;1:13057. 12. zuckier ls, dohan o, li y, et al. kinetics of perrhenate uptake and comparative biodistribution of perrhenate, pertechnetate, and iodide by nai symporter-expressing tissues in vivo. j nucl med 2004;45: 500-7. 13. kuni cc. manual of nuclear medicine imaging. new york: thieme medical publishers; 1997. 14. moro l, rossi bartoli l, cesari m, et al. pulmonary gas exchange after foam sclerotherapy. jama dermatol 2014;150:207-9. 15. parsi k, exner t, connor de, et al. thelytic effects of detergent sclerosants on erythrocytes, platelets, endothelial cells and microparticles are attenuated by albumin and other plasma components in vitro. eur j vasc endovasc surg 2008;36:216e23. 16. parsi k, exner t, connor de, et al. in vitro effects of detergent sclerosants on coagulation, platelets and microparticles. eur j vasc endovasc surg 2007;34,731-40. 17. parsi k, exner t, low j, et al. in vitro effects of detergent sclerosants on antithrombotic mechanism. eur j vasc endovasc surg 2009;38:220-8. 18. watkins mr. deactivation of sodium tetradecyl sulphate injection by blood proteins. eur j vasc endovasc surg 2011; 41:521-5. 19. tessari l, izzo m, cavezzi a, et al. timing and modality of the sclerosing agents binding to the human proteins: laboratory analysis and clinical evidences. venis and lymphatics 2014;3:3275. no n c om me rci al us e o nly early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. eissn 2279-7483 https://www.pagepressjournals.org/index.php/vl/index publisher's disclaimer. e-publishing ahead of print is increasingly important for the rapid dissemination of science. the early access service lets users access peer-reviewed articles well before print / regular issue publication, significantly reducing the time it takes for critical findings to reach the research community. these articles are searchable and citable by their doi (digital object identifier). veins and lymphatics is, therefore, e-publishing pdf files of an early version of manuscripts that have undergone a regular peer review and have been accepted for publication, but have not been through the typesetting, pagination and proofreading processes, which may lead to differences between this version and the final one. the final version of the manuscript will then appear in a regular issue of the journal. e-publishing of this pdf file has been approved by the authors. all legal disclaimers applicable to the journal apply to this production process as well. https://www.pagepressjournals.org/index.php/vl/index early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. veins and lymphatics 2023 [online ahead of print] to cite this article: lorenzo tessari, mirko tessari. foam-glue syringe: a novel combined echo-guided endovascular treatment. veins and lymphatics. 2023;12:11594. doi:10.4081/vl.2023.11594 ©the author(s), 2023 licensee pagepress, italy early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. foam-glue syringe: a novel combined echo-guided endovascular treatment lorenzo tessari, mirko tessari tessari studi legs medical institute, peschiera del garda, italy corresponding author: mirko tessari, via oscar righetti 2, 37019 peschiera del garda, italy. e-mail: mirko@tessaristudi.it key words: glue, foam, sclerofoam, sclerotherapy, varicose vein. mailto:mirko@tessaristudi.it early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. background i would like to begin this introduction by describing what bassi called the "mixed method". the "mixed" or "combined" method of treatment aims to use surgery and sclerosis only to the best of their respective aptitudes and at the same time to take advantage of the functional restoration capabilities of the residual varicosities. the aim of combining the two techniques was to allow one technique to partially or totally annul the limitations or defects of the other.1,2 bassi said: “the advantages of the mixed method are numerous, important and varied”. physiopathological advantages first of all, limiting stripping to the proximal vein tract allows avoiding unnecessary venous sacrifice, as it has been demonstrated that the distal segment of the internal saphenous vein is not insufficient in the most advanced cases sclerotherapy, for its part, is greatly facilitated by the preliminary suppression of ostial reflux, so that the process of fibrous transformation of the injected varices takes place in the best possible way.1,2 in this way bassi argued for the necessity of combining surgery and sclerotherapy, limiting the former to the closure of the leakage points or so-called compartment jumps and the latter to the cleaning of the limb of all residual varicosities after closure of the leakage points. this principle later became the basis of the conservatrice hemodynamique de i'insuffisancie veineuse en ambulatoire (chiva) method/philosophy3 wonderfully decribed by claude franceschi that will lead us all to perform our treatments on the guidance of a meticulous haemodynamic examination, and in respect of the venous haemodynamic of the lower limbs. early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. nowadays, the application of the mixed method can be found in the techniques known as mechanochemical ablation (moca) and the latest sclero foam assisted laser treatment (sfalt), which uses the combination of laser and sclerofoam. based on these premises, we fully agree on the need for conservative haemodynamic phlebological therapy for varicose veins of the lower limbs with the characteristics of: i) invasiveness reduced to a minimum; ii) no use of operating theatres; iii) ltrasound control of the therapeutic act; iv) easy repeatability and correctability; v) perfect compliance with chiva haemodynamic standards. i had the idea of building a device "syringe for successive injection of substances" with which it is possible to replace the series of ligatures proposed by c. franceschi with this device, which combines the advantages of sclerofoam and glue with an extremely simple act, without the use of operating room, without anaesthesia, and with a simple act under ultrasound guidance. it is therefore possible to perform all the chiva manoeuvres listed above for a haemodynamic conservative therapy of the superficial venous system (interruption of the leakage points and fragmentation of the haematic column).4 the synergy between two well-known and established therapeutic methodologies lies in the symbiosis of the two techniques, one correcting the limitations and errors of the other in an easy and practical outpatient therapeutic procedure. chiva is a strategy and not a technique. so advanced technology may permit to perform chiva with more sophisticated and less invasive techniques.5,6 let us now list the merits and limitations of each technique performed individually and the advantages of symbiosis (table 1). early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. the symbiosis between the two procedures only creates advantages because: i) the echogenicity of the foam allows an act as precise and safe as a phlebography; ii) the aspiration of blood into the syringe does not create polymerization of the glue as this is only injected after the foam; iii) the spasm that the foam generates eliminates the need for compression after glue injection; iv) no need for anaesthetist nor operating room. the above allows us to treat the leakage points, the so-called compartment jumps, and the splitting of the varicose blood column in accordance with the chiva rules written by c. franceschi with a simple, easy and ambulatory act. materials and methods: the preparation of the sclerosing foam needs no further explanation, i will however summarise some key steps: two 5 ml syringes with little or no silicone are used, joined together by a three-way tap with, in my modus operandi, a 2-micron filter in between, which allows the foam to be homogeneous; in the first syringe, 1 ml of drug (3% sodium tetradecyl sulphate or 3% polyethoxydodecane) is sucked in; in the second syringe, 4/5 ml of air or biocompatible gas co2 + o2 or air alone is sucked in; about 20 passes are made between one syringe and the other, and the foam is ready to be injected.7-12 the cyanacrylate glue is drawn into a second 2ml syringe. some glues are very viscous and therefore requires a needle no smaller than g21 to be injected. syringe and needles can be pre-washed with glucosate solution if necessary, for some glues.13 there is currently an italian glue composed by n-butyl 2 cyanoacrylate (nbca) early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. monomer plus methacryloxy-sulpholane monomer (ms) that does not need this procedure as it has a density similar to water.14 after having used the various types of glue offered by the american and turkish markets (cases 1-3), with the various limitations that the products had excessive viscosity, delayed polymerization, the need to pre-wash needles and syringes with the glucose solution, i started using an italian glue (case 4) nbca + ms. it is a very fluid product, not need pre-washed with glucosate solution, it is well distributed inside the vessel, polymerizes rapidly in the release zone and therefore can be used in small quantities. once the foam has been prepared with the 5 ml foam glue syringe, the 2 ml syringe pre-filled with the glue to be used and its g21 needle, 16 mm short, is inserted into the syringe's perforated plunger (figure 1, figure 2). under ultrasound guidance the perforant or the compartment jump to be treated is identified, the chosen foam is injected, immediately the spasm is observed with the complete gluing of the vein itself, at this point the glue syringe is advanced into the foam-glue syringe so that the needle of the 2 ml syringe pierces the rubbery diaphragm of the first syringe. you can then inject the glue at the precise point where you want the closure of the compartment jump with the certainty that since the vein walls are firmly clamped on themselves for a period of 15/20 minutes you will have a perfect bonding of the walls themselves without any need for external compression (figure 3). early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. clinical cases v. r., male, 65 years old 2008 left internal saphenous vein varicophlebitis, the haemocoagulative genetics check showed hyperhomocysteinemia (mthfr heterozygosity), in the same year the left internal saphenous vein was deconnected from the femoral to saphenous vein, subsequently due to the appearance of scotomas after sclerotherapy with foam, patency of the foramen ovale was diagnosed. on december 17th, 2020, check-up shows marked incontinence of boyd's perforant on the left. it is therefore decided to proceed with joint foam-glue therapy at the same time (figure 4). with the foam-glue syringe 5ml of foam sodium tetradecyl sulfate 3% is injected followed by 0,5 ml of glue (n-bca-polymer). the patient was monitored for 2 years and half from the start of the foam-glue treatment. the follow-up highlighted the elimination of the reflux in boyd's perforator (figure 5). f. m. t., female, 65 years old in 1990 the patient underwent a left internal safenectomy with multiple varicectomies and ligation of left gluteal perforant. on december 7th, 2020, during the ecd examination, a perforant incontinence of left thigh of gluteal origin was found, above the scar from a previous ligation (figure 6). early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. with the foam-glue syringe 5ml of foam sodium tetradecyl sulfate 3% is injected followed by 0,5 ml of glue (n-bca-polymer). the patient was monitored for 2 years and half from the start of the foam-glue treatment. the follow-up highlighted the elimination of the reflux in gluteal perforant. (figure 7) f. m. t., female, 65 years old (the same patient of case 2, but in a different reflux point) in 1990 the patient underwent a left internal safenectomy with multiple varicectomies and ligation of left gluteal perforant. on february 26th, 2021, during the ecd examination, a perforant incontinence of left thigh of thiery or perforating popliteal fossa was found (figure 8). with the foam-glue syringe 5ml of foam sodium tetradecyl sulfate 3% is injected followed by 0,5 ml of glue (n-bca-polymer). the patient was monitored for 2 years from the start of the foam-glue treatment. the follow-up highlighted the elimination of the reflux in thiery’s perforant (figure 9). early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 9. follow up case 3. a) no reflux by ecd in gluteal perforant at 1 month. b) check at 6 months, no reflux. c) check at 12 months, no reflux. d) after 24 months, no reflux in thiery’s perforant. c. r., male, 39 years old for 2 years the patient has been reporting that he has a post-trauma varicose vein. the ecd examination reveals a reflux of the atypical postero-lateral perforant of the left thigh (figure 10). early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 10. a) haemodynamic cartography by ecocolordoppler (ecd). in red, the incontinent perforant vein. b) leg area to be treated. c) reflux of perforant vein to the ecd investigation, with the foam-glue syringe 5ml of foam sodium tetradecyl sulfate 3% is injected followed by 0,3 ml of glue (nbca + ms). the patient was monitored for 2 years from the start of the foam-glue treatment. the follow-up highlighted the elimination of the reflux in perforant vein (figure 11). early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 11. follow up case 4. a) foam-glue coaxial injection site. note the hyperechogenicity on b-mode analysis. b) check at 6 months, no reflux. c) check at 12 months, no reflux. d) after 24 months, no reflux in atypical postero-lateral perforant vein. conclusions we used the novel technique mainly on non-terminal perforators, which are very challenging both by using open surgery and endovascular technique. our preliminary results seem to suggest that this novel technique could be also applied to classic gsv, ssv varicose vein, and maybe this could merit a clinical trial. however, it is mandatory to respect the chiva indication for the treatment of the sfj or just of the n2-n3 escape points.15,16 these first data from clinical cases are encouraging. after more than two years of follow-up, no adverse events early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. and/or allergies were found. the venous symptomatology and the reflux were eliminated with a simple treatment. a new revolution in the field of phlebology is born with this method. the combination of these two methods creates a synergy that allows the phlebologist, under echo guidance, to treat any venous pathology in a simple way and with a precise act and in line with the concept of a haemodynamic conservative phlebology of the superficial venous system. references 1) bassi g. compendio di terapia flebologica. ed minerva medica 1990. 2) bassi g. varicose veins of lower members edition doins 1967 3) franceschi c. theory and practice of the conservative and hemodynamical cure of veinous in ambulatory insufficiency edition de l'armancon 1988 4) bellmunt-montoya s, escribano jm, pantoja bustillos pe, et al. chiva method for the treatment of chronic venous insufficiency. cochrane database syst rev. 2021;9:cd009648. 5) zamboni p, mendoza e, gianesini s. saphenous vein-sparing strategies in chronic venous disease. ed springer 2018 6) gianesini s, menegatti e, zuolo m, et al. short endovenous laser ablation of the great saphenous vein in a modified chiva strategy. veins and lymphatics 2013;2:e21 7) tessari l. new technique for obtaining sclero-foam. phlebology 2000;53:129. https://link.springer.com/book/10.1007/978-3-319-70638-2#author-1-0 https://link.springer.com/book/10.1007/978-3-319-70638-2#author-1-1 https://link.springer.com/book/10.1007/978-3-319-70638-2#author-1-2 early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 8) tessari l. frullini a. cavezzi a. sclero mousse with fibro-vein® (bloom technique) new alternative practice to sclerotherapy of varicose diseases. xxiith meeting european society of phlebectomy brussels april 1, 2000 9) tessari l, cavezzi a, frullini a. preliminary experience with a new sclerosing foam in the treatment of varicose veins. dermatol surg. 2001;27:58-60. 10) cavezzi a, tessari l, frullini a. a new sclerosing foam in the treatment of varicose veins: tessari method. minerva cardioangiol. 2000;48:248. 11) cavezzi a, tessari l, rosso m, cabrera garrido a. variables in foam sclerotherapy with tessari method: experimental data. int angiol. 2009;28:9. 12) cavezzi a, tessari l. foam sclerotherapy techniques: different gases and methods of preparation, catheter versus direct injection. phlebology 2009; 24:247-51. 13) parsi k, roberts s, kang m et al. cyanoacrylate closure for peripheral veins: consensus document of the australasian college of phlebology. phlebology. 2020;35:153-75. 14) montanaro l, arciola cr, cenni e, et al. cytotoxicity, blood compatibility and antimicrobial activity of two cyanoacrylate glues for surgical use. biomaterials. 2001;22:59-66. 15) zamboni p. 2016: the year of phlebological olympic games. veins and lymphatics 2016;5:6249. 16) p zamboni et al. great saphenous varicose vein surgery without saphenofemoral junction disconnection, british journal of surgery. 2010;97:820-5. early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. glue foam limits advantages limits advantages complex use of the device now in use perfect closure of the treated segment foam dislocation due to spasm effect extreme ease and versatility of use immediate polymerization of the glue on contact with the blood rapid stabilisation of the treatment neutralisation of the effect high echogenicity, which allows the treatment to be controlled like a phlebography need compression to bring the venous walls closer together (difficult for compression of muscle perforant) only one treatment for that area production of a long and power spasm leading to venous wall collapsing no anaesthesia no operating room no anaesthesia no operating room table 1. limits and advantages of glue and foam during the single treatment. early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 1. foam-glue syringe. early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 2. foam glue syringe system ready for treatment early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 3. foam glue syringe system echo-guide injection. early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 4. a) haemodynamic cartography by ecocolordoppler (ecd). in red, the incontinent perforant vein. b) leg area to be treated. c) reflux of boyd's perforant vein to the ecd investigation. early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 5. follow up case 1. a) no reflux by ecd in boyd's perforant at 1 month. b) at 3 months no reflux. c) check at 6 months, no reflux. d) check at 12 months, no reflux. e) after 30 months, no reflux in boyd's perforant. early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 6. a) haemodynamic cartography by ecocolordoppler (ecd). in red, the incontinent perforant vein. b) leg area to be treated. c) reflux of perforant vein to the ecd investigation. early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 7. follow up case 2. a) no reflux by ecd in gluteal perforant at 1 month. b) check at 6 months, no reflux. c) check at 12 months, no reflux. d) after 30 months, no reflux in gluteal perforant. early access veins and lymphatics how i do it the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 8. a) haemodynamic cartography by ecocolordoppler (ecd). in red, the incontinent perforant vein. b) leg area to be treated. c) reflux of perforant vein to the ecd investigation. hrev_master veins and lymphatics 2014; volume 3:1938 [veins and lymphatics 2014; 3:1938] [page 23] associations of anterior accessory or thigh posterior tributary and great saphenous reflux patterns in early stages of chronic venous valvular insufficiency carlos alberto engelhorn,1,2 ana luiza dias valiente engelhorn,1,2 sergio xavier salles-cunha,2 carolina b. andreatta,1 daniella b. santos,1 gustavo t.m. nakata,1 fernando a. haida1 1pontifícia universidade católica do paraná, school of medicine; 2angiolab-laboratório vascular não invasivo, curitiba, pr, brazil abstract varicose veins are a common disorder. extensive ultrasound (us) mapping of lower extremity chronic venous valvular insufficiency includes the great saphenous vein (gsv), anterior accessory saphenous vein (aasv) and thigh posterior tributary to gsv such as the posterior accessory saphenous vein (ptsv, pasv). the aim of this study was to determine associations between gsv-aasv-ptsv (including pasv) reflux in a specific sample population of southern brazilian women, mostly euro descendents, with telangiectasias, reticular veins, varices and/or intermittent edema. us performed in 1016 extremities of 513 women, 43±18 (18-81) years old were included. women with previous venous thrombosis, surgery, suspicion of pelvic congestion syndrome, and men were excluded. small saphenous vein and related thigh veins were excluded from analysis. gsv-aasv-ptsv reflux patterns were analyzed; prevalence was compared using χ2 statistics. reflux prevalence in aasv and/or thigh ptsv was 5.8% (59/1016): 1.3% at ptsv (n=13) and 4.5% at aasv (n=46), significantly lower than gsv reflux: 72% (n=727) (p<0.001). aasv and/or ptsv reflux was associated with gsv reflux (81%, n=48/59); common pattern was diffuse reflux, starting at aasv/ptsv saphenous junctions (56%, n=33/59; otherwise, short, non-diffuse reflux was noted in part of the aasv/ptsv evaluated. isolated aasv or ptsv reflux was rare (1%, n=11/1016): 9 at the aasv, and 2 at the ptsv. us mapping of aasv/ptsv in early stages of disease, in women without pelvic congestion syndrome, increased reflux detection by 1%, and improved definition of reflux patterns in about 6% of the extremities. introduction varicose veins and telangiectasias, associated with chronic venous valvular insufficiency (cvvi) of lower extremities, are common and deserving special attention.1-12 cvvi is a common subset of chronic venous insufficiency (cvi). modern tendency is to become more specific on phlebologic investigation. the focus of this work was on cvvi exclusively, to avoid confusion with thrombosis or malformations. the following paragraphs summarize the focus on early cvvi, introduce our great saphenous vein (gsv) reflux findings in early stages of disease, and questions if we should evaluate the anterior accessory saphenous vein (aasv) and thigh posterior tributaries (ptsv) such as the posterior accessory saphenous vein (pasv) in patients with aesthetics more so than pathophysiological conditions. an international consensus created the clinical, etiological, anatomic and pathophysiological classification (ceap).10 ceap has improved description of populations studied but investigation of specific subgroups is needed. we have focused on women with early stage.2,8-9 gsv reflux has been related to its diameter.13 patterns of saphenous vein reflux were created, improving communication with referring physicians.2,8-9,14 these patterns specified reflux sources and drainage points. tributaries were more associated to gsv reflux than perforating veins in c1-c2 women.14,15 most gsv reflux in c2 women was segmental, from one tributary to another.2,9 gsv reflux was mostly in the leg, rarely in the saphenofemoral junction (sfj).9 telangiectasias were associated to segmental saphenous vein reflux.8 segmental reflux, if not treated, evolved to multi-segmental saphenous reflux.2 non-saphenous vein reflux has received its due attention.16 reflux in gluteal, lateral or anterior thigh, or pubic veins raise suspicion of pelvic varicosities, particularly in the presence of symptoms of pelvic congestion syndrome.17 patients with suspected pelvic varicosities were not included in this analysis. thigh accessory or tributaries to the gsv may be associated with saphenous or nonsaphenous reflux. most findings already described, however, were noted in patients with longterm cvi. the present analysis focuses on ultrasound (us) of the aasv and thigh ptsv in women with early telangiectasias, reticular veins, varicose veins and/or intermittent swelling. materials and methods patients were referred by a variety of specialists to an iso accredited noninvasive vascular laboratory, angiolab-curitiba, of a major city in southern brazil. venous duplex examinations were pre-approved by insurance companies. a data base has been maintained prospectively. retrospective analysis of gsv, aasv and ptsv patterns of reflux was performed. this project was part of protocol number 207-0084-000111 of the national commission on ethics of research and approved by the ethics research committee of pontificia universidade católica do paraná. correspondence: carlos alberto engelhorn and sergio xavier salles-cunha, rua josé casagrande, 1310, bairro vista alegre, curitiba, pr, cep 80820-590 brazil. tel.: (55).41.3362.0133. e-mail: carlos.engelhorn@pucpr.br ; sallescunha@yahoo.com key words: venous valvular insufficiency, duplexdoppler ultrasound, great saphenous vein, anterior accessory saphenous vein, posterior accessory saphenous vein, posterior tributary vein. contributions: cae, aldve, primary conception, primary design, data acquisition, data interpretation, data storage, manuscript critical revision, final approval of the version to be published, fully accountable; sxsc, general conception, general design, data analysis, data interpretation, drafting the work, final approval of the version to be published, fully accountable; cba, dbs, gtmn, fah, secondary conception, secondary design, data retrieval, manuscript revision, initial approval of manuscript, secondary accountability. conflict of interests: cae and ale own the private angiolab, inc, noninvasive vascular laboratory; sxsc is a research, quality assurance consultant for angiolab, inc. funding: angiolab, inc, curitiba, pr, brazil. conference presentation: oral presentation, society for vascular ultrasound, 2012 society for vascular ultrasound (svu) annual conference, national harbor, md, usa. received for publication: 23 september 2013. revision received: 19 may 2014. accepted for publication: 21 may 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright c.a. engelhorn et al., 2014 licensee pagepress, italy veins and lymphatics 2014; 3:1938 doi:10.4081/vl.2014.1938 no nco mm er cia l u se on ly article [page 24] [veins and lymphatics 2014; 3:1938] inclusion criteria women with telangiectasias or reticular veins (ceap clinical class c1), varicose veins (c2), or intermittent swelling (suggested c3a versus constant c3 edema) were candidates for the study. etiology (e) was primary; anatomy (a) included superficial veins of the thigh; and pathophysiology (p) was reflux only. data entry stopped when over 1000 extremities were posted. exclusion criteria exclusion of all men avoided gender variability. women with constant, chronic edema, skin changes, and healed or open ulcers (c3, c4a, c4b, c5, c6), history of previous deep venous thrombosis (dvt), suspicion of pelvic venous insufficiency, venous malformations, and/or previous direct treatment of lower extremity veins were excluded. exclusion based on treatment included surgery, minimally invasive thermal ablation, and chemical ablation with foam or sclerosant. venotonic oral medication, or compression stockings, or deep venous reflux due to valvular insufficiency only were not reason for exclusion. small saphenous vein (ssv), respective thigh extensions, and other leg veins besides gsv were not analyzed. patient population us data from 1016 limbs of 513 women, 43±13 (range 18-81) years-old, were analyzed. patients represented an educated, middle class of southern brazil, mostly european descendants, from portuguese, spanish, italian, german, and ucranian ancestry. this sample population did not represent the brazilian multi-ethnicity, neither the various social classes. specifically, rural or community groups were not represented. the women evaluated had aesthetic and/or functional interests; visual appearance, itching or slight burning sensation were common causes to seek medical attention. clinical presentations c1c2 and suggested-c3a, intermittent swelling, could be combined, varying from almost none to easily detectable. ultrasonographic duplex-doppler examination international recommendations were followed and adapted to cases of early stage venous valvular insufficiency.18,19 us examinations were performed and interpreted by physicians certified in vascular noninvasive testing. patients received instructions prior to and during the examination. siemens (issaquah, wa, usa) elegra or antares scanners were employed. the most commonly used transducer was centered at 7 mhz (4-9 mhz). dvt, venous obstruction, and/or malformations were ruled out with the patient supine or standing. superficial venous mapping was performed in the standing position. patient movement and periods of rest avoided fainting. examinations lasted around 40 min. valsalva or valsalva-like maneuvers such as talking and laughing were employed according to individual behavior. muscle and venous compression maneuvers were performed manually, proximal and distally to probe placement. backflow causing venous filling was commonly tested with multiple compression maneuvers to avoid false reflux data. reverse flow through potentially normal, valveless, limited saphenous segments, however, was reported if a draining tributary had reflux; apparently normal draining via a perforating vein was described as reflux, particularly if a diameter dilatation was noted in such segment. short reflux segments, as short as 4 cm, were detectable with this compression technique.8 this approach emphasized testing variety and completeness, taking into consideration that daily life conditions were difficult to be reproduced in the vascular laboratory. local changes in venous diameters were noted. segmental reflux was recorded with information about source and drainage points. according to the original concept, reflux lasting less than 0.5 s was normal.20 consequently reflux lasting longer than 0.5 s was considered not normal. superficial vein reflux lasted longer than 1 s in most cases. gsv and its tributaries were evaluated from the groin to the ankle. although modern consensus mandates that the gsv term be used for the vein within the saphenous compartment, long, gsv reflux patterns may have included small tributary segments outside the saphenous compartment. diffuse gsv reflux included either the gsv proper in the calf or the posterior arch-posterior accessory vein extending to the ankle level. in general, the sfj defined common femoral yes-or-no source of reflux and gsv yes-or-no reflux from a source at or near the junction. the superficial epigastric vein is an example of a non-common femoral source of gsv reflux. non common femoral reflux source, however, was expected to have low prevalence in the population studied. gsv reflux patterns as shown in figure 1: i) segmental if from a tributary or perforating vein distal to the sfj to a tributary or perforating vein proximal to the ankle; segmental reflux is most common in the calf than in the thigh or knee;9 ii) distal from a tributary or perforating vein to the ankle; iii) multi-segmental with two or more distinct refluxing segments but a normal sfj; iv) multi-segmental with reflux at the sfj; v) proximal from the sfj to a tributary or perforating vein at the thigh or calf above the ankle, having a normal distal segment; vi) diffuse throughout the entire vein, from sfj to the ankle; vii) perijunction if nonfemoral-saphenous, femoro-nonsaphenous, nonfemoral-nonsaphenous reflux at the junction; or viii) no reflux. aasv and ptsv were investigated in the thigh. the aasv drained the anterior surface of the thigh, running parallel to the gsv, into the saphenous-femoral junction.19,21 aasv alignment with the femoral artery and vein were searched for proper identification. the ptsv, including pasv, drained the posterior surface of the thigh into the proximal gsv segment.19,21 a classical, noticeable, predominant giacomini vein from the ssv to the gsv was not part of ptsv statistics in this study. the ptsv included as such in this study drained primarily the posterior thigh. origin and drainage of varicose veins were noted. usual mapping included disfigure 1. diagrams exemplifying common great saphenous vein reflux patterns, from left to right of the observer: segmental, distal, multi-segmental with normal saphenofemoral junction (sfj), multisegmental with refluxing sfj, proximal, and diffuse throughout the vein (modified from engelhorn et al.,9 drawings by monique salles-cunha). no nco mm er cia l u se on ly article [veins and lymphatics 2014; 3:1938] [page 25] tances from source and drainage points of reflux to anatomic landmarks. aasv and ptsv reflux were classified as diffuse or non-diffuse. diffuse aasv reflux, throughout the vein segment studied, started at the femoral junction and continued at least to the mid-distal thigh or knee. non-diffuse reflux occurred in segments shorter than the venous segment studied. ptsv reflux was diffuse if included the junction to the gsv and extended distally for the entire segment evaluated, usually to mid-distal thigh. ptsv reflux was non-diffuse if shorter than the venous segment evaluated. figure 219,21 diagrams common configurations. figure 3 exemplifies aasv reflux at the femoral junction. statistics descriptive statistics indicated frequency or prevalence of gsv, aasv and/or ptsv reflux. prevalence was compared using χ2 statistics from excel files. results this session describes patterns and prevalence of gsv, aasv and ptsv reflux, and the relations between aasv or ptsv and gsv patterns of reflux. prevalence of great saphenous vein, anterior accessory saphenous vein and posterior tributary saphenous vein reflux all gsv were examined. there were high percentages of insignificant or undetected aasv or ptsv; aasv and ptsv were evaluated for reflux in 40% (406/1016) of the limbs: aasv in 34% (348/1016), a ptsv in 9% (88/1016), and combined in 3% (30/1016) of the extremities. reflux was most prevalent in the gsv, 72% (727/1016), then in the aavs, 4.5% (46/1016), and least prevalent in ptvs, 1.3% (13/1016) (p<0.001 for all comparisons). percentages of reflux per aasv or ptsv examined were 13% (46/348) and 15% (13/88) respectively. total prevalence of reflux in either gsv, aasv and/or pasv was 73% (738/1016). single or multiple locations of reflux were: i) gsv only: 679 limbs (66.8% of 1016 limbs); ii) aasv only: 9 limbs (0.9%), 3 with diffuse and 6 with non-diffuse reflux; iii) ptsv only: 2 limbs (0.2%) with non-diffuse reflux; iv) gsv and aasv: 37 limbs (3.6%), 23 with diffuse and 14 with non-diffuse aasv reflux; v) gsv and ptsv: 11 limbs (1.1%), 7 with diffuse and 4 with non-diffuse pasv reflux; vi) aasv and pasv: 0; vii) gsv, aasv and pasv: 0 limbs; and viii) no reflux in the gsv, aasv and ptsv: 278 limbs (27%). non-diffuse reflux predominated in cases of isolated aasv or ptsav reflux, 73% (8/11) vs 27% (3/11) with diffuse reflux (p=0.03). patterns of great saphenous vein reflux prevalence of gsv flow or reflux patterns were, from most to least common: i) segmental reflux, 32.0% (n=325/1016 limbs); ii) no reflux, 28.4% (n=289/1016); iii) multi-segmental reflux with normal sfj, 11.8% (n=120/1016); iv) proximal, 8.8% (n=89/1016); v) distal, 8.0% (n=81/1016); vi) multi-segmental reflux with sfj reflux, 7.3% (n=74/1016); vii) diffuse reflux, 3.1% (n=31/1016); and viii) peri-sfj reflux, 0.7% (n=7/1016). segmental or multi-segmental reflux patterns with normal sfj were noted in 44% figure 2. diagrams exemplifying diffuse or non-diffuse reflux of the anterior accessory saphenous vein (aasv) or thigh posterior tributary to saphenous vein (ptsv) in red, located anterior or posteriorly in the thigh in relation to the great saphenous vein in blue. identification of the aasv and ptsv were consistent with descriptions by cavezzi et al. and caggiati et al.19,21 diffuse reflux was present in the entire segment evaluated. nondiffuse reflux was limited to small vein segments, components of the entire venous segment evaluated. short length, proximal reflux was included in the non-diffuse group. dotted line indicating that the small to great saphenous connecting vein was not part of the ptsv analysis. figure 3. duplex doppler ultrasound showing anterior accessory saphenous vein (aasv) reflux at the femoral junction. a) doppler reverse flow signal from the femoral to the aasv; b) color flow image of the common femoral and great saphenous vein (gsv) in blue and the aasv in red (anatomic variations are described, for example, in http://www.phlebologia.com/en/jonction_sapheno_femorale.asp); and c) color flow image of a normal gsv in blue and doppler signal showing gsv flow toward the common femoral vein. no nco mm er cia l u se on ly article [page 26] [veins and lymphatics 2014; 3:1938] (n=445/1016) of extremities. with the addition of distal reflux, gsv reflux with normal sfj was noted in 52% (n=526/1016) of limbs, equivalent to 72% (n=526/727) of refluxing gsv. junction reflux (iv+vi+vii+viii) was noted in 20% (n=201/1016) of limbs. sfj reflux was significantly less common than normal sfj flow (p<0.001). patterns of anterior accessory saphenous vein reflux prevalence of aasv flow or reflux patterns were, from most to least common: i) insignificant flow or size, 65.7% (n=668/1016); ii) no reflux, 29.7% (n=302/1016); iii) diffuse reflux, 2.6% (n=26/1016); and iv) non-diffuse reflux segmental away from the junction or short proximal segment, 2.0% (n=20/1016). prevalence of aasv diffuse, proximal or segmental reflux was 4.5% (n=46/1016). patterns of posterior tributary to saphenous vein reflux prevalence of ptsv flow or reflux patterns were, from most to least common: i) insignificant flow or size, 91.3% (n=928/1016); ii) no reflux, 7.4% (n=75/1016); iii) diffuse reflux, 0.7% (n=7/1016); and iv) non-diffuse reflux – segmental away from the junction or short proximal segment, 0.6% (n=6/1016). prevalence of ptsv diffuse, proximal or segmental reflux was 1.3% (n=13/1016). relations between anterior accessory saphenous vein and great saphenous vein reflux patterns table 1 shows cross-tabulation between patterns of reflux in the aasv and gsv. distribution of gsv reflux patterns was significantly different as a function of aasv patterns (p<0.001, χ2 applied to 4¥8 data of table 1). diffuse aasv reflux was associated with higher prevalence of sfj reflux. some two-by-two comparisons provided the following statistics: i) diffuse aasv plus sfj reflux showed significantly higher prevalence, n=14 of 26 (54%), than the expected prevalence of approximately 20%, n=5, as shown in table 2 (p<0.001); and ii) non-diffuse aasv plus sfj reflux showed a real prevalence, n=4 of 20 (table 1), equal to the expected prevalence of 20% (p=0.98). relations between posterior tributary to saphenous vein and great saphenous vein reflux patterns table 3 shows cross-tabulation between patterns of reflux in the ptsv and gsv. distribution of gsv reflux patterns was not significantly different as a function of ptsv table 1. cross-correlation between anterior accessory saphenous vein and great saphenous vein patterns of reflux. type gsv aasv* dif msp pro pej mseg dst seg nor total diffuse 2 8 2 2 3 2 4 3 26 non-diffuse 0 2 0 2 1 3 6 6 20 no reflux 5 11 16 1 44 23 100 102 302 insignificant 24 53 71 2 72 53 215 178 668 total 31 74 89 7 120 81 325 289 1016 percentages diffuse 7.7 30.8 7.7 7.7 11.5 7.7 15.4 11.5 100% non-diffuse 0.0 10.0 0.0 10.0 5.0 15.0 30.0 30.0 100% no reflux 1.7 3.6 5.3 0.3 14.6 7.6 33.1 33.8 100% insignificant 3.6 7.9 10.6 0.3 10.8 7.9 32.2 26.6 100% total 3.1 7.3 8.8 0.7 11.8 8.0 32.0 28.4 100% gsv, great saphenous vein reflux patterns; aasv, anterior accessory saphenous vein; dif, diffuse; msp, multisegmental proximal, including saphenofemoral junction; pro, proximal; pej, perijunction; mseg, multisegmental; dst, distal; seg, segmental; nor, no reflux. *diffuse aasv started at the femoral junction reflux. non-diffuse reflux was detected only in part of the aasv examined. table 2. cross-correlation between anterior accessory saphenous vein and great saphenous vein patterns of reflux. type gsv-sfj reflux* diffuse aasv° yes no total real prevalence yes 14 (54%) 12 (46%) 26 (100%) no 187 (19%) 803 (81%) 990 (100%) total 201 815 1016 expected prevalence yes 5 (19%) 21 (81%) 26 (100%) no 196 (20%) 794 (80%) 990 (100%) total 201 815 1016 gsv, great saphenous vein; sfj, saphenofemoral junction; aasv, anterior accessory saphenous vein. *sfj reflux: diffuse, multisegmental, proximal or perijunctional; °diffuse aasv started at the femoral junction reflux. non-diffuse reflux was detected only in part of the aasv examined. table 3. cross-correlation between thigh posterior tributary to saphenous vein and great saphenous vein patterns of reflux. type gsv ptsv* dif msp pro pej mseg dst seg nor total diffuse 0 2 0 0 0 0 5 0 7 non-diffuse 0 0 0 0 0 0 4 2 6 no reflux 2 2 4 0 12 11 18 26 75 insignificant 29 70 85 7 108 70 298 261 928 total 31 74 89 7 120 81 325 289 1016 percentages diffuse 0.0 28.6 0.0 0.0 0.0 0.0 71.4 0.0 100% non-diffuse 0.0 0.0 0.0 0.0 0.0 0.0 66.7 33.3 100% no reflux 2.7 2.7 5.3 0.0 16.0 14.7 24.0 34.7 100% insignificant 3.1 7.5 9.2 0.8 11.6 7,5 32.1 28.1 100% total 3.1 7.3 8.8 0.7 11.8 8.0 32.0 28.4 100% gsv, great saphenous vein reflux patterns; ptsv, posterior tributary to saphenous vein; dif, diffuse; msp, multisegmental proximal, including saphenofemoral junction; pro, proximal; pej, perijunction; mseg, multisegmental; dst, distal; seg, segmental; nor, no reflux. *diffuse ptsv started at the gsv. non-diffuse reflux was detected only in a short segment of the ptsv examined. no nco mm er cia l u se on ly article [veins and lymphatics 2014; 3:1938] [page 27] patterns (p=0.17, χ2 applied to 4¥8 data of table 3). summary the population studied had a prevalence of 73% (738/1016) of reflux in the gsv and thigh aasv, ptsv. reflux prevalence was 72% (727/1016) in the gsv, 4.5% (46/1016) in the aasv, and 1.3% (13/1016) in ptsv. testing for aasv and ptsv reflux increased detection of reflux by 1% (11/1016) and improved definition of patterns of reflux in 5.8% (59/1016) of the lower extremities. aasv diffuse reflux correlated with a 2.5 times higher prevalence of gsv-sfj reflux than expected in general (54% vs 20%). discussion we emphasized ultrasound findings in early stages of cvvi in women. cvvi emphasizes valvular insufficiency, not highlighted when the cvi expression, that includes thrombosis, is used. attention to cvvi increased with development of minimally invasive thermal and chemical ablation treatments such as laser or radio frequency and foam sclerotherapy.1,3,6,7,12 advances in duplex-doppler ultrasonography have contributed to cvvi understanding, diagnosis, treatment and followup.2,8-9,13-20,22-24 international consensuses occurred to minimize confusion in past phlebologic literature.1,5,10 description of patient populations studied improved but studies of even more specific sample populations, based on gender for example,25 should be promoted. any venous segment could become an initial source of reflux and varicose veins. segmental gsv reflux from a tributary source to a tributary drainage is the most common. a perforating vein source of reflux is not common finding in early stages of disease. perforating vein drainage was considered reflux, particularly if segmental diameter changes were noted at source and drainage points. segmental reflux propagates mostly to multi-segmental reflux if not treated;2 reflux evolves from the weakest to the next weakest point, regardless of anatomic relationships. we investigated if aasv or ptsv could be weak sites for reflux development early on. ptsv were originally interpreted as the posterior accessory saphenous vein; but this specific interpretation has been questioned leading to a more general ptsv description. most prevalence data represent a select clinic group and not the population in general. the sample in this study had gsv reflux with similar prevalence (72%) as previously reported for a varicose vein c2 group (77%), almost double than reported for a telangiectasia c1 group (44%).8,9 saphenofemoral junction reflux is uncommon in early stages of disease; previously published prevalence in women with varicose veins or telangiectasias was less than 20%,8,9 the prevalence found in the sample population of this study (table 2). reflux at the aasv contributed to sfj reflux; sfj reflux prevalence almost tripled in cases of diffuse aasv reflux (table 2). garcia-gimeno described aasv reflux prevalence over 10% for a sample population with over 60% sfj reflux,22 a group apparently with more advanced diseased than the one in this work. determination of terminal valve patency is significant to design type of treatment.23 brazilian custom is to treat telangiectasias and small reticular veins with 75% dextrose liquid sclerosant. modern tendency includes foam sclerotherapy with polydocanol for relatively larger veins. advanced technology has been implemented in clinics specialized in both symptomatic and aesthetic phlebology.26-29 cold air sedation, laser ablation and liquid sclerosis with 75% dextrose have been combined to treat small veins, resulting in the cryo laser and cryo sclerotherapy or clacs technique.26 this procedure is guided by a near infra red imaging vein viewer (luminetx co, memphis, tn, usa).27 this device colors over the skin more superficial veins than noted by the human eye or detected by us. the technique denominated augmented reality shows small nutrient veins underneath telangiectasias consistently.28 results of the clacs technique was reported at the 2013 international union of phlebology (uip) meeting showing improvement of skin conditions with 1% of the patients complaining of hyperpigmentation.29 in this investigation, we focused on aasv and ptsv, not frequently included in cvvi studies. aasv and ptsv rarely were the initial location of reflux in c1-c2-c3a women. our and seidel’s data suggested propensity for early reflux and varicosity abnormalities more so in the calf than in the thigh.8-9,24 calf veins other than the gsv were not included in this analysis. above-knee source of ssv reflux was expected to be less than 3% in c2 women.9 saphenous accessory and tributary veins in the thigh are less vulnerable to hydrostatic pressures and kinetic energies than the great saphenous and the veins in the calf. approximately 1 in 17 extremities tested may have aasv or ptsv reflux. on another angle, 1 in 100 extremities may have only aasv or ptsv reflux. if the goal is to detect cvvi early to follow or treat patients, aasv and ptsv should be evaluated despite low reflux prevalence. significant changes in patterns of reflux are expected if a woman presents with pelvic congestion syndrome.17 veins in all anatomic regions of the thigh have been evaluated if pelvic venous reflux is suspected, particularly if thigh varicosities are present. these patients, however, were excluded from this early stage of disease study. also, the prevalence described herein cannot be applied to men in general or women c4, c5-c6 or even true c3 with constant edema. in summary, it was reconfirmed that most women with early stages of cvvi had segmental or distal gsv reflux not involving the sfj. furthermore, prevalence of aasv or ptsv reflux was low, and mostly associated with gsv reflux. aasv or ptsv localized reflux, however, was the only abnormality detected in 1% of the extremities. us of these veins altered reflux pattern definition in about 6% of the extremities, and aasv diffuse reflux indicated more prevalence of sfj reflux in the affected gsv. references 1. rabe e, breu f, cavezzi a, et al. european guidelines for sclerotherapy in chronic venous disorders. phlebology 2013;29:33854. 2. engelhorn ca, manetti r, baviera mm, et al. progression of reflux patterns in saphenous veins of women with chronic venous valvular insufficiency. phlebology 2012;27: 25-32. 3. chaar ci, hirsch sa, cwenar mt, et al. expanding the role of endovenous laser therapy: results in large diameter saphenous, small saphenous, and anterior accessory veins. ann vasc surg 2011;25: 656-61. 4. seidel ac, mangolim as, rossetti lp, et al. prevalence of lower limb superficial venous insufficiency in obese and non-obese patients. j vasc bras 2011;10:124-30. 5. gloviczki p, comerota aj, dalsing mc, et al. the care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the society for vascular surgery and the american venous forum. j vasc surg 2011;53:2s-48s. 6. theivacumar ns, darwood rj, gough mj. endovenous laser ablation (evla) of the anterior accessory great saphenous vein (aagsv): abolition of sapheno-femoral reflux with preservation of the great saphenous vein. eur j vasc endovasc surg 2009;37:477-81. 7. yamaki t, nozaki m, sakurai h, et al. multiple small-dose injections can reduce the passage of sclerosant foam into deep veins during foam sclerotherapy for varicose veins. eur j vasc endovasc surg 2009;37:343-8. 8. engelhorn ca, engelhorn al, cassou mf, salles-cunha s. patterns of saphenous venous reflux in women presenting with lower extremity telangiectasias. no nco mm er cia l u se on ly article [page 28] [veins and lymphatics 2014; 3:1938] dermatol surg 2007;33:282-8. 9. engelhorn ca, engelhorn al, cassou mf, salles-cunha sx. patterns of saphenous reflux in women with primary varicose veins. j vasc surg 2005;41:645-51. 10. eklöf b, rutherford rb, bergan jj, et al. revision of the ceap classification for chronic venous disorders: consensus statement. j vasc surg 2004;40:1248-52. 11. beebe-dimmer jl, pfeifer jr, engle js, schottenfeld d. the epidemiology of chronic venous insufficiency and varicose veins. ann epidemiol 2005;15:175-84. 12. frullini a, cavezzi a. sclerosing foam in the treatment of varicose veins and telangiectases: history and analysis of safety and complications. dermatol surg 2002;28:11-5. 13. engelhorn c, engelhorn a, salles-cunha s, et al. relationship between reflux and great saphenous vein diameter. j vasc technol 1997;21:167-71. 14. engelhorn ca, engelhorn al, cassou mf, et al. functional anatomic classification of saphenous vein insufficiency in the planning for varicose vein surgery based on color doppler ultrasound. j vasc bras 2004;3:13-9. 15. engelhorn c, engelhorn a, casagrande c, salles-cunha sx. sources and drainages of saphenous vein reflux in patients with primary varicose veins. poster, final program of the american venous forum 11th annual meeting of the, dana point, ca, february 18-21, 1999, p 96. 16. labropoulos n, tiongson j, pryor l, et al. nonsaphenous superficial vein reflux. j vasc surg 2001;34:872-7. 17. barros fs, gomez perez jm, zandonade e, et al. evaluation of pelvic varicose veins using color doppler ultrasound: comparison of results obtained with ultrasound of the lower limbs, transvaginal ultrasound and phlebography. j vasc bras 2010;9:15-23. 18. coleridge-smith p, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs-uip consensus document. part i. basic principles. eur j vasc endovasc surg 2006;31:83-92. 19. cavezzi a, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs-uip consensus document. part ii. anatomy. eur j vasc endovasc surg 2006;31:288-99. 20. labropoulos n, tiongson j, pryor l, et al. definition of venous reflux in lowerextremity veins. j vasc surg 2003;38:793-8. 21. caggiati a, bergan jj, gloviczki p, et al. nomenclature of the veins of the lower limb: extensions, refinements, and clinical application; international interdisciplinary consensus committee on venous anatomical terminology. j vasc surg 2005; 41:719-24. 22. garcía-gimeno m, rodríguez-camarero s, tagarro-villalba s, et al. duplex mapping of 2036 primary varicose veins. j vasc surg 2009;49:681-9. 23. zamboni p, gianesini s, menegatti e, et al. great saphenous varicose vein surgery without saphenofemoral junction disconnection. br j surg 2010;97:820-5. 24. seidel ac, miranda f jr, juliano y, et al. prevalence of varicose veins and venous anatomy in patients without truncal saphenous reflux. eur j vasc endovasc surg 2004;28:387-90. 25. beebe hg, scissons rp, salles-cunha sx, et al. gender bias in use of venous ultrasonography for diagnosis of deep venous thrombosis. j vasc surg 1995;22:538-42. 26. miyake rk, duarte fh, fidelis rj, miyake h. new leg veins air cooled treatment using 1064nm laser combined with sclerotherapy: technique description and one year follow-up. lasers med sci 2003; 18:s22. 27. miyake rk, zeman hd, duarte fh, et al. vein imaging: a new method of near infrared imaging, where a processed image is projected onto the skin for the enhancement of vein treatment. dermatol surg 2006;32:1031-8. 28. miyake k. prevalence of small varicosities among patients with or without telangiectasias on the lower limbs estimated by augmented reality examination. int angiol 2013;32:124-5. 29. miyake k. case report of 195 patients classified by duplex scanning and augmented reality and treated by cryo-laser and cryosclerotherapy: results and complications. int angiol 2013;32:153. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2013; volume 2:e16 [veins and lymphatics 2013; 2:e16] [page 55] relevant factors affecting the outcome of ultrasound guided foam sclerotherapy of the great saphenous vein giorgio falaschi,1 fabrizio giannelli,2 raffaele molino lova3 1center for venous diseases, prato; 2university of florence; 3don gnocchi foundation, florence, italy abstract ultrasound guided foam sclerotherapy (ugfs) constitutes a valid ablative treatment for superficial vein diseases for the great saphenous vein (gsv), but no standardized protocol for its execution has yet been defined. different variable factors involved in this procedure influence the final outcome and clinical results. the aim of our study was to analyze the respective influence on efficacy and side effects of three variable factors (foam volume, foam concentration, and contact time between the foam and the endothelium) for ugfs procedures for gsv insufficiency in order to select the best protocol for treatment. a retrospective analysis was made of ugfs procedures (190 patients, 201 legs) performed for gsv insufficiency in our institute from january 2007 to january 2010. all great saphenous veins included in our study exhibited a trans-ostial reflux and caliber range was 7-11 mm. in all cases, foam was prepared according to the tessari method, using polidocanol (pol) and a gas mixture of co2 (70%) and filtered room air (30%), in a proportion of 1:4. a single injection procedure in the gsv was performed under doppler ultrasound guidance at mid to lower third of the thigh. legs were randomly assigned to one of three different treatment protocols: group a (71 legs): pol 3%, mean foam volume 4.5 cc, intermittent groin pressure 5 min, supine bed rest 10 min; group b (61 legs): pol 2%, mean foam volume 9 cc, intermittent groin pressure 5 min, supine bed rest 10 min; group c (69 legs): pol 2%, mean foam volume 9 cc, continuous groin pressure 5 min followed by intermittent groin pressure 5 min, continuous leg compression 5 min, supine bed rest 10 min. efficacy of treatment and occurrence of side effects were evaluated in each group at two weeks and again at two years after the procedure and the cumulative results compared. analysis of outcomes did not show any significant difference between the complete obliteration rate (p=0.825) or occurrence of local inflammatory reactions (p=0.883) between legs in group a and in group b. however, a significantly better outcome was observed between the complete obliteration rates and the local inflammatory reaction for legs in group c compared to both legs in group a (p=0.020 and p=0.015, respectively) and legs in group b (p=0.013 and p=0.018, respectively). the type of procedure did not seem to have any effect on the extent of recanalization (over or less than 50% of the original lumen). no major adverse events such as deep vein thrombosis, significant allergic reactions, or serious neurological events occurred in any patient in any group. further studies are still necessary to identify the best concentration ratios, volumes and length of contact time between foam and endothelium according to class size of specific veins to promote possible standardization of the procedure. however, measures to increase the contact time between foam and endothelium were shown to improve late results. in addition, the same efficacy and side effects are observed with lower pol concentration if foam volumes are increased. introduction ultrasound guided foam sclerotherapy (ugfs) of the great saphenous vein (gsv), has become a widely accepted treatment for gsv disease with trans-ostial reflux. efficacy and safety of this treatment have been well documented in the literature.1-21 properties of foam include echogenicity, homogeneous filling of the vein lumen, a prolonged contact with the endothelium and the need for a low dose of sclerosant. the efficiency of the foam for gsv ablation is now well documented for the short to medium term. however, a significant rate of recanalization of the vein’s lumen at five years5,20,22,23 could compromise this procedure, although it can easily be repeated if the patient agrees. the published results concerning this procedure, however, are often discordant and not easily comparable. this mainly depends on the different criteria used in performing this treatment. the main flaw of ugfs seems to arise from the lack of homogeneous protocols for the procedure.20,23 in particular, there is as yet no consensus as to optimal foam characteristics such as, foam volume:sclerosant concentration ratios or the correct contact time between the foam and the endothelium according to specific vein size ranges. our results regarding efficacy and side effects after using different foam concentrations, volumes and contact times with the endothelium were evaluated to identify the best protocol for a specific gsv class size. materials and methods we carried out a prospective analysis of ugfs procedures performed for gsv insufficiency at our center from january 2007 to january 2010. we examined the outcomes of 190 patients (201 legs) that had been randomly treated according to one of three different protocols. results of both the efficacy of the procedure and the occurrence of side effects were analyzed at two weeks and at 2-years after treatment and compared. all treatments were made by a single injection in the gsv at mid to lower third of the thigh under doppler ultrasound (dus) guidance in a recumbent position. treatment protocol 1: mean foam volume 4.5 cc (range 4-5 cc); polidocanol (pol) 3%; gentle, intermittent compression immediately on evidence of arrival of foam by dus probe at saphenous/femoral junction (sfj) for 5 min. treatment protocol 2: mean foam volume 9 cc (range 8.3-10 cc); pol 2%; gentle intermittent compression immediately on evidence of arrival of foam by dus probe at sfj for 5 min. treatment protocol 3: mean foam volume 9 cc (range 7.5-10.2 cc); pol 2%; continuous compression below the knee by sphygmo cuff inflated at 50 mmhg just before the injection and maintained for 5 min thereafter; gentle compression immediately on evidence of arrival of foam by dus probe at the sfj, maintained continuously for first 5 min and intermittently (after release of distal sphygmo compression) for an additional 5 min. it should be noted that in all cases the compression maneuvers at the sfj (pre-marked on the skin) with the dus probe were tailored so as to occlude the last segment of the gsv while maintaining full patency of the femoral vein (tables 1 and 2). correspondence: giorgio falaschi, viale montegrappa 282, prato, italy. tel.: +39.0574.575744. e-mail: g.falaschi@studiomedicofalaschi.it key words: ultrasound guided foam sclerotherapy, great saphenous vein, saphenous/femoral junction, doppler ultrasound, polidocanol, superficial vein diseases, deep vein thrombosis, femoral vein, small saphenous vein. received for publication: 9 may 2012. revision received: 8 march 2013. accepted for publication: 8 april 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright g. falaschi et al., 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e16 doi:10.4081/vl.2013.e16 no nco mm er cia l u se on ly article [page 56] [veins and lymphatics 2013; 2:e16] patients were divided into three groups (a, b or c) according to the treatment protocol (1, 2 or 3) to which they had been randomly assigned. four patients in group a, 3 patients in group b and 4 patients in group c had similar bilateral gsv disease and received the same treatment protocol for both sides. inclusion criteria were: i) presence of a gsv trans-ostial reflux by dus examination. gsv caliber range 7-11 mm (at 5 cm below sfj in standing position); ii) availability for follow up for at least two years (clinical, etiological, anatomic, pathophysiological classification: class ii-iv). exclusion criteria were: i) recurrent gsv disease after any sort of ablative procedure; ii) presence of localized dilatations of more than 50% of the original caliber at 5 cm from sfj; iii) presence of associated small saphenous vein disease. procedures and materials foam was prepared according to the tessari method with 2 silicone-coated 10 cc syringes (pentaferte spa, campli, te, italy), and one 3way stopcock (15 strokes) mixing a 2% or 3% standard pol solution (kreussler pharma inc., tampa, fl, usa) with a gas mixture made up of 70% sterile medical co2 and 30% filtered room air in a proportion of 1:4 liquid and gas. the correct proportion of room air was added to co2 in the same syringe by direct aspiration of the room air through a membrane disc filter with a luer slip attack to the syringe (whatman 0.0002 mm air filter fp 30/02 puradisc 25; whotman int'l. ltd., meadstone, uk). a single injection technique was performed in the gsv at mid to lower third of the thigh under dus guidance through a straight 20g-1.5" needle (chemo srl., kevilmare holding gmbh, vienna, austria) with the patient in a supine position and the bed tilted at a 10-15° trendelemburg position.all patients rested supine for 10-12 min after injection and a 35-mmhg single leg stocking (mediven-struva 35; medi italia, bologna, italy) was positioned up to the groin with the aid of the medi butler introducer before standing. all patients were discharged after a 30-min observation period during which they walked up and down in a room contiguos to the treatment room. patients were instructed to engage in normal activities of daily life and to wear the stocking continuously for the following ten days. all patients were checked at two weeks and at two years. response to treatment was assessed through dus. a positive response was considered to be the absence of any color or sound signals during hand compression maneuvers together with no lumen compressibility by dus probe from 2-4 cm below the sfj to at least the knee. a patent proximal stump up to 4 cm below the sfj was accepted and considered physiological (drainage of inguinal collaterals). recanalizations, either partial or total, were considered as treatment failure. however, clinical evidence showed that partial recanalizations, if homogeneous and of moderate extent (generally less than 50% the original lumen), were often associated with a very short reflux time (usually <1 s) while still obtaining a good cosmetic result and safeguarding patient wellbeing. side effects side effects were either local or general. local side effects were: i) significant venous and/or perivenous inflammatory reactions with pain and need for additional therapeutic measures; ii) residual skin pigmentation; iii) matting. transient localized skin reactions were excluded. general side effects were: i) deep vein thrombosis; ii) neurological disturbances; iii) allergic reactions. while both femoral and popliteal veins were routinely examined by dus at every checkup, no routine assessment of the calf veins was made nor was this ever considered necessary. results were evaluated using pearson’s χ2 test. results all procedures were completed uneventfully by a single injection. the gsv was usually centered at mid to lower third of the thigh at the first attempt. occasionally a second or third attempt was necessary and in these cases fresh foam was used. the presence of an assistant helped ensure the injection point was centered by the dus probe while the fresh foam was being prepared, to correctly inflate the sphygmo cuff on the leg, and also to tilt the electric bed (trendelemburg tilting) at the start of injection. results are summarized in table 3. a complete obliteration of the gsv was achieved after two weeks in 66 legs (93%) in group a, in 57 legs (93.4%) in group b, and in 65 legs (94.2%) of group c. failures (early recanalizations) occurred in 5 legs (7%) in group a, in 4 legs (6.6%) in group b, and in 4 legs (5.8%) in group c. at two years, a complete gsv obliteration was still present in 49 legs (69%) in group a, in 41 legs (67.2%) in group b, and in 58 legs (84%) in group c, while a partial or total recanalization had occurred in 22 legs (31%) in group a, in 20 legs (32.8%) in group b, and 11 legs (16%) in group c. in addition, partial recanalization of less than 50% the original caliber (measured at 5 cm below the sfj) was observed in 8 legs (11.3%) in group a, in 9 legs (14.8%) in group b, and in 6 legs (8.7%) in group c. in these cases, no reflux or minimal diastolic reflux (<1 s) was present at ultrasound examination while these patients remained generally asymptomatic. soon after the injection, a diffusion of the foam into the gsv below the knee and also into leg collaterals was reported in 69 legs (97%) in group a, in 61 legs (100%) in group b and only in 19 legs (27.6%) in group c. this caused often a transient inflammatory reaction of the smallest collaterals (see above). statistical analysis of closure rates at two years showed no difference between groups a and b (p=0.825), but a significantly better outcome in group c versus either group a (p=0.020) or group b (p=0.013). most patients tolerated the full procedure well withtable 1. patients’ characteristics. group a group b group c no. patients (no. legs) 67 (71) 58 (61) 65 (69) female/male (ratio) 46/21 (2.19) 45/13 (3.46) 48/17 (2.82) age in yrs, range (mean) 30-81 (56.2) 32-80 (57.7) 34-80 (57.6) gsv calib,* in mm, range, (mean) 7-11 (8.1) 7-11 (7.9) 7-11 (8.2) yrs, years; gsv, great saphenous vein; calib, caliber. *measured at 5 cm below saphenous/femoral junction in a standing position. table 2. the 3 treatment protocols used in the study. protocol 1 protocol 2 protocol 3 mean foam volume (cc) 4.5 9 9 pol (%) 3 2 2 sfj intermittent comp. (min) 5 5 sfj cont. intermittent comp. (min) 5+5 leg comp. (min) 5 pol, polidocanol; sfj, saphenous/femoral junction; comp., compression; cont. intermittent comp., continuous followed by intermittent compression. no nco mm er cia l u se on ly article [veins and lymphatics 2013; 2:e16] [page 57] out any major events. no evidence of deep vein thrombosis or allergic reactions was reported. a very few patients in all three groups exhibited transitory hypotension, sweating or tremors at the start of the procedure (or just before); this was clearly related to emotional distress and these cases were not considered as side effects. transitory visual disturbances (blurred vision, flashes of light) lasting a few minutes were reported by one patient in each group 3060 min after injection with no further sequelae. in one patient (group b), the visual disturbance was accompanied by frontal headache. one patient (group a), exhibited paresthesia and transitory motor palsy of her right arm soon after injection; she made a full recovery spontaneously within 10 min. finally, one patient (group c) experienced sudden cervical pain, moderate dizziness and face flushing 10 min after injection on standing up; intravenous betamethasone was promptly administered and the patient fully recovered within 15 min. localized minimal skin inflammatory reactions that cleared up spontaneously in a few days occurred quiet frequently in all groups and were not considered as side effects. in 18 legs (25.4%) in group a, in 15 legs (24.6%) in group b, and in 8 legs (11.6%) in group c, venous inflammatory reactions with extension to contiguous tissues occurred from a few days to a few weeks after treatment. these involved segments of the gsv or, most frequently, superficial leg/thigh collaterals. treatment was often needed; this included clotted blood evacuation, site compression, and, occasionally, administration of low molecular weight heparin. it is worthy of note that none of the patients in group c exhibited a significant inflammatory reaction in the leg. all patients eventually recovered well; local tissue induration only reoccurred in a few cases. faint skin pigmentations were fairly common in all groups: most of them vanished spontaneously during the observation period. persistent skin pigmentations were always related to the closeness of the vein to the skin and/or to the extent of previous inflammatory reactions. these were most often localized around the medial knee and upper leg levels. persistent skin pigmentations occurred in 19 legs (26.8%) in group a, in 17 legs (27.9%) in group b, and in only 9 legs (13%) in group c. this implies a significantly better result in group c than in either group a (p=0.015) or group b (p=0.018). matting also sometimes occurred and was often concomitant with excessive local inflammatory reactions. this was subsequently alleviated by local low concentration pol sclerotherapy with the aid of a trans-illuminating device and/or by local intense pulsed light applications. visible spots of matting, however, reoccurred in 9 legs (12.7%) in group a, in 6 legs (9.8%) in group b, and in 4 legs (5.8%) in group c. discussion foam is a physical dispersion of a gas (e.g. air) into a surfactant. the polyhedral bubbles constituting the foam display an outer layer of surfactant encasing the gas inside. complex laws regulate the behavior of the bubbles that are highly unstable. they slowly coalesce into bigger-sized bubbles and eventually the liquid portion separates from the gas (drainage). the speed of degradation depends mainly on: i) the quality of foam (gas/fluid proportion and size of bubbles; ii) the properties of the surfactant; iii) the physical characteristics of the environment.24,25 pol (atossisclerol/lauromacrogol 400) is a surfactant that acts by irreversibly denaturing the endothelial membrane. this ultimately results in endothelial cell death and inflammatory reaction, thrombus formation, and activation of fibroblasts. experiments have shown that hemolysis also occurs in whole blood samples at pol concentrations greater than 0.45%;26 however, erythrocyte lysis, platelet lysis and platelet-derived microparticle formation have not been a significant concern in reports of any clinical trials of sclerosant therapy.16 after injection, the foam displaces the blood and homogeneously fills the vein’s lumen. the spontaneous degradation of the foam is responsible for its contraction in volume and progressive loss of activity.24 in an empty tubular system, however, foam of good consistency can persist for several minutes;27 the same occurs in the vein’s lumen if, by appropriate manual compression, the blood flow is stopped. complete and homogeneous damage of the endothelium by the injected foam is chiefly dependent on three major variable factors: i) the volume of foam; ii) the concentration of the sclerosant; and iii) the length of the contact time between the foam and the endothelium, in relation to the total surface area to be treated (vein caliber and length). specific individual sensitivity to the sclerosant also constitutes an additional variable factor that will certainly need further investigation. in vivo, the plug of the foam displaces the fluid content of the vessel, thus allowing the sclerosant to gain proper contact with the inner wall of the vessel. however, this only occurs if the volume of the foam is appropriate for the caliber and length of the vein; in fact, poor volumes of foam are the main cause of an incomplete and inhomogeneous filling.25 spastic vein reaction evoked by high sclerosant concentrations (disappearance of lumen) tends to instantly displace the foam, thus preventing its correct action. this does not happen if bigger volumes of foam are injected. another important factor is the concentration of the sclerosant in the foam. this determines the aggressiveness of the foam’s action and its penetration. an accurate selection of the scletable 3. efficacy at 2-week and at 2-year checkup. checkup 2 weeks 2 years group a group b group c group a group b group c total 71 n (%) 61 n (%) 69 n (%) 71 n (%) 61 n (%) 69 n (%) no. legs complete 66 (93) 57 (93.4) 65 (94.2) 49 (69) 41 (67.2) 58 (84) obliteration recanalization 8 (11.3) 9 (14.8) 6 (8.7) <50% recanalization 14 (19.7) 11 (18) 5 (7.3) 5 (7) 4 (4.61) 4 (5.81) >50% table 4. local and general side effects 0-2 years post-procedure. total 201 legs. group a group b group c total no. legs 71 61 69 side effects local inflammatory reactions 18 (25.4) 15 (24.6) 8 (11.6) pigmentation 19 (26.8) 17 (27.9) 9 (13.5) matting 9 (12.7) 6 (9.8) 4 (5.8) general neurological 2 (2.8) 1 (1.6) 2 (2.9) deep vein thrombosis 0 0 0 allergic reactions 0 0 0 no nco mm er cia l u se on ly article [page 58] [veins and lymphatics 2013; 2:e16] rosant concentration in relation to the vessel caliber and thickness of the vessel wall is required to achieve a proper efficacy while avoiding serious overreactions.21 chemical kinetics studies the complex laws that regulate the molecular aspect of all biochemical reactions which are determined by specific collisions between particles of reactants: the number of such collisions determines the progress and completion of the reaction.28 factors influencing the biochemical reactions mainly include: concentration of reactants, surface characteristics, temperature, and time.28 sclerotherapy is a biochemical reaction between two reactants: surfactant and lipoproteins of the cellular membrane. proper contact time between the foam and the venous inner wall is, therefore, essential for optimal ugfs efficacy. the disappointing results in the past with liquid sclerotherapy were probably caused not only by the excessive dilution of the sclerosant inside the vein and by its partial inactivation by the blood, but also by its rapid wash out. our experience with same volume/same concentration foams (i.e. protocols 2 and 3) in veins of similar calibers has proved a better efficacy in terms of occlusion rate when foam drainage was significantly slowed by appropriate compressive maneuvers, thus providing a prolonged contact. a successful venous chemical ablation implies a proper sequential activation of the following processes: complete and homogeneous endothelial necrosis, damage of sub-endothelial layers and fibroblastic activation, homogeneous thrombus formation, progressive fibrinolytic and thrombolytic activity, concomitant proliferation of fibroblasts and synthesis of new collagen. the correct evolution of this sclerosing process is in part critically determined by the specific extent of the damage to the vessel wall. characteristics and type of local reflux can also have an influence. it has been demonstrated that obliteration of the gsv can be achieved also with low pol concentrations and appropriate foam volumes,26 but no studies have as yet identified the most appropriate techniques and foam concentrations to achieve the best results.20 it seems essential to establish the proper ratios between sclerosant concentrations, foam volumes and lengths of contact time in relation to specific ranges of vein caliber/length (total surface areas). in terms of complete occlusion rate at two years, better outcomes were reported for legs in group c compared to legs in group a (p=0.020) and in group b (p=0.013), while no significant difference was found between legs in group a and in group b (p=0.825). these results imply the effectiveness of a prolonged contact time for the foam regardless of its concentration. in contrast, no difference was reported in the extent or speed of recanalization in any of the groups. in fact, recanalization, when it occurs, is probably influenced by local factors such as persistence of significant collaterals or points of re-entry of the original reflux. however, patient wellbeing is maintained when recanalization stabilizes at a substantial degree of lumen narrowing. neurological disorders were rare. the pathological mechanisms resulting in cerebrovascular events and transient ischemic attacks are likely to be different to those leading to migraine and visual disturbances.29 in general, occurrence of neurological disorders is frequently associated with right to left shunting conditions (patent foramen ovale).29,30 however, no direct relationship has ever been documented with foam volume and concentration.17,23,31-34 also, although less frequently, occurrence of neurological disorders has been described with liquid sclerotherapy. recently, there has been growing evidence to support the hypothesis that, at least for some neurological disorders, chemical mediators (endothelin) act as pathophysiologically causative agents.32,35 the cumulative incidence of neurological disorders in all our patients was consistent with published data and no significant difference was found between the three groups. local inflammatory reactions with residual skin pigmentation and matting are reported as a common occurrence after ugfs.1,9,10,31 one view of four randomized controlled trials including a total of 517 patients documented skin pigmentation at a median rate of 32% after the procedure at 1-year follow up.13 excessive inflammatory reaction eventually leads to massive transparietal migration of macrophages and deposition of hemosideryn in sub-dermal layers. legs in group c exhibited a significantly lower incidence of skin pigmentations than legs in group a (p=0.015) and in group b (p=0.018). also, general inflammatory reactions were significantly less common in group c than in group a (p=0.044), and lower than in group b (p=0.072). these data clearly show the benefits of both the lower pol concentration and the protection of the superficial below the knee collaterals of the gsv by leg compression so to avoid undesirable excessive inflammation in certain areas. it is also worth noting that leg compression during the procedure provides a prophylactic protection from deep vein thrombosis by increasing the deep vein blood flow in the calf. conclusions more investigations are undoubtedly necessary to identify the most accurate foam volumes, foam concentrations and contact time ratios for specific vein class sizes to ensure the best results of ultrasound guided foam sclerotherapy for superficial vein diseases of the great saphenous vein. the aim for the future must be to achieve a proper standardization of procedures. references 1. rabe e, otto j, schliephake d, pannier f. efficacy and safety of great saphenous vein sclerotherapy using standardized polidocanol foam. eur j vasc endovasc surg 2008;35:238-45. 2. breu fx, guggenbichler s, wollmann jc. second european consensus meeting on foam sclerotherapy. tegernsee. vasa 2008; 37:90-5. 3. alos j, lopez ja, estadella b, serraprat m. efficacy and safety of sclerotherapy using polidocanol foam. a controlled clinical trial. eur j vasc endovasc surg 2006;94: 925-36. 4. cabrera j, cabrera j jr, garcia-olmedo a. treatment of varicose long saphenous veins with microfoam form: long term outcomes. phlebology 2000;15:19-23. 5. grondin l. foam echosclerotherapy of incompetent saphenous veins. phleboly mphology 2003;42:s24. 6. coleridge-smith p, wright d, tristram s. foam sclerotherapy of saphenous trunk varices. phlebology 2002;17:75. [abstract]. 7. cavezzi a.,frullini a,ricci s,tessari l.treatment of varicose veins by foam sclerotherapy;two clinical series.phlebology 2002;17:13-18. 8. van den bos r, arends l, kockaert m, et al. endovenous therapies of lower extremities varicosities: a meta analysis. j vasc surg 2009;49:230-9. 9. frullini a, cavezzi a. sclerosing foam in the treatment of varicose veins and teleangectases: history and analysis of safety and complications. dermatol surg 2002;28:11-5. 10. barrett jm, allen b, ockelford a, goldman mp. microfoam ultrasound guided sclerotherapy of varico veins in 100 legs. dermatol surg 2004;30:6-12. 11. wright d, gobin jp, bradbury aw, et al. varisolve polidocanol microfoam compared with surgery or sclerotherapy in the management of varicose veins in the presence of trunk vein incompetence. european randomized controlled trial. phlebology 2006;21:180-90. 12. hamel-desnos c, desnos p, wallman jc, et al. evaluation of the efficacy of polidocanol in the form of foam compared with liquid form in sclerotherapy of the greater saphenous vein: initial results. dermatol surg 2003;29:1170-5. 13. nihce engl. ultrasound guided foam sclerotherapy for varicose veins, overview and no nco mm er cia l u se on ly article [veins and lymphatics 2013; 2:e16] [page 59] guidance ipg 440; august 2009, updated february 2012. available from: http://publications.nice.org.uk/ultrasound-guidedfoam-sclerotherapy-for-varicose-veinsipg440 14. coleridge smith p. chronic venous disease treated by ultrasound guided foam sclerotherapy. eur j vasc endovasc surg 2006;32:577-83. 15. hamel-desnos c, guias b, jousse s, et al. foam echosclerotherapy by puncture direct injection: technique and quantities. j mal vasc 2006;31:180-9. 16. eckmann dm. polidocanol for endovenous microfoam sclerosant therapy. expert opin investig drugs 2009;18:1919-27. 17. rathbun s, norris a, stoner j. efficacy and safety of endovenous foam sclerotherapy: meta-analysis for treatment of venous disorders. phlebology 2012;27:105-17. 18. coleridge-smith p. sclerotherapy and foam sclerotherapy for varicose veins. phlebology 2009;24:260-9. 19. bradbury aw, bate g, pang k, et al. ultrasound guided foam sclerotherapy is safe and clinically effective treatment for superficial venous reflux. j vasc surg. 2010;52:939-45. 20. myers ka, robert s. evaluation of published reports of foam sclerotherapy: what do we know conclusively? phlebology 2009;24:275-80. 21. myers ka, jolley d, clough a, kirvan j. outcome of ultrasound guided sclerotherapy for varicose veins: medium term results assessed by ultrasound survellance. eur j vasc endovasc surg 2007;33:116-21. 22. chapman-smith p, browne a. prospective five-year study of ugfs. phlebology 2009;24:183-8. 23. morrison n. foam sclerotherapy. how to improve results and reduce side effects. phlebology 2008;37:211-20. 24. wollmann jc. sclerosant foams stabilities, physical properties and biological behavior. phlebologie 2010;39:208-17. 25. mengual o, meunier g, cayre i, et al. characterization of instability of concentrated dispersion by a new optical analizer. colloids surf physicochem eng aspects 1999;152:111-13. 26. parsi k, exner t, low j, et al. in vitro effects of detergent sclerosants in cloth formation and fibrinolysis. eur j vasc endovasc surg 2011;41:267-77. 27. wong kc. rheology of sclerosant foam in vitro. sydney: university of sidney; 2009. sid 310334209. available from: http://www.aeromech.usyd.edu.au/rheologyofsclerosantfoam 28. house je. fundamental concepts of kinetics and reaction mechanisms. in: house je, ed. principles of chemical kinetics, 2nd ed. burlingtom, ma: academic press; 2007. pp 1-30. 29. sarvananthal t, shepherd ac, willemberg t, davies ah. neurological complications of sclerotherapy for varicose veins. j vasc surg 2012;55:243-51. 30. raymond-martinbeau p. transient adverse events positively associated with patent foramen ovale after ultrasound guided foam sclerotherapy. phlebology 2009;24: 114-9. 31. jillet jl, guex jj, hamel desnos c, et al. side effects and complications of foam sclerotherapy of gsv and ssv. phlebology 2009;24:131-8. 32. gillet jl, donnet a, laurecker m, et al. pathophysiology of visual disturbances occurring after foam sclerotherapy. phlebology 2010;25:261-6. 33. bush rg, derrick m, manjonej d. major neurological events following foam sclerotherapy. phlebology 2008;23:189-92. 34. hartman k, harms l, simon m. reversible neurological deficits after foam sclerotherapy. eur j vasc endovasc surg 2009;38:648-9. 35. 35. frullini a, felici e, burchielli s, di stefano r. high production of endothelin after foam sclerotherapy: a new pathogenetic hypotesis for neurological and visual disturbances after foam sclerotherapy. phlebology 2011;26:203-8. no nco mm er cia l u se on ly mirko tessari the history of sugar dressing in infected venous leg ulcers mirko tessari vascular diseases center, university of ferrara, italy. correspondence: mirko tessari, e-mail: mirko.tessari@unife.it in the current issue of veins and lymphatics, franceschi and co-authors publish an original article proposing sugar as an advanced dressing in infected venous leg ulcers.1 the first observation about this method was published in early ‘70s in phlebologie by leger et al. from lyon.2 since this article is maybe difficult to find out, despite was cited by franceschi et al., we invite our readership to read and learn from it, by contacting the glauco bassi library at the azienda ospedaliera universitaria di ferrara, which is available for everybody who is searching the cornerstones of phlebology3 (figure 1). while i was consulting the article of leger i also found the abstract of the article originally typed in italian language by glauco bassi himself (figure 2). figure 1. figure 2. references franceschi c, bricchi m, delfrate r. anti-infective effects of sugar-vaseline mixture on leg ulcers. veins and lymphatics 2017;6:6652. leger l, marchal j, et al. traitement local des plaies par la bagasse. phlebologie 1974;27:123-8. bresadola m. the bassi historical international library of phlebology at the ferrara university hospital. veins and lymphatics 2014;3:4150. [top] hrev_master veins and lymphatics 2014; volume 3:4707 [veins and lymphatics 2014; 3:4707] [page 97] italian chronic cerebrospinal venous insufficiency national epidemiological observatory methodology and preliminary data sandro mandolesi,1 aldo d’alessandro,2 marco matteo ciccone,3 annapaola zito,3 tarcisio niglio,4 ettore manconi,5 dimitri mandolesi,6 alessandro d’alessandro,7 aldo bruno,8 francesco fedele1 1department of cardiovascular and respiratory sciences, la sapienza university, roma; 2department of neuroscience, imaging and clinical sciences, g. d’annunzio university, chieti-pescara; 3cardiovascular diseases section, department of emergency and organ transplantation, university of bari; 4higher health institute, roma; 5department of cardiovascular and neurological sciences, university of cagliari; 6occupational medicine, la sapienza university, roma; 7faculty of medicine, university of foggia; 8department of vascular surgery, clinica gepos, telese terme (bn), italy abstract the aim of our work is to describe the memnet program’s use and potential and to show the data of italian chronic cerebrospinal venous insufficiency (ccsvi)-national epidemiological observatory (neo) activity in the first three years (http://www.osservatorioccsvi.org). from 2011 to 2014, all echo-colordoppler (ecd) assessments were stored by mem-net program into ccsvi-neo web site (http://www.mem-net.it). mem-net is a tool for multicenter data collection based on the international society for neurovascular disease consensus and position statement, where we can insert patients (pts) history, neurological visits, ecd assessments, different examinations, therapies and surgical procedures. the website provides an epidemiological and statistical program for data analysis in real time. at present, 7 medical centers, affiliated to ccsvi-neo, input their symptomatic and asymptomatic subjects with ccsvi. data were storage using the mem-net program. we analyzed data of only four centers on seven (rome, bari, cagliari and benevento). total pts number with multiple sclerosis (ms) was 1109, mean age 46.0±13.4 [male 422 (38.05%); female 687 (61.95%)]. ccsvi positive pts were 937 (84.49%), ccsvi negative pts were 172 (15.51%). the ccsvi type 1 subjects were 530 (56.56%), ccsvi type 2 subjects were 20 (2.13%), ccsvi type 3 subjects were 387 (41.30%). we found 800 (85.38%) pts with criterion 1; 725 (77.37%) with criterion 2; 519 (55.39%) with criterion 3; 483 (51.55%) with criterion 4; 88 (9.39%) with criterion 5. the venous hemodynamic insufficiency severity score mean score was 3.8; the ccsvi mean score was 2.8; the mem mean score was 34.7; the expanded disability status scale mean score was 4.5; the disease mean duration was 12.5±5.7 years. ms clinical types were divided as follows: relapsing-remitting pts were 449 (47.92%), secondary progressive pts were 144 (15.37%), primary progressive pts were 72 (7.68%). the ccsvi-neo database and memnet software may be useful medical and researching tools for recording, storing, analyzing and studying ecd and vascular data. preliminary data of neo show an elevated prevalence of ccsvi in ms. introduction chronic cerebrospinal venous insufficiency (ccsvi) is characterized by multiple stenosis/obstructions affecting the principal extracranial outflow pathways of the cerebrospinal venous system, the internal jugular veins (ijvs), the vertebral veins (vvs) and the azygos vein, distributed in four main hemodynamic patterns.1-3 furthermore, ccsvi determines significant changes in cerebral venous hemodynamic, with a very high incidence of reflux in both intraand extra-cranial venous segments as well as loss of the postural regulation of cerebral venous outflow.4-6 zamboni suggested five echo-color-doppler (ecd) venous criteria for this syndrome.1-3 criterion 1: constantly reflux or bidirectional present in an outflow pathway in supine and up-right; criterion 2: reflux propagated upward to the deep cerebral veins, including internal cerebral vein, basal vein, galen vein, criterion 3: evidence of ijvs anatomical stenosis or presence of anomalies and block, reflux constantly or bidirectional in the other, criterion 4: flow no detectable in the ijvs and vvs in clino and upright or in one position and presence of anomalies and reflux constantly or bidirectional in the other, criterion 5: negative difference in cross sectional area of the ijv (csa) assessed in supine and standing posture (0° and 90°) in the ijv (�csa). the presence of two of them is enough to diagnose ccsvi.1-2 these criteria for ecd diagnosis of ccsvi proposed by zamboni in 2009 was approved in 2011 by a consensus of experts of seven international scientific societies of vascular area.3 the aim of our work is to describe the memnet program’s use and potential and to show the data of italian ccsvi-national epidemiological observatory (neo) activity in the first three years. the italian ccsvi-neo has all database stored at http://www.osservatorioccsvi.org. materials and methods the department of cardiovascular, respiratory and morphologic sciences of umberto i polyclinic of rome, la sapienza university, developed in 2010 the neo and in 2011 it made the digitalized platform ccsvidatabase: the mem-net program. mem-net is a tool for multicenter data collection based on the international society for neurovascular disease (isnvd) consensus and position statement.3 this software is accessible at http://www.mem-net.it. in this software we can insert patient history, neurological visit, ecd assessment of brain veins, magnetic resonance imaging, venography examination, interventional procedure, physical therapy and surgical procedures. the website provides an epidemiological and statistical program for data analysis in real time. at present, seven medical centers, affiliated to ccsvi-neo, input their symptomatic and asymptomatic ccsvi subjects’ data. the ecd assessments of ms symptomatic and asymptomatic patients were stored on years from 2011 to 2014 using mem-net program. in this study we analyzed data of only four centers on seven (rome, bari, cagliari and benevento). all the sonographers of these centers received a correspondence: sandro mandolesi, via montebello 17, 00185 roma, italy. tel: +39.335.6512303 fax: +39.06.4873984. e-mail: s.mandolesi@email.it key words: chronic cerebrospinal venous insufficiency (ccsvi), ccsvi national epidemiological observatory, mem-net, multiple sclerosis. conflict of interest: all authors declare to have no financial associations that might pose a conflict of interest. received for publication: 16 september 2014. revision received: 3 february 2015. accepted for publication: 5 february 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s. mandolesi et al., 2014 licensee pagepress, italy veins and lymphatics 2014; 3:4707 doi:10.4081/vl.2014.4707 no n c om me rci al us e o nly article [page 98] [veins and lymphatics 2014; 3:4707] course to use the mem-net program. we studied 1109 patients suffering from multiple sclerosis, which was diagnosed according to the revised mcdonald’s criteria.7,8 the study did not include patients having undergone an acute relapse and/or steroid treatment within the 30 days before the enrollment, suffering from preexisting clinical conditions related to brain pathology, systemic vasculitis, vascular malformations of the brain (i.e. arterio-venous and cavernous malformations, venous hemangioma, telangiectasias) and congenital malformations leading to hydrocephalus (i.e. arnoldchiari syndrome, aqueduct atresia or stenosis and dandy-walker disease). a full clinical evaluation of each patient was performed by one expert physician in order to assess age, gender, onset of disease symptoms, clinical variants of multiple sclerosis and, finally, disability and cognitive impairment degree was assessed by the expanded disability status scale (edss).9 according to the multiple sclerosis type, the patients were classified in three subgroups: i) relapsing remitting form, i.e. unpredictable attacks followed by slow remission (symptoms and signs improvement); ii) secondary progressive form, i.e. progressive form with initially relapsing remitting course; and iii) primary progressive form, with gradually worsening of symptoms.8,9 the study was approved by the ethical committee of our institution, and carried out in accordance with the principles of the helsinki declaration. all patients gave their written consent for ultrasonographic examination. ultrasound evaluation of cerebrospinal venous outflow all subjects underwent an ecd examination of the cerebrospinal venous flow. in order to reduce bias, all the ecd evaluations were performed by a single, expert ultrasonographer for each center. the examination was performed with the patients in the sitting and supine positions. the physician tried not to exert any pressure on the internal jugular veins because of their collapsibility. we investigated the morphology and hemodynamics of the internal jugular veins by means of high resolution bmode ultrasounds (mylab vinco echo-colordoppler system, esaote spa, genova, italy, equipped with 2.5 and 7.5-10 mhz probes). we tried to detect venous anatomical abnormalities such as septa/valve malformations and membranes which are able to influence the hemodynamics of cerebral veins in these patients. according to ciccone et al.10,11 we defined: septa/valve malformations as valvular abnormalities of the veins able to create an obstacle to the blood flow in the internal jugular veins and/or brachiocephalic/anonymous trunk junction; membranes as membranes are able to occlude cerebral veins. hemodynamics parameters and symbols considered in our figure 1. map scheme for an echo-color-doppler report. rdcv, right deep cerebral veins; ldcv, left deep cerebral veins; rvv, right vertebral vein; lvv, left vertebral vein; vplex, vertebral plexus; rbct, right common-brachiocephalic trunk anonymous; lbct, left common-brachiocephalic trunk anonymous; rsvc, right superior cava vein; lsvc, left superior cava vein; ivc, inferior cava vein; azygos, azygos vein; lren, left renal vein; riv, right iliac vein; liv, left iliac vein; j1r, lower right internal jugular vein; j2r, middle right internal jugular vein; j3r, upper right internal jugular vein; j1l, lower left internal jugular vein; j2l, middle left internal jugular vein; j3l, upper left internal jugular vein; v1r, lower right vertebral vein; v2r, middle right vertebral vein; v3r, upper right vertebral vein; v1l, lower left vertebral vein; v2l, middle left vertebral vein; v3l, upper left vertebral vein; srv, subclavian right vein; slv, subclavian left vein; scv, superior cava vein. no n c om me rci al us e o nly article [veins and lymphatics 2014; 3:4707] [page 99] work were those used in the glossary of the isnvd consensus and position statement.3 patients made a neck rotation test which is still not included in the position statement.3 this maneuver was described in the 80’s and showed that rotation in normal people opens the ijv from one side and close from the other.12 the test consists in the rotation of the head to the outside and inwards, at the same time we check the changes of ultrasound images of the internal jugular veins and vertebral veins to highlight the venous compressive syndrome of these vessels. we defined: physiological internal jugular vein flow when the cross area is more than 6.0 mm2 without flow block or reflux; white compression when the internal jugular vein flow blocked by fully compression; black compression when the internal jugular vein cross area less than 6.0 mm2 by severe compression.13 neurological ms clinical assessment kurtzke’s edss9 was adopted to evaluate neurological impairments of multiple sclerosis patients. it evaluated the functionality of eight neurologic functional systems [pyramidal (ability to walk); cerebellar (coordination); brain stem (speech and swallowing); sensory (touch and pain); bowel and bladder functions; visual; mental; other (includes any other neurological findings due to multiple sclerosis) each scored from 0 (preserved function) to 6 (totally impaired function)]. furthermore, a judgment about the autonomy of the patients fulfilled the edss final score. the final edss ranged from 0 (no symptoms) to 10 (death due to multiple sclerosis). the venous map the edc map scheme is a stylized diagram of the veins draining the brain and spinal cord (figure 1). the internal jugular and the vertebral veins, on the map, are divided into three segments. the proximal segments are j1-v1, the medium segments are j2-v2 and the distal are j3-v3. j1, j2 and j3 are the segments of internal jugular veins. j1 segments goes from the confluence into subclavian vein to the inferior level of thyroid. j2 segment goes from inferior level of thyroid to the jugular point; this point is when the vein crosses the bifurcation of carotid arteries. j3 segment goes from the jugular point to the higher point detectable by ecd. v1,v2 and v3 are the segments of vertebral veins. v1 segment goes from the confluence into subclavian vein to the point in which the vertebral vein goes up from vertebral channel. v2 segment goes from this last point to c3 bone. v3 segment above this level. the veins are represented by blue lines and on them are reported the morphological and the hemodynamic symbols that correspond to the assessment of ecd. with color red are reported the symbols of the ecd assessment in supine position; with green color the symbols in the upright position. when the sonographer finds a morphological anomaly or a hemodynamic pathological flow he immediately puts the equivalent symbol on the correspondent point of the map (figure 1). a legend with all the symbols are close to the map and you can pick which you need to put on the map by using the mouse. the mem-net program to enter in the mem-net program, of neo on ccsvi platform, you must register yourself putting yours personal id and password to have the access to the program. you can insert a new patient in the archive and automatically the program creates its id number for the privacy. ones entering in the program you can put all the personal and clinical data of the patient. then you can enter in the hemodynamic page where you find the symbols and the mem-net map for ecd report (figure 2). after saved the figure 2. digitalize the map (mem-net). ccsvi, chronic cerebrospinal venous insufficiency; csa, cross-sectional area; vhiss, venous hemodynamic insufficiency severity score; mem, hemodynamic morphological map. no n c om me rci al us e o nly article [page 100] [veins and lymphatics 2014; 3:4707] map of ecd assessment you can print the map (figure 3) and the written report (figure 4). the mem-net report shortens the time of ecd written reporting. the mem-net program allows collecting all the ecd examination data and, by its algorithm, making uniform the report. the input of the hemodynamic and morphological symbols on memnet map automatically allows the follows prints: ecd morphological hemodynamic map with the legend of the symbols, the written reporting, the criteria we founded, the ccsvi score, the venous hemodynamic insufficiency severity score (vhiss) score, the ccsvi types (type 1, type 2 or type 3), the ms clinical types [relapsing-remitting (rr), secondary progressive (sp), primary progressive (pp)], the edss, the years of disease duration, the first symptom, age and sex, the identification code for the privacy of the patient. you can also use the statistic area for general or clinical data analysis of patients. this software makes faster, easier and topographic ecd report of ccsvi, reduces human error, standardize the ecd report, by the shared symbols of consensus conference, write the report of ecd assessment, prints automatically the report, saves all hemodynamic and morphological findings in its data base, clinical and hemodynamic follow-up become faster and easier. statistical analysis mem-net ecd archives are a web complex database based on structured query language (sql) software architecture. all stored medical information are classified in sql table. after registration, authorized users may perform frequency statistics by using preconfigured query in the web page dedicated to statistics. every mem-net collaborator may control her/his data choosing many parameters of their patients (sex, age, pathologies, symptoms, illness duration, etc). the central server elaborates the requests building a specific query. mem-net software elaborate data giving a detailed printable report. in real time, this function permits to all mem-net collaborators to know statistical situation of her/his patients with related patients from other center. mem-net neo has an epidemiological and statistical team that perform periodical analysis on data quality and medical research in collaborations with mem-net centers. to perform this activity, data are periodically extracted from mem-net sql server database into microsoft database format (mdb) or in microsoft excel office format (xls). these mdb or xls files are completely compatible with all statistical software programs (bmdp, spss, epi-info, etc.). analysis of variance (anova) or analysis of co-variance (ancova) are performed on continuous variables to determine statistical significance between or within data groups. on the same time, logistic analysis is performed on categorical variables by non parametric statistical tests. these activities permit the mem-net database maintenance for showing: i) each patient correct and complete information list; ii) epidemiological changes inside etiologic and pathological evolution of illness; iii) unknown and new typical patient profile with specific characteristics. results we analyzed data of only four centers on seven (rome, bari, cagliari and benevento). total patients number was 1109, mean age 46.0±13.4 [male 422 (38.05%); female 687 (61.95%)]. ccsvi positive patients were 937 (84.49%), ccsvi negative patients were 172 (15.51%). the ccsvi type 1 subjects were 530 (56.56%), ccsvi type 2 subjects were 20 (2.13%), ccsvi type 3 subjects were 387 (41.30%). we found 800 (85.38%) patients figure 3. report printing of the echo-color-doppler examination with hemodynamic and morphological symbols. ccsvi, chronic cerebrospinal venous insufficiency; csa, cross-sectional area; sp, secondary progressive; edss, expanded disability status scale; vhiss, venous hemodynamic insufficiency severity score; mem, hemodynamic morphological map; dx, left; sx, right. no n c om me rci al us e o nly article [veins and lymphatics 2014; 3:4707] [page 101] with criterion 1; 725 (77.37%) with criterion 2; 519 (55.39%) with criterion 3; 483 (51.55%) with criterion 4; 88 (9.39%) with criterion 5. the vhiss mean score was 3.8; the ccsvi mean score was 2.8; the mem mean score was 34.7; the edss mean score was 4.5; the disease mean duration was 12.5±5.7 years. multiple sclerosis clinical types were divided as follows: rr patients were 449 (47.92%), sp patients were 144 (15.37%), pp patients were 72 (7.68%) (table 1). discussion in 2011 laupacis and colleagues in canada identified a strong and statistically significant relationship [odds ratio (or) 13.5; 95% confidence interval (ci) 2.6-71.4] between ccsvi and ms, but there was extensive, unexplained heterogeneity across studies (i2=89%).14 in 2013 tsivgoulis et al. published a meta-analysis of case-control studies, he identified 19 eligible studies including 1250 patients with ms and 899 healthy controls. the pooled analysis showed that ccsvi was associated with ms (or 8.35; 95% ci 3.44-20.31; p<0.001) with considerable heterogeneity across studies (i2=80.1%). the greatest factor contributing to this heterogeneity appears to be the involvement of investigators in other publications supporting endovascular procedures as a novel ms treatment.15 in 2013 comi et al. published an observational case-control study of the prevalence of chronic cerebrospinal venous insufficiency in multiple sclerosis: results from the cosmo study.16 the study involved 35 ms centers across italy and included 1874 subjects aged 18-55. 1767 (94%) were evaluable: 1165 ms patients, 226 patients with other neurological diseases (onds) and 376 healthy controls (hcs). ccsvi prevalence was 3.26%, 3.10% and 2.13% for the ms, ond and hc groups, respectively. the conclusions were that ccsvi figure 4. written report of the echo-color-doppler examination. table 1. chronic cerebrospinal venous insufficiency national epidemiological observatory statistical analysis from four centers. patients’ characteristics no. ccsvi classification no. (%) scores no. (%) total number of patients 1109 ccsvi type 1 530 (56.56%) mean vhiss 3.8 total mem-net patients 1109 ccsvi type 2 20 (2.13%) mean ccsvi score 2.8 mean age (years) 46.0±13.4 ccsvi type 3 387 (41.30%) mean mem score 34.7 male 422 criterion 1 800 (85.38%) mean edss score 4.5 female 687 criterion 2 725 (77.37%) mean disease duration (years) 12.5±5.7 positive ccsvi 937 criterion 3 519 (55.39%) rr 449 (47.92%) negative ccsvi 172 criterion 4 483 (51.55%) sp 144 (15.37%) criterion 5 88 (9.39%) pp 72 (7.68) cis 2 (0.21%) ccsvi, chronic cerebrospinal venous insufficiency; vhiss, venous hemodynamic insufficiency severity score; mem, hemodynamic morphological map; edss, expanded disability disease score; rr, relapsing-remitting; sp, secondary progressive; pp, primary progressive; vhiss, venous hemodynamic insufficiency severity score. no n c om me rci al us e o nly article [page 102] [veins and lymphatics 2014; 3:4707] is not associated with ms. all centers were with conflicting interests with pharmaceutical company, used different ecd devices and their sonographers were not approved by zamboni university vascular department. to overcome that incredible difference in results between neuro-sonographers and vascular sonographers we created a tool and a method of ccsvi data collection (ccsvi national epidemiological observatory). the project involves the construction of a ccsvi diagnostic centers network throughout the country, linked all together on internet. the venous ecd for the diagnosis of ccsvi is complex, for that we realized a reporting system on a digitalized map (mem-net) to easily store the data of this ultrasound assessment. to join the observatory network the sonographers must confirm either the attendance of a training course at the vascular diseases center of prof. zamboni or in a center affiliated than an observatory course for the use of the venous hemodynamics morphological map (mem-net) that permit us to value their adequate ecd assessment reproducibility.17,18 conclusions the ecd data are collected by the same standard procedure (map report) that permit an ecd assessment reproducibility and eliminate the possibility of heterogeneity. the mem-net statistical data analysis program allows having homogeneous samples in short time. the ccsvi-neo database and mem-net software may be useful medical and researching tools for recording, storing, analyzing and studying ecd and vascular data all over the world. we hope that italian experience will be the first step for reaching european and international ccsvi-neo database. we hope that some critical issue in the mem-net can be improved in the future and that it becomes a tool widely distributed for standardized analysis of the chosen 90 statistical items for ccsvi. finally, preliminary data of neo show an elevated prevalence of ccsvi in ms. references 1. zivadinov r, bastianello s, dake md, et al. recommendations for multimodal noninvasive and invasive screening for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency: a position statement of the international society for neurovascular disease. j vasc interv radiol 2014 [epub ahead of print]. 2. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:3929. 3. zamboni p, menegatti e, galeotti r, et al. the value of cerebral doppler venous haemodynamics in the assessment of multiple sclerosis. j neurol sci 2009;282:21-7. 4. zamboni p. chronic cerebrospinal venous insufficiency. int angiol 2010;29:91-2. 5. zamboni p, menegatti e, weinstockguttman b, et al. the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis is related to altered cerebrospinal fluid dynamics. funct neurol 2009;24:133-8. 6. zamboni p, menegatti e. doppler haemodynamics of vertebral venous return. curr neurovasc res 2008;5:260-5. 7. polman ch, reingold sc, edan g, et al. diagnostic criteria for multiple sclerosis: 2005 revisions to the mcdonald criteria. ann neurol 2005;58:840-6. 8. mcdonald wi, compston a, edan g, et al. recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. ann neurol 2001;50:121-7. 9. kurtzke jf. rating neurological impairment in multiple sclerosis: an expanded disability scale (edss). neurology 1983;33:1444-52. 10. ciciarello f, mandolesi s, galeandro ai, et al. age-related vascular differences among patients suffering from multiple sclerosis. curr neurovasc res 2014;11:23-30. 11. ciccone mm, galeandro ai, scicchitano p, et al.. multigate quality doppler profiles and morphological/hemodynamic alterations in multiple sclerosis patients. curr neurovasc res 2012;9:120-7. 12. muhammad jk, pugh nd, boden l, et al. the effect of head rotation on the diameter of the internal jugular vein: implications for free tissue transfer. j craniomaxillofac surg 2001;29:214-8. 13. mandolesi s, manconi e, niglio t, et al. incidence of anatomical compressions of the internal jugular veins with full block of their flow in patients with chronic cerebro-spinal venous insufficiency and multiple sclerosis. in: allegra c, antignani pl, eds. proc. 21st eurochap-iua european chapter congress of the international union of angiology. sept 28-oct 1, 2013, rome, italy. turin: ed. minerva medica; 2013. pp 12-17. 15. laupacis a, lillie e, dueck a, et al. association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis. cmaj 2011;183:e1203-12. 16. tsivgoulis g. chronic cerebrospinal venous insufficiency and multiple sclerosis: a comprehensive meta-analysis of case-control studies. ther adv neurol disord 2013;25:269-79. 17. comi g, battaglia ma, bertolotto a, et al. observational case-control study of the prevalence of chronic cerebrospinal venous insufficiency in multiple sclerosis: results from the cosmo study. mult scler 2013;19:1508-17. 18. dolic k, marr k, valnarov v, et al. sensitivity and specificity for screening of chronic cerebrospinal venous insufficiency using a multimodal non-invasive imaging approach in patients with multiple sclerosis. funct neurol 2011;26:205-14. 19. menegatti e, genova v, tessari m, et al. the reproducibility of colour doppler in chronic cerebrospinal venous insufficiency associated with multiple sclerosis. int angiol 2010;29:121-6. no n c om me rci al us e o nly hrev_master veins and lymphatics 2015; volume 4:4676 [page 18] [veins and lymphatics 2015; 4:4676] ultrasound-guided perisaphenous tumescence infiltration improves the outcomes of long catheter foam sclerotherapy combined with phlebectomy of the varicose tributaries attilio cavezzi,1 giovanni mosti,2 sonia di paolo,3 lorenzo tessari,4 fausto campana,5 simone ugo urso1 1eurocenter venalinfa, s. benedetto del tronto (ap); 2clinica barbantini, lucca; 3clinica stella maris, s. benedetto del tronto (ap); 4fondazione glauco bassi, trieste; 5vascular medicine unit, cesena hospital, cesena (fc), italy abstract a prospective comparative observational study was performed to assess the short--term efficacy and safety of the peri-saphenous infiltration of tumescence solution (pst) in great saphenous vein (gsv) long catheter foam sclerotherapy (lcfs) combined with phlebectomy of the varicose tributaries. since november 2006 through november 2010 fifty-one consecutive patients (16 males and 35 females, mean age 51.5 years) who underwent lcfs of gsv + multiple phlebectomies were prospectively enrolled, without any pre-selection criteria, in three different groups (17 patients per group) and reviewed as to their outcomes: i) patients without additional pst; ii) with pst under visual control; iii) with ultrasound-guided pst. all procedures were performed in local anesthesia and an average of 7 ml [interquartile range (iqr) 6.5-7.5] of 3% sodiumtetradecylsulfate co2+o2-based sclerosant foam was injected in the diseased segment of gsv (median caliber 7) (iqr 6-8) by means of a 4f long catheter. clinical and color-duplex ultrasound (cdu) follow-up was performed at regular intervals, the last of which 14 months after the treatment. at 14 months follow-up no varicose veins were visible in 94%, 94% and 100% of the cases in group i, ii and iii respectively. the cdubased outcomes were the following: 71%, 71% and 84% gsv occlusion rate in group i, ii and iii respectively; reflux was found in 5, 4 and 1 cases in group i, ii and iii respectively. clinical and cdu morphologic and hemodynamic results were assembled and scored through an arbitrary system. the relative statistical analysis showed a significant (p<0.0001) improvement of the results for patients who received ultrasound guided pst over the other two groups. no relevant complications were recorded in all 51 cases. gsv treatment by means of lcfs + phlebectomy of varicose tributaries proved to be effective and safe in this prospective observational study. the addition of ultrasound guided pst resulted in a significant improvement of gsv occlusion rate and of varicose vein clinical resolution. introduction varicose veins of the lower limbs affect about 15% male and 25% of female population.1 different treatment methods have been proposed including surgery, endothermal ablation and chemical ablation by means of foam sclerotherapy, all of them facing some degree of recurrence in the long term.2 ultrasound guided foam sclerotherapy (ugfs) is performed by injecting a foamed sclerosant agent, usually sodium-tetradecylsulphate (sts) or polidocanol into the target vessel under duplex ultrasound guidance. ugfs has been proved effective and safe in the treatment of great saphenous vein (gsv), small saphenous vein, tributaries, perforators, recurrences and venous malformations.3 recent systematic reviews show an overall inferiority, in terms of venous occlusion rate, of ugfs in comparison to other endovenous techniques, such as laser and radiofrequency, or to surgery.4-8 for ugfs most clinical series show an increased recanalization rate for larger saphenous diameters,9-11 which is likely due to the higher amount of blood, hence to a higher dilution and especially in the deactivation of sclerosant drug by blood protein binding.12-16 the peri-saphenous infiltration of tumescence solution (pst) is performed in endovenous thermal ablation to reduce the venous diameter, thus resulting in a smaller amount of blood within the target vein, to reduce/abolish procedure-related pain and protect the peri-saphenous tissues.17,18 aim of the study was to assess if pst, minimizing the saphenous caliber prior to foam delivery, and reducing venous blood content and blood inflow from tributaries and perforators into the saphenous stem, may improve the outcome as regards occlusion rate and varicose vein clinical resolution. materials and methods since november 2006 through november 2010, fifty-one consecutive patients, 16 males and 35 females, with mean age of 52.5 +/6.9 (range 48-72) years were enrolled in the study on an intention-to-treat basis. all patients were submitted to long catheter foam sclerotherapy (lcfs) of gsv + phlebectomy of the varicose tributaries in local anesthesia. inclusion criteria were primary varicose veins related to gsv incompetence (reflux >1 s), in absence of any previous active treatment. exclusion criteria were: pregnancy, acute deep or superficial vein thrombosis, severe peripheral arterial occlusive disease (e.g. basal ankle-brachial index below 0.6), symptomatic patent foramen ovale, cardiac or renal failure, immobility, relevant thrombophilia (e.g. deficit of at iii, protein c and s), allergy to sts. all patients underwent clinical and colorduplex ultrasound (cdu) (7.5-13 mhz linear probe, toshiba ssa-340 or ge vivid 3) investigation in standing position, with measurement of gsv caliber 3 cm below the terminal valve and at mid thigh, excluding any saccular dilation from measurements. the final gsv diameter was calculated as the mean of the two measurements above. sapheno-femoral junction (sfj) and gsv were assessed as to previously published international union of phlebology (uip) recommendations and protocols.19-21 patients were fully informed on the subsequent procedures and gave their consent to be enrolled into the study. the patients were divided in three different groups (17 patients each group) in a consecutive sequence; each patient had one limb operated on. all patients were operated on an outpatient basis by one of the authors (ca) and the whole procedure was performed in local anesthesia (buffered mepivacaine 0.125%, 250 ml per procedure as average), with pre-operative oral administration of 0.8 mg of delorazepam, with correspondence: attilio cavezzi, eurocenter venalinfa, viale dello sport 14, 63074 s. benedetto del tronto (ap), italy. e-mail: info@cavezzi.it key words: sclerotherapy, ultrasound-guided sclerotherapy, long-catheter-foam-sclerotherapy, perisaphenous tumescence infiltration. acknowledgements: thanks to paul thibault, ken myers, and kurosh parsi for having shared their studies and knowledge on tumescence infiltration in foam sclerotherapy with us. received for publication: 22 august 2014. revision received: 24 november 2014. accepted for publication: 29 january 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright a. cavezzi et al., 2015 licensee pagepress, italy veins and lymphatics 2015; 4:4676 doi:10.4081/vl.2015.4676 no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:4676] [page 19] elevated limbs (trendelemburg position). sclerosant foam was prepared according to tessari method, mixing sts 3% (fibrovein 3%®; std pharmaceutical products, hereford, uk) with co2 70% + o2 30% one-to-four ratio, in silicon-free syringes. the incompetent segment of gsv trunk and the varicose veins were marked on the skin pre-operatively. the distal part of the incompetent gsv trunk was hooked through a 3-4 mm incision, disconnected and ligated, and a 4f catheter was advanced inside the proximal gsv trunk with the tip positioned about 5 cm below the tv of sfj. one group of patients (group i: no tum) did not receive any tumescence solution infiltration. in a second group of patients (group ii: visual tum) pst was delivered under visual control following the gsv marks on the skin. in the third group of patients (group iii: ug tum) pst was delivered under ultrasound guidance, strictly within the saphenous compartment. tumescence solution was made up with 5 ml of 2% mepivicaine, 10 mg of ethylephrine hydrochloride, 5 ml of sodium bicarbonate 10 meq/10 ml and 250 ml of saline solution. the tumescence solution amount was decided as to the dose to fully collapse gsv trunk for the whole targeted length. while performing tumescence infiltration, gsv trunk was continuously flushed with saline solution, through the in situ catheter, in order to minimize blood content. after pst completion, 1 ml of 3% sts foam every 5 cm was delivered within the incompetent tract of gsv while retrieving the catheter (figure 1). simultaneously to lcfs procedure, hook phlebectomies through mini-incisions (1-2 mm) were performed to remove the visible varicose tributaries. phlebectomy was interrupted in all cases some ten centimetres above the most distal visible varicose tract. post-operative compression consisted in 35 mmhg stocking (struva 35®; medi gmbh, bayreuth, germany) + pads along the treated areas, which were worn 24 h a day for 7 days. subsequently medical elastic stocking class i (18-21 mmhg) was prescribed for 40-60 days in daytime. ambulation was allowed 30-60 min after the treatment and the patients were discharged 1-2 h afterwards. one single injection of low molecular weight heparin at prophylactic dose was administered pre-operatively. during the follow-up period no additional sessions of ugfs were performed after the original procedure. clinical and full limb cdu follow up was performed by one author (ca) after 40 days (and earlier in case of alerting symptoms and signs) and at sixth month, and by two independent observers (usu and cf) at 12-15 months [median value 14.4 months, interquartile range (iqr) 13-15.5 for all groups] after the treatment, in order to assess the technical success of gsv sclerotherapy and to check for any side effects/complications (primarily of thrombotic nature during the early follow-up). any possible residual/recurrent visible/palpable varicose vein in the treated area was reported. as to gsv assessment, cdu investigation was performed in standing position and with 5-10 cm threshold color/doppler flow velocity setting, in order to pick up also tiny refluxes. complete occlusion was defined as total incompressibility of gsv trunk and absence of color/doppler flow in more than 80% of the length of the treated segment. partial recanalization was defined as partial compressibility of the treated segment and/or an occlusion below 80% of the intended length treated. a fully recanalized vein had a completely compressible lumen in more than 20% of the treated segment. when gsv was partially or completely recanalized, the inner residual lumen was measured and an antegrade or retrograde flow was highlighted in the targeted gsv segment (figure 2). in order to get an overall evaluation of the final results and of the possible differences among the three groups, morphological and hemodynamic cdu findings, together with clinical results, were taken in consideration and plotted according to an arbitrary scoring system as follows: occlusion was scored as 0 point, 1 point was assigned to recanalization and 1 point each for visible varicose veins, for recanalization larger that 1 mm and for venous reflux above 1 s was added as well. statistical analysis the data were submitted to statistical analysis. kruskall-wallis test was used to analyze vein diameter and foam dosage; mannwhitney test was used for tumescence solution amount. friedman test was used to analyze the clinical + cdu outcomes. the software prism 5 (graphpad; san diego, ca, usa) was used for statistical analysis and to create the graphs. results the three different groups didn’t show any significant difference as regards demographic and duplex data (see below); figure 3 shows the details of the statistical analysis of gsv diameter variation in the three groups. group i (no tum): patients who underwent lcfs + phlebectomy without additional pst (4 males and 13 females); distribution of c of figure 1. sclerosant foam delivery while retrieving the long catheter inside great saphenous vein. figure 2. color-duplex ultrasound follow-up shows retrograde flow in a previously treated great saphenous vein (gsv) stem, with an inner diameter of 1.2 mm. no n c om me rci al us e o nly article [page 20] [veins and lymphatics 2015; 4:4676] clinical-etiology-anatomy-pathophysiology (ceap) classification was as follows: c2 13 patients; c3 2 patients; c4 1 patient; c5 1 patient; mean gsv caliber before the treatment was 7.23 [standard deviation (sd) 1.29] mm. group ii (visual tum) : patients with additional pst along the marked path, under visual control (6 males and 11 females); distribution of c of ceap was as follows: c2 11 patients; c3 5 patients; c4 1 patient. mean gsv caliber before the treatment was 7.35 (sd 1.74) mm. group iii (ug tum): patients with ultrasound-guided pst (6 males and 11 females); distribution of c of ceap was as follows: c2 14 patients; c3 3 patients; mean gsv caliber before the treatment was 7.32 (sd 1.55) mm. median dose of injected sclerosant foam was 7 ml (iqr 6.25-7 in group i; 6.5-7.5 in group ii; 6.50-8 in group iii) without any statistical differences between groups (figure 4a). median dose of injected tumescence solution in groups ii and iii was 150 ml (iqr 140160 in group ii; 142.5-150 in group iii, without any statistically significant difference (figure 4b). concerning the clinical and cdu followup results, data differentiated along the followup in favor of group iii. at first month follow-up all 51 patients showed no varicose veins and a fully obliterated gsv trunk. at the second clinical and cdu check-up (6 months) group i and group ii had one patient with recanalized and refluxing gsv, whereas group iii had one recanalized gsv with antegrade flow. no recurrent/residual varicose veins were evident at the clinical observation. at the last clinical and cdu follow-up (14 months after the operation) the three groups showed different findings (figure 5). in patients of group i one patient (6%) presented clinically visible recurrent varicose veins, although of small caliber (3-4 mm). at cdu control 12 gsvs (70.6%) were occluded, five limbs (29.4%) had a partially recanalized gsv trunk with reflux exceeding one second. the mean diameter of the residual patent gsvs was 2.9 mm. in patients of group ii two patients (11.8%) had recurrent varicose veins and at cdu control 12 gsvs (71%) were occluded, one patient (5.9%) had partially recanalized gsv trunk with antegrade flow and 4 patients (23.1%) showed partially recanalized gsv trunk with retrograde flow. the average residual caliber was 3.0 mm. in patients of group iii (ug tum) there was no clinical recurrence in all 17 patients. cdu investigation highlighted full occlusion in 14 gsvs (82.4%), partial recanalization with antegrade flow in two patients (11.7%) and partial recanalization with short duration (below one second) reflux in one patient (5.9%). the average residual caliber was 0.9 mm. according to our scoring system concerning the clinical and duplex post-treatment findings, no difference was recorded between group i and ii (no tumescence vs visual tumescence), while a statistically significant (p<0.0001) improvement of the outcomes was recorded in group iii [ultrasound-guided thrombin injection (ugti)] in comparison to group i and group ii (figure 6). no relevant complications were recorded in all 51 cases. more specifically patients did not report any neurologic/pulmonary/cardiac symptoms intraoperatively, or in the following hours or days; no deep or superficial vein thrombosis was detected at clinical and cdu follow-up. concerning side effects, two patients reported skin induration along a few phlebectomy sites. discussion gsv treatment is still based on stripping in most countries, but endovenous thermal ablative treatments have become more and more popular worldwide. ugfs on one side, and hook-phlebectomy on the other side represent mini-invasive treatments, which have undergone a growing diffusion as well.22-24 in a recent meta-analysis, on the effectiveness of endovenous therapies for lower limb varices found, after 3 years, the estimated pooled success rates for stripping, ugfs, radiofrequency ablation, and laser therapy was 78%, 77%, 84% and 94% respectively.25 also in rasmussen’s randomized clinical trial at one year 5.8%, 4.8%, 16.3% and 4.8% of the gsvs were patent and refluxing in the laser, radiofrequency, foam and stripping groups respectively (p<0.001). various observational studies26-28 have clearly showed the negative impact of larger saphenous caliber on the final outcome of ugfs. gonzalez zeh29 reported 93% vs 33% obliteration rate for gsv trunk below 8mm and above 12 mm respectively after ugfs. despite the good short/mid-term results of foam sclerotherapy, this method is characterized by objective limitations when dealing with large-caliber veins, for which higher doses of sclerosant foam are required, which may decrease the overall safety of ugfs.30 actually there is strong evidence that blood figure 3. comparative statistical analysis of the pre-treatment great saphenous vein diameter in the three groups. figure 4. a) comparative statistical analysis of the injected dose of sclerosant foam in the three groups; b) comparative statistical analysis of the injected dose of tumescence solution in groups ii and iii. no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:4676] [page 21] components denaturate/inactivate sclerosant drugs,12-16 mainly through protein binding. stagnating blood in the saphenous trunk prior to sclerosant foam injection is proportional to vein size and it objectively dilutes/inactivates sclerosant drug, notwithstanding the clearing effect of foam in proximity of the injected site and for the first seconds/minutes. similarly inflow of blood drainage within gsv stem, via tributaries and perforators, contribute to clear foam away from the targeted segment and especially this inflow brings new aliquots of fresh blood, which negatively interferes with sclerothrombus formation. compression by means of bandages, stockings with or without pads, has been proposed in liquid and foam sclerotherapy, in order to address the problems as to above, with uncertain results.3 elevation of the limb prior to foam injection has been advocated since the early introduction of ugfs,31 with the aim to reduce vein size (hence blood content) and to improve ugfs efficacy/safety. milleret32 showed improved results of foam sclerotherapy by means of long catheter usage and esmarck’s bandage application to minimize blood in gsv prior to foam delivery. in 2006 paul thibault as first proposed the injection of a tumescent solution around the vein after its injection with sclerosant foam, and he reported lower visual disturbance incidence and some outcome improvement.33 in the latest years further publications on pst34-37 have confirmed the possible role of this complementary technique in foam sclerotherapy, especially when treating larger veins which present a higher rate of recanalization in the medium and long-term follow up. for this reason, since 2000 the usage of a long catheter as an alternative to ugfs was highlighted.38 subsequently other authors reported interesting results with lcfs.39-44 in fact the use of a long catheter on one side may allow a more targeted and homogenous distribution of the sclerosant foam; on the other side the placement of a long catheter within the saphenous stem allows fluid tumescence infiltration within the saphenous compartment to minimize saphenous caliber prior to foam delivery. the peri-saphenous tumescence infiltration is routinely used in laser treatment and radiofrequency ablation, in order to provide anesthesia, compress the veins and disperse the generated heat. in long catheter foam sclerotherapy the perisaphenous tumescence infiltration is effective in decreasing significantly the caliber of the vein and the blood inflow from the tributary veins, aiming at achieving the so called empty vein technique, which was postulated by george fegan decades ago.45 the injected volume of sclerosant foam was about 1 ml per 5 cm length of treated gsv, which contributed to standardize the procedure and to fill adequately catheter and the targeted vein segment. just in order to get a longer and more consistent vasoconstriction of the target vein, in our experience the tumescence solution included saline solution and a buffered anesthetic drug combined with ethylephrine, which may induce a longer saphenous spasm in comparison to the infusion of saline solution alone. our data clearly show that when tumescence infiltration in the saphenous compartment is performed under duplex guidance, patients may achieve a better gsv occlusion rate and a lower clinical recurrence rate (p<0.0001), when compared both to patients without tumescence and to patients submitted to tumescence under visual control. the observational nature of our study, which was based on limited number of patients per group, presented a statistical power below 80%, but objectively the patients submitted to ug tum had statistically significantly better duplex and clinical results over the patients of the other two groups. in fact ultrasound guided infiltration allows a homogeneous distribution of the tumescence solution within the saphenous compartment, with a greater reduction of the vein caliber and likely with a lower blood flow from the inlets of the tributary veins and perforators. interestingly the outcomes in patients without any tumescence and with tumescence infiltration without duplex guidance were very similar; this fact confirms that tumescence must be precisely injected into the intravenous compartment to be effective. in a randomized clinical trial devereux et al.46 recently showed no benefit from pst on lcfs. nevertheless in this study unfortunately adrenaline or another spasm-inducing drug was not used in the tumescence solution, which may decrease the effectiveness of this complementary procedure. in addition the published pictures in the article above show tumescence solution injected intraand extrasaphenous compartment, hence devereux’s results could interestingly mimic our group ii results. furthermore eight out of 50 patients (more precisely 20% in the non-tumescence group and 8% in the tumescence group) were lost to follow-up, which objectively represents a limitation of the statistical analysis of the study. figure 5. color-duplex ultrasound follow-up at 14 months of the three groups. figure 6. comparative statistical analysis of the color-duplex ultrasound results at 14 months follow-up in the three groups. no n c om me rci al us e o nly article [page 22] [veins and lymphatics 2015; 4:4676] the overall safety of lcfs has been proved in literature and in our experience, which well compares with the outcomes of the other thermal ablation techniques. efficacy of lcfs with ultrasound guided pst may reach levels of other thermal ablative techniques, even in large caliber veins, while using quite low volumes of sclerosant foam. these positive features may potentially lead to overcome the main limitations and critical issues of ugfs. finally, compared to laser and radiofrequency ablation (rf), this procedure is quicker as both the time to perform ugti (lower doses are needed) and the time to inject foam through the catheter are shorter than the corresponding times of the thermoablative procedures. finally it is of great importance to highlight how the costs of lcfs are significantly lower than the costs of rf and laser. a limitation of the study is represented by the small number of the enrolled patients but this was designed as a pilot, observational study and no randomization was planned. however the consecutive prospective feature of the trial and the significant diagnostic and therapeutic homogeneity of the three groups reinforce the value of our data. more consistent data need to be collected by larger trials with longer follow-up to provide adequate evidence in favor of ultrasound guided pst in foam sclerotherapy. however our experience with this procedure is providing more and more robust data, which highlight a promising profile of efficacy and safety for lcfs with additional ultrasound guided tumescence infiltration. conclusions gsv treatment by means of lcfs + phlebectomy of varicose tributaries proved to be effective and safe in this prospective observational study at short/mid-term clinical and cdubased follow-up. the addition of ultrasound guided pst resulted in a statistically significant improvement of gsv occlusion rate and of varicose vein clinical resolution. furthermore a significant improvement of the overall morphologic and hemodynamic features of the treated veins was reached as well. references 1. maurins u, hoffmann bh, losch c, et al. distribution and prevalence of reflux in the superficial and deep venous system in the general population results from the bonn vein study, germany. j vasc surg 2008;48:680-7. 2. de maeseneer m, cavezzi a etiology and pathophysiology of varicose vein recurrence at the saphenopopliteal junction: an update. veins and lymphatics 2012;1:e4. 3. rabe e, breu fx, cavezzi a, et al. european guidelines for sclerotherapy in chronic venous disorders. phlebology 2014 , vol. 29(6) 338-354. 4. o’flynn n, vaughan m, kelley k. diagnosis and management of varicose veins in the legs: nice guideline. br j gen pract 2014; 64:314-5. 5. biemans aa, kockaert m, akkersdijk gp, et al. comparing endovenous laser ablation, foam sclerotherapy, and conventional surgery for great saphenous varicose veins. j vasc surg 2013;58:727-34. 6. badri h, bhattacharya v. a review of current treatment strategies for varicose veins. recent pat cardiovasc drug discov 2008;3:126-36. 7. rasmussen lh, lawaetz m, bjoern l, et al. randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins. br j surg 2011;98:1079-87. 8. nesbitt c, eifell rk, coyne p, et al. endovenous ablation (radiofrequency and laser) and foam sclerotherapy versus conventional surgery for great saphenous vein varices. cochrane database syst rev 2011;10:cd005624. 9. coleridge-smith p. sclerotherapy and foam sclerotherapy for varicose veins. phlebology 2009;24:260-9. 10. myers ka, jolley d, clough a, kirwan j. outcome of ultrasound-guided sclerotherapy for varicose veins: medium-term results assessed by ultrasound surveillance. eur j vasc endovasc surg 2007;33: 116-21. 11. frullini a, cavezzi a. sclerosing foam in the treatment of varicose veins and telangiectases: history and analysis of safety and complications. dermatol surg 2002;28:11-5. 12. parsi k, exner t, connor de, et al. in vitro effects of detergent sclerosants on coagulation, platelets and microparticles. eur j vasc endovasc surg 2007;34:731-40. 13. parsi k, exner t, connor de, et al. the lytic effect of detergent sclerosant on erithrocytes, platelets, endothelial cells and microparticles are attenuated by albumin and other plasma components in vitro. eur j vasc endovasc surg 2008;36:216-23. 14. parsi k, exner t, ma ddf, joseph je. in vitro effects of detergent sclerosant on fibrinolytic enzymes and inhibitors. thromb reserch 2010;126:328-36. 15. watkins mr. deactivation of sodium tetradecyl sulphate injection by blood proteins. eur j vasc endovasc surg 2011;41: 521-5. 16. tessari l, izzo m, cavezzi a, et al. in vivo demostration of sodiumtetradecysulphate sclerosant foam binding with blood proteins. veins and lymphatics 2014;3:3275. 17. toonder im, lawson ja, wittens cha. tumescence, how do i do it? phlebology 2013;28:15-20. 18. alomari ai. simple system for perivenous tumescent infusion for endovenous laser ablation. phlebology 2012;27:242-4. 19. coleridge-smith p, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs--uip consensus document. part i. basic principles. eur j vasc endovasc surg 2006;31:83-92. 20. cavezzi a, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs uip consensus document part ii: anatomy. eur j vasc endovasc surg 2006;31:288-99. 21. de maeseneer m, pichot o, cavezzi a, et al. duplex ultrasound investigation of the veins of the lower limbs after treatment for varicose veins uip consensus document. eur j vasc endovasc surg 2011;42:89-102. 22. coleridge-smith p. chronic venous disease treated by ultrasound guided foam sclerotherapy. eur j vasc endovasc surg (england) 2006;32:577-83. 23. pittaluga p, chastanet s, rea b, barbe r. midterm results of the surgical treatment of varices by phlebectomy with conservation of a refluxing saphenous vein. j vasc surg 2009;50:107-18. 24. bradbury aw, bate g, pang k, et al. ultrasound-guided foam sclerotherapy is a safe and clinically effective treatment for superficial venous reflux. j vasc surg 2010;52:939-45. 25. van den bos r, arends l, kockaert m, et al. endovenous therapies of lower extremity varicosities: a meta-analysis. j vasc surg 2009;49:230-9. 26. cavezzi a, frullini a, ricci s, tessari l. treatment of varicose veins by foam sclerotherapy: two clinical series. phlebology 2002;17:13-8. 27. myers ka, jolley d, clough a, kirwan j. outcome of ultrasound-guided sclerotherapy for varicose veins: medium-term results assessed by ultrasound surveillance. eur j vasc endovasc surg 2007;33: 116-21. 28. coleridge-smith p. sclerotherapy and foam sclerotherapy for varicose veins. phlebology 2009;24:260-9. 29. gonzalez-zeh r, armisen r, barahona s. endovenous laser and echo-guided foam ablation in great saphenous vein reflux: one-year follow-up results. j vasc surg 2008;48:940-6. 30. cavezzi a, parsi k. complications of foam no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:4676] [page 23] sclerotherapy. phlebology 2012;27:46-51. 31. cavezzi a. duplex guided sclerotherapy of long and short saphenous vein with sclerosing foam. in: henriet jp, ed. foam sclerotherapy: state of the art. paris: edit. phlébologiques françaises; 2001. pp 61-71. 32. milleret r, garandeau c, brel d, allaert fa. foam sclerotherapy of the great saphenous veins via ultrasound-guided catheter in an empty vein: the alpha-technique. phlebologie 2004;57:15-8. 33. thibault p. internal compression (perivenous) following ultrasound guided sclerotherapy to the great and small saphenous veins. aust n z j phleb 2005;9:29-32. 34. parsi k. catheter-directed sclerotherapy. phlebology 2009;24:98-107. 35. cavezzi a, tessari l. foam sclerotherapy techniques: different gases and methods of preparation, catheter versus direct injection. phlebology 2009;24:247-51. 36. cavezzi a, di paolo s, campana f, et al. peri-saphenous tumescence infiltration in long catheter foam sclerotherapy of great saphenous vein combined with phlebectomy of varicose tributaries: any benefit? phlebology 2012;27:323. [abstract] 37. jaworucka-kaczorowska a, jaworucki m. echoskleroterapia piankowa przy uzyciu wenflonow wspomagana tumescencja w leczeniu przewleklej niewydolnosci zyly odpiszczelowej. przeglad flebologiczny 2013;21:28. [abstract] 38. tessari l. mousse de sclérosant et utilisation d’un cathéter endoveineux dans le traitement dell’insuffisance veineuse superficielle. phlébol ann vasc 2002;55: 293-97. 39. wildenhues b. endovenöse katheter gestützte schaumsklerosierung. phlebologie 2005;34:165-70. 40. brodersen jp, geismar u. catheter-assisted vein sclerotherapy: a new approach foam sclerotherapy of the greater saphenous vein with a double-lumen balloon catheter. dermatol surg 2007;33:469-75. 41. kölbel t, hinchliffe rj, lindblad b. catheter-directed foam sclerotherapy of axial saphenous reflux: early results. phlebology 2007;22:219-22 42. hahn m, schulz t, jünger m. sonographically guided, transcatheter foam sclerotherapy of the great saphenous vein. medical and oeconomic aspects. phlebologie 2007;36:309-12. 43. williamsson c, danielsson p, smith l. catheter-directed foam sclerotherapy for insufficiency of the great saphenous vein: occlusion rates and patient satisfaction after one year. phlebology 2012:1-6. 44. asciutto g, lindblad b catheter-directed foam sclerotherapy treatment of saphenous vein incompetence. vasa 2012;41: 120-4. 45. fegan g. continuous uninterrupted compression technique of injecting varicose veins. proc roy soc med 1960;35:837-40. 46. devereux n, recke al, westermann l, et al. catheter-directed foam sclerotherapy of great saphenous veins in combination with pre-treatment reduction of the diameter employing the principals of perivenous tumescent local anesthesia. eur j vasc endovasc surg 2014;47:187-95. no n c om me rci al us e o nly stefano ricci comment to: interobserver variability in the assessment of the clinical severity of superficial venous insufficiency by sinabulya h, holmberg a, blomgren l. phlebology 2013 [epub ahead of print] doi:10.1177/0268355513515474 stefano ricci abstract the study took place between august 2011 and february 2012 at venous centre, a private, specialist clinic for treatment of vv in stockholm. the aim of this study was to test the inter-observer reproducibility of the c of ceap when used in a clinical setting where the patients’ clinical signs and symptoms were evaluated if severe enough for treatment within the national health insurance system. strict medical indication for treatment consisted of at least one of the following: present or previous venous ulcers, venous skin changes, significant edema, thrombophlebitis, or bleeding from vv. patients with vv without skin changes but with symptoms from their legs were considered to have a medical indication if they either had severe symptoms affecting their quality of life, no other obvious cause of leg symptoms, improvement of symptoms with compression stockings, or significant venous reflux found on examination with duplex or doppler. three physicians, consisting of a surgical resident (hs), a consultant vascular surgeon from a university hospital (lb), and a consultant vascular surgeon from the private clinic, assessed the patients independently and their respective assessments were blinded to each other. a total of 78 patients (106 limbs) agreed to participate in this study [11 men and 67 women; median age 58.5 (23-91) years]. total agreement between the three observers was obtained in 61% of all cases suggesting moderate to substantial agreement. least agreement was seen for class c3, followed by c2 and c4. the number of patients with a medical indication for treatment for each observer was 57, 44, and 33, respectively. agreement between all three observers occurred in 60% of all cases suggesting fair to moderate agreement. this study shows that assessments differed considerably for both c of ceap and assessment for the medical indication for treatment. possible cause: lack of training among the participating doctors or the simultaneous assessment of reimbursement that may influence the clinical classification may influence the individual doctor differently depending on where he or she is employed (waiting list, reimbursement policy). least agreement was seen for c3, as defining edema was difficult. another difficulty is the discrimination between hyperpigmentation and extensive telangiectasies, where the latter would sometimes be classified as c4.skin changes, such as eczema, can be present on other parts of the body besides the legs and have other causes than venous insufficiency, thus, the class may either be c2 or c4. as a consequence, scientific studies using the ceap may not be reliable if the participating doctors are classifying differently. patients are disappointed with the decision refusing reimbursement seek a second opinion in another clinic where the doctor might judge differently (the so called post code lottery). in spite of the results in this study, the authors still consider the ceap classification as the best available, and intention is to find a way to practice ceap together for more reproducible assessments. comment by stefano ricci this paper touches a very important subject that overlaps with another important one: what are the true symptoms of the cvd. our patients are becoming very cunning, and know that if they will say that the ugly vein in the leg make their life unhappy, they will be easily accepted in the reimbursement list. probably an instrumental assessment (photopletismography, cited in the paper) could give useful objective data; same, a scoring system of the ultrasound exploration (not available, but we could work on it), taking attention to: ostial incompetence, gsv calibers, varicose network extension, location of perforators. concerning the papers results, c3 is the true problem of ceap and should be under estimated, same as the corona phlebectatica, often present in c1 patients as well. finally, it would be interesting to know how many of the 84 consecutive patients attending the clinic were operated and how many reimbursed. [top] hrev_master veins and lymphatics 2017; volume 6:6849 [veins and lymphatics 2017; 6:6849] [page 101] a time-dependent multi-layered mathematical model of filtration and solute exchange, the revised starling principle and the landis experiments laura facchini,1 alberto bellin,2 eleuterio f. toro3 1department of mathematics, university of trento; 2department of civil, environmental and mechanical engineering, university of trento; 3laboratory of applied mathematics. department of civil, environmental and mechanical engineering, university of trento, italy abstract cell oxygenation and nutrition is vitally important for human and animal life. oxygen and nutrients are transported by the blood stream and cross microvessel walls to penetrate the cell’s membrane. pathological alterations in the transport of oxygen, and other nutrition elements, across microvessel walls may have serious consequences to cell life, possibly leading to localized cell necrosis. we present a transient model of plasma filtration and solute transport across microvessel walls by coupling flow and transport equations, the latter being non-linear in solute concentration. the microvessel wall is modeled through the superimposition of two or more membranes with different physical properties, representing key structural elements. with this model, the combined effect of the endothelial cells, the glycocalyx and other coating membranes specific of certain microvessels, can be analyzed. we investigate the role of transient external pressures in the study of trans-vascular filtration and solute exchange during the drop of blood capillary pressure due to the pathological decrease of blood volume called hypovolaemia, as well as hemorrhage. we discuss the advantage of using a multi-layered model, rather than a model considering the microvessel wall as a single and homogeneous membrane. introduction all cells of the human body need constant oxygenation and sustenance, provided by blood circulation and an efficient microvascular exchange. in order to preserve volume homoeostasis, the plasma volume that globally filtrates through microvessels is removed from the interstitium. the traditional view, by now disproved, is that small veins and venules continuously re-absorb interstitial fluid. this seems no longer true, because, under steadystate conditions, capillary volumetric flow leads to a rise of the peri-capillary interstitial osmotic (oncotic) pressure, which impedes flow reversal.1 the modern view is that reabsorption is operated by the lymphatic system (see e.g. levick, chapter 112). the volumetric flux per unit area (jv/a) of plasma through capillary wall is controlled by the starling equation:3 jv/a = lp[(pc–po)– σ(πc–πo)], (1) where p and π indicate fluid pressure and osmotic pressure, respectively, while the subscript indicates where the pressures are considered, with c referring to the lumen of the capillary and o referring to the interstitium, outside the microvessel. furthermore, lp = ℓp ∆r is the mechanical filtration capacity, given by the product of the permeability ℓp and the thickness ∆r of the membrane. finally, σ ≤ 1 is the reflection coefficient (see e.g. katchalsky and curran, chapter 10.34), which should be introduced to take into account the permeability of the microvessel wall to plasma proteins. according to equation (1), a reduction of pc might lead to reabsorption of interstitial fluid, i.e. a negative jv, under the hypothesis that both πo and po remain constant. this observation leads to the traditional interpretation that volume homoeostasis in the tissues is ensured by reabsorption of microvascular filtration by low-pressure capillaries and venules. this view has been recently corrected by accurate interpretations of experimental studies, including those of landis.5,6 in these experiments, a sudden drop of pc resulted in a temporary absorption, which however is rapidly counterbalanced by the rise of πo due to the increase of plasma proteins concentration in the interstitium, which re-establishes a positive flux.1,7-9 sustained absorption is possible only in specialized tissues, such as the intestinal mucosa, the renal cortex and lymph nodes, where the interstitium receives an external source of fluid compensating for the reabsorbed fluid, such that πo remains constant, despite the reabsorption. the reasoning behind the demonstration that absorption cannot be maintained in low-pressure microvessels, is based on a static interpretation of starling’s equation (1) through the construction of the absorption curve, i.e. a curve showing the evolution of the absorption pressure πc −πo against the filtration rate jv. in particular, this curve is compared with starling’s equation (1), which is depicted in the same graph as a straight line (see e.g. levick, figure 71). this analysis has the merit of evidencing the main mechanisms controlling filtration across microvessels, but cannot be used to actually model the transient behavior resulting from perturbation of one of the four terms in equation (1). before discussing existing models of microvascular filtration and formulate our objectives, we will describe the structure of correspondence: laura facchini, laboratory of applied mathematics, department of civil, environmental and mechanical engineering, university of trento, italy. e-mail: lari317@yahoo.it key words: revised starling principle; landis experiments; filtration and solute transport; time-dependent multi-layer one-dimensional model. funding: this work is partially funded by fondazione cassa di risparmio di trento e rovereto (caritro, italy), project no. 2011.0214. contributions: lf, ab and eft conceived the work and derived the model; lf performed the simulations; lf and ab wrote the paper. conflict of interest: the authors declare no potential conflict of interest. received for publication: 12 june 2017. revision received: 12 september 2017. accepted for publication: 13 september 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright l. facchini et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6849 doi:10.4081/vl.2017.6849 no n c om me rci al us e o nly article [page 102] [veins and lymphatics 2017; 6:6849] microvessels, because it is crucial to the construction of the conceptual model. the extra-cranial capillary vessel wall is known to be composed by a one-cell-thick layer of endothelial cells, internally coated by the surface glycocalyx, and currently recognized as crucial for microvascular wall homoeostasis. measurements show that glycocalyx thickness varies between 50 and 500 nm,10 though they may underestimate the real thickness due to the dehydrating effect of electron microscopy fixation and processing.11 in fact, more recent measurements using cryo-em12 show that glycocalyx may be as much as 10 to 20-times thicker than previously thought. the fiber matrix of the glycocalyx was recently described by squire et al.13 as a quasi-periodic three-dimensional fibrous mesh work with a characteristic spacing of 20 nm and anchoring foci (forming a hexagonal array), emanating from the underlying cortical cytoskeleton and extending from the luminal side of the endothelial cell surface into outer regions of the intercellular clefts.10 the presence of the glycocalyx and its sieving effect was first observed by michel7 and weinbaum,8 who argued that volumetric flow and solute transport across microvessel wall are driven by drops in pressures between the lumen and the endothelial cleft, just outside the glycocalyx, instead of between the lumen and the interstitium, as commonly assumed before. the endothelial cells are separated by clefts, which are seen as long slits partially sealed by dynamic complexes of cell-cell junctional proteins. they provide anchorage and cell stability, as in the case of the adherent junctions, or form an almost impermeable barrier to plasma and macromolecules (tight/occludens junctions), in particular in the continuous capillaries composing the blood-brain barrier.2,14 a number of mathematical models have been developed to simulate trans-vascular transport, chiefly across the arterial wall in the study of atherosclerosis, such as the model proposed by pertktold et al.,15 based on early works by quarteroni et al.16 and prosi et al.,17 and recently extended to retinal microcirculation by causin et al.18 this model couples volumetric flux across the vessel wall with hemodynamics under the hypotheses that the flux across the microvessel wall is steady and that the osmotic pressure can be neglected such that the volumetric flux is given by the darcy’s law. in addition, solute flux is modeled through the linear advection-diffusion-reaction equation (decoupled from the flow equation), while the navier-stokes equations are used to model hemodynamics in the lumen. the glycocalyx layer is lumped into an interface, together with the endothelium, and considered as a membrane through the non-linear algebraic kedem-katchalsky equations.19 this study highlighted difficulties in coupling darcy’s with the navier-stokes equations.15 in the works by khakpour and vafai20-22 and ai and vafai,23 flow and transport equations are decoupled. a review of some attempts to couple flow and transport equations can be found in khakpour and vafai.24 several oneand three-dimensional interpretations have been proposed since 1950s,10,25 showing that permeability to water and hydrophilic solutes in microvessels is controlled by the geometry of inter-endothelial cleft pathways and junction strands, leading to discontinuous leakages, and by a surface fiber layer (the glycocalyx), coating internally the endothelial cells. in the present paper, we propose a fully coupled non-linear model of flow and transport of macromolecules across microvessel walls, under the hypothesis that the vessel is circular and that flow and transport are radial and transient. the microvessel wall is represented as the superimposition of two membranes, one internal and the other external, representing the glycocalyx and the endothelium, respectively. the mathematical model statement of the problem the microvessel wall is represented as two concentric circular hollow cylinders, both with homogeneous but contrasting properties, representing the glycocalyx and the endothelial cells, respectively. owing to the relatively small variation of both hydrostatic and osmotic pressures in the direction of vessel’s axis, flow and transport are assumed radial in the cross-section of the vessel. furthermore, deformations due to membrane compressibility are assumed to be small enough to neglect their effect on the geometry of the computational domain. blood is a non-newtonian fluid, but since red blood cells concentrate at the center of the vessel only plasma flows across the microvessel wall. plasma is well represented by a newtonian fluid with characteristics similar to those of water.10 one of the most reliable theories describing the molecular filter of the trans-vascular pathway, confirmed by quantitative evidence of ferritin exclusion, is the fiber matrix theory.10 this theory describes the trans-vascular molecular filter through the assumption of glycocalyx extension from the luminal side of the endothelial cell surface into outer regions of intercellular clefts.10 this justifies our assumption of smooth, though sharp, transition between the properties of the two membranes. governing equations in dimensionless form under the above assumptions, the volumetric flow (specific discharge) qv = qv(x,y,z,t) and the total solute flow qs = qs(x,y,z,t) are related to the hydrostatic p = p(x,y,z,t) and the osmotic π = π(x,y,z,t) pressures through the following phenomenological expressions, derived from the application of the onsager law (see katchalsky and curran, chapters 8 and 104 and facchini et al.26): (2) where ℓp is the hydraulic conductivity, σ is the membrane reflection coefficient and ℓd is the diffusional permeability. osmotic pressure and macromolecules concentration c = c(x,y,z,t) are related through the van’t hoff law:2 π = r t c, (3) where r is the gas constant and t is the absolute temperature. mass conservation of blood plasma and of the solute (i.e., macromolecules such as plasma proteins), applied under the hypothesis that the solid matrix is at rest and that the solution is diluted such that the density of the mixture differ slightly from the density of the blood plasma, leads to the following two coupled governing equations:4 (4) where the volumetric and solute fluxes appearing on the left-hand side of equation (4) assume the expressions given in the system of no n c om me rci al us e o nly article equations (2) and the left-hand terms take into account the variations in time of the fluid volume and solute stored within the membrane. in equations (4), ρ is the fluid (blood plasma) density, g is the standard gravitational acceleration and ss is the specific storage, which measures the storage capacity of the vessel walls, and is given by the following expression: ss = ρg (βm + nβw), (5) where βm and n are blood vessel wall compressibility and porosity, respectively, and βw is fluid compressibility. the hypothesis here is that during the transient state changes of porosity are small such that changes in the stored blood plasma occur with the membrane total volume remaining almost constant. consequently, according to the classical theory of porous media,27 the combined effect of membrane and blood plasma compressibility can be represented through the specific storage ss given by the equation (5). after these preparatory steps, system (4) can be rewritten as follows (after switching to cylindrical coordinates): (6) for r ∈ (0,1) and t > 0, where α = (βm + nβw) pr, ξ = rc/(ro − rc), a = ℓp (σ − 1) and b = ℓpσ − ℓd. hereafter, all the quantities are dimensionless, if not explicitly stated differently. all pressures are made dimensionless with respect to the reference pressure pr given by the (dimensional) initial external hydrostatic pressure |p0o|, the distances with respect to the thickness ro − rc of the vessel shifted by the internal radius of the vessel wall identified with the internal surface of the glycocalyx rc, and time with respect to reference time given by tr=(∆r)2/(ℓphpr). furthermore, the reference for the physiological parameters is the harmonic mean ℓph of hydraulic conductivity, weighted by vessel wall thickness: (7) where ℓpg refers to glycocalyx i.e. for r ∈ (rc,rg) and ℓpw to the endothelial cells composing the vessel wall r ∈ (rg,ro). the volumetric jv and solute js fluxes crossing the microvessel wall are obtained by integrating the respective flows along a circle of radius r as follows: (8) (9) where volumetric and solute fluxes are dimensionless with respect to ℓph |po0| and ℓph |po0|2/(rt), respectively. physiological parameters the reflection coefficient is let to vary according to the following expression:26 (10) with the usual meaning of the subscripts. similar expressions are used for ℓp and ℓd. the transition between the two layers is smooth for ε > 0, and becomes discontinuous for ε → 0. in the present work, we assume ε2 = 10–4, unless otherwise stated, which produces a smooth, yet sharp, transition in line with experimental observations.10 we consider passive transport of albumin, which accounts for half the plasma protein mass and generates about two-thirds of the colloid osmotic pressure.2 table 1 shows typical values of geometrical and physiological properties of an intact capillary, as well as osmotic and hydrostatic pressures within the lumen and in the external interstitial space, at initial (with superscript 0) and final state of the transient experiment (see the reproduction of the landis experiment section). also the compressibility of the fluid and of the membrane composing the microvessel wall, as well as media porosity, are reported. reproduction of the landis experiment during its experiments,5,6 landis found a linear relation between the rates of filtration/absorption jv and capillary pressure pc in a population of frog mesentery capillaries. the traditional interpretation of the landis5 experiment assumes that both hydrostatic and osmotic pressures in the interstitium remain constant during reabsorption induced by a sudden drop of hydrostatic pressure below the osmotic pressure in the lumen. as discussed in the introduction, this leads to the wrong interpretation that at the lower end of capillary beds and in venules absorption might be permanent. however, more accurate interpretations by levick1 and michel7 showed that reabsorption can only occur temporarily. the main mechanism preventing reabsorption in steady state is the increase of protein concentration in the interstitium due to flow reversal. this causes πo to increase, thereby opposing flow reversal and finally leading to a steady-state condition with a smaller than before, but still positive (i.e., from the lumen to the interstitium) volumetric flow.2,9 this mechanism has been demonstrated by levick1 by using a quasi-static interpretation (as discussed in the introduction) and here we show that this is implied in the structure of the model (6). initial and boundary conditions to numerically solve the pde system (6), proper initial conditions should be assigned to both hydrostatic p(r,0) = p0(r) and osmotic π(r,0) = π0(r) pressures. the initial conditions for p0(r) and π0(r) are provided according to the analytical solutions of the steady-state counterpart of the model (6), obtained by facchini et al.26 and reported in the steady-state implicit exact solutions section. the boundary conditions of hydrostatic and osmotic pressures used in the steady-state solutions are reported in table 1 with subscripts c and o referring to the lumen of the capillary and the interstitial space, respectively. the thickness of the two membranes representing the glycocalyx and the endothelial cells, as well as the respective phenomenological parameters (i.e., ℓp, ℓd and σ), are also [veins and lymphatics 2017; 6:6849] [page 103] no n c om me rci al us e o nly article reported in table 1. furthermore, the maximum simulation time is set to t = 3 min. at = t/5 the hydrostatic pressure, pc0, at the lumen is suddenly reduced from 22 mmhg to 7 mmhg, while the osmotic pressure is kept constant and equal to πc0 = 24 mmhg (figure 1): (11) where h(x) is the heaviside step function36 defined as: (12) in the following we assume two different conditions for the interstitial pressures. first, we assume that both hydrostatic and osmotic pressures remain constant and equal to po0 and πo0, respectively, during the time interval t = [0, t] spanning the entire simulation period, as shown in the last two rows of figure 1a: (13) this condition mimics the traditional interpretation, which implies persistent reabsorption if the hydrostatic pressure in the lumen (pc) drops below po + σ (πc − πo). in fact, according to equation (1), this is the value of pc below which volumetric flow jv reverses becoming negative. then we consider the following boundary conditions for the interstitial pressures (figure 1b): figure 1. behavior of the boundary conditions for (a) constant external pressures as described in equations (11)-(13), and (b) pressures varying with time according to equations (11)-(14). [page 104] [veins and lymphatics 2017; 6:6849] a b table 1. typical values of the material properties of a capillary: σ is the reflection coefficient, ℓp is the hydraulic conductivity, ℓd is the diffusional permeability. the superscripts g and w indicate the glycocalyx and the endothelial layers, respectively. as described in initial and boundary conditions section, the boundary conditions change following equations (11)-(13)-(14) with initial (at t = 0) and final (at t = t) values of pressures during the transient experiment are denoted by superscripts 0 and t, respectively. the coefficient βw refers to the compressibility of horse blood plasma, while βm is the maximum value of blood vessel wall compressibility measured in dog descending thoracic aorta. the porosity n was measured in arterial graft prosthesis. parameter [unit] value reference rc [µm] 5 [28] rg [µm] 5.15 [29] ro [µm] 5.5 [28] πc0 [mmhg] 25 [9] πo0 [mmhg] 8 [9] pc0 [mmhg] 22 [9] po0 [mmhg] −1.3 [9] πot [mmhg] 15 [9] pct [mmhg] 7.36 [9] pot [mmhg] −3.6 [9] σg 0.9 [30] σw 0.1 [31] ℓpg [µm2sec−1mmhg−1] 0.6013 [32] ℓpw [µm2sec−1mmhg−1] 4.1520 [32] ℓdg [µm2sec−1mmhg−1] 0.5357 [26] ℓdw [µm2sec−1mmhg−1] 3.6995 [26] βw [mmhg−1] 5.45 · 10−8 [33] βm [mmhg−1] 9.21 · 10−6 [34] n 0.5 [35] no n c om me rci al us e o nly article (14) with (15) where w(x) is the lambert w function,37,38 also called omega function or product logarithm, which is the inverse function of z → z ez. in addition, τ is the time at which pressures in the interstitium reach steady state. in the present example, we assumed τ = 0.6 t, such as to mimic the recorded behavior of the pressures in the interstitium during the landis5 experiment, as reported in fig. 3 of levick and michel.9 results of the transient simulations we first consider a vessel wall composed by two nearly homogeneous layers, with physiological parameters varying according to equation (10) with ε2 = 10−4 (same for ℓp and ℓd), assuming either constant or time-varying pressures at the interstitium, according to equations (13) or equations (14), respectively. the physiological parameters are therefore nearly constant inside the two layers and vary sharply, yet continuously at the interface between the two layers. table 2 shows volumetric and solute fluxes at initial (t = 0) steady-state condition, immediately before and after the drop of the luminal hydrostatic pressure at t=t̂, and at the successive time t = t. volumetric and solute flows reverse, i.e. both become negative, immediately after the drop of the luminal pressure (figure 2). successively, volumetric flux remains negative if the interstitium pressures are kept constant according to the scheme shown in figure 1a, but it rebounds and becomes positive at successive times for the more realistic transient boundary conditions shown in figure 1b. these boundary conditions represent better than the case of constant interstitium pressures the physiological response table 2. volumetric and solute fluxes at selected times obtained by solving pde system (18). the numerical solutions for the pressures were computed using a spatial grid of 1000 points and dt = 500·(dx)2. the external pressures are assumed constant as in equations (13) and transient according to equations (14). the values of the fluxes are reported both for the twoand single-layer model with equivalent dimensionless parameters equal to σeq = 0.798802, ℓpeq = 0.831226 and ℓdeq = 0.578381, computed by following the procedure described by facchini et al.26 layers bcs t = 0 t = t̂ – t = t̂ + t = t volumetric flux [10−3 µm/sec] 2 constant 27.4867 27.4867 −25.6272 −14.5961 2 transient 27.4867 27.4867 −25.6267 3.1622 1 transient 27.4867 27.4867 −12.1853 4.7463 solute flux [10−2 mol/µm/sec] 2 constant 14.6849 14.6849 −8.52912 6.3217 2 transient 14.6849 14.6849 −8.53067 8.08544 1 transient 14.6849 14.6849 −1.95824 4.9169 [veins and lymphatics 2017; 6:6849] [page 105] figure 2. behavior of the volumetric (a) and solute (b) fluxes obtained by numerically solving the system of differential equations (22) subjected to the initial and boundary conditions described in initial and boundary conditions section and reported in figure 1. in particular, the external pressures are assumed constant as in equations (13) (dashed curves) and varying with time following equations (14) (solid curves). the numerical solutions for the pressures are computed using a spatial grid of 1000 points and dt = 500 · (dx)2. a bno n c om me rci al us e o nly article to flow reversal, which causes a temporary reduction of plasma volume within the interstitium, accompanied by a rise of the osmotic pressure, due to the increase of solute concentration, thereby contrasting flow reversal. comparison between the singleand two-layer models in our recent work, we showed that in order to properly model transport of proteins across microvessel walls and the loss of the barrier effect consequent to glycocalyx damage, a two-layer model should be used, with the internal layer representing the glycocalyx and the external one the endothelial cells.26,39 however, in applications, a single-layer model is typically used, requiring the definition of equivalent properties encapsulating the effects of both glycocalyx and of the surrounding endothelial cells. to properly address the single-layer case we suggest computing the reflection coefficient by means of the expression proposed by sugihara-seki and fu:10 (16) while ℓpeq and ℓdeq are obtained by imposing that at the initial steady-state condition volumetric and solute fluxes are the same in the two-layer model, considered here with discontinuous (step) transition of the physical properties, and in the single-layer homogeneous equivalent model: (17) where (pc,πc) and (po,πo) are the initial values of the pressures at r = 0 and within the interstitium at r = 1, respectively. figure 3 shows the comparison between volumetric and solute fluxes obtained with the singleand the two-layer models. before the drop of the pressure at t=t̂, the two fluxes are the same in the two-layer and single-layer equivalent model as imposed to compute ℓpeq and ℓdeq. at larger times, the single-layer model produces higher volumetric, but lower solute fluxes during the transitory and the following new steady-state condition (table 2). at the beginning of the transient phase following the drop of the pressure pc, solute flux reverses and assumes the following values: js = −8.53067 and −1.95824 for the twoand single-layer model, respectively (table 2). in agreement with what we already observed for the stationary case,26 which here has been assumed as initial condition, most of the excess of pressure is dissipated within the glycocalyx. due to the sudden drop in the lumen, the hydrostatic pressure reduces sharply, though smoothly, assuming values smaller than po (the value in the interstitium) in the last portion of the glycocalyx and across the endothelial cells, where it slightly rises while approaching the interstitium (figure 4a). this causes a temporary reversal volumetric flow, which induces an increase of solute concentration and therefore of osmotic pressure in the outer portion of the glycocalyx and in the clefts (figure 4b). in fact, due to the relatively high velocity of the plasma in the glycocalyx and the solute slow motion in the endothelial clefts, which is the consequence of the small gradient of the osmotic pressure in this region, plasma proteins are expelled to the interstitium while flow prevents them from going back by diffusion, thus creating a zone at the contact between the glycocalyx and the endothelial cells in which their concentration (and thus the osmotic pressure) is lower than in the surroundings (figure 4b). this dynamic, due to the coupling between flow and transport in a composite membrane, contrasts the reversal of the volumetric flow, which after a relatively short transient behavior becomes again positive, though much smaller than in the initial steady-state conditions (figure 3a). this behavior is in line with the physiological explanation provided by levick1 and discussed in the introduction. the single-layer model does not reproduce correctly the behavior of the hydrostatic and osmotic pressures across the glycocalyx and the endothelial cells, though the transient regime of both figure 3. comparison of volumetric (a) and solute (b) fluxes obtained with the singleand two-layer models with boundary conditions given by equations (14). the numerical solutions for the pressures are computed using a spatial grid of 1000 points, dt = 500 · (dx)2 and physiological parameters σ(r), ℓp(r) and ℓd(r) varying according to equation (10) for σ and a similar expression for the other two parameters. for the single-layer case, the equivalent dimensionless physiological parameters are: σeq = 0.798802, ℓpeq = 0.831226 and ℓdeq = 0.578381. [page 106] [veins and lymphatics 2017; 6:6849] a bno n c om me rci al us e o nly article the volumetric and solute fluxes is somewhat captured. in particular, the single-layer model is unable to reproduce the dilution effect at the contact between the glycocalyx and the endothelial cells (compare figures 4 and 5), and the solute flux is underestimated during the transient behavior and the following new steady-state condition (figure 3b). concluding remarks we have presented and discussed a two-layer model of transient flow and transport of solutes across microvessel walls. the dynamic model allows computing the evolution in time of volumetric and solute fluxes resulting from perturbations of state variables, such as the hydrostatic and osmotic pressures. we have applied the model to represent the transient behavior occurring after a sudden drop in the luminal pressure, as done in the famous experiment by landis.5 our model is able to dynamically reproduce the evolution in time of pressures and fluxes and confirms the emergence of a transient state of reabsorption as observed by landis5 and successively justified by phenomenological analyses.1,7-9 this transient state ends with the development of a new steady-state condition in which reabsorption disappears since all fluxes are positive, thereby ruling out the interpretation that reabsorption of interstitial fluid occurs at the level of low-pressure capillaries and venules, in agreement with the most recent physiological studies.9 in the present work, we have attempted to reproduce the values of the fluxes in landis experiments at our best, due to the lack of exact values for the physiological parameters of the microvessels involved in the experiment. nonetheless, we obtained an analogous behavior and plausible values of pressures and fluxes. one advantage of our model is that it allows simulating the consequence of glycocalyx damage in all pathologies in which this is deemed important. figure 4. hydrostatic (a) and osmotic (b) pressures in the two-layer model as a function of distance from the internal glycocalyx surface for external pressures varying according to equations (14), and for several times. pde system (18) has been numerically solved with a spatial grid of 1000 points and dt = 500 · (dx)2 and physiological parameters σ(r), ℓp(r) and ℓd(r) varying according to equation (10) for σ and a similar expression for the other two parameters. figure 5. hydrostatic (a) and osmotic (b) pressures in the single-layer model as a function of distance from the internal glycocalyx surface for external pressures varying according to equations (14), and for several times. pde system (18) has been numerically solved with a spatial grid of 1000 points and dt = 500 · (dx)2. the equivalent dimensionless physiological parameters are σeq = 0.798802, ℓpeq= 0.831226 and ℓdeq = 0.578381. [veins and lymphatics 2017; 6:6849] [page 107] a b a bno n c om me rci al us e o nly article [page 108] [veins and lymphatics 2017; 6:6849] in a broader context, the present model may be extended and used in conjunction with global models for the dynamics of the human circulation.40-42 in particular, it has been hypothesized that extracranial venous strictures43 that hamper brain venous return may induce cerebral venous hypertension.42,44,45 it would be of interest, for example, to study the effect of cerebral venous hypertension on brain perfusion. numerical solution of the governing equations numerical scheme to simplify the notation of the numerical scheme, we rewrite the non-linear system of pdes (6) as follows: (18) for r ∈ (0,1) and t > 0, in the unknown p and π, both functions of r and t, where the auxiliary functions are defined as: (19) to numerically solve system (18), we apply the implicit cranknicolson finite-difference scheme proposed by freeze,46 for a constant spacing ∆x, which leads to the following nonlinear system of algebraic equations: (20) with the following source terms: (21) notice that the governing equations are written in a radial reference system, such that ∆x is the spacing along the radial coordinate. the algebraic non-linear system (20) is solved by using newton method. in equations (20) and (21), ∆x is the mesh spacing of the spatial grid {ri}i=0..n+1 and ∆t denotes the time step between two adjacent temporal grid points {tn}n=0..m+1, while hydrostatic and osmotic pressures are approximated by pin ≈ p(ri,tn) and πin ≈ π(ri,tn), respectively. furthermore, in order to solve system (6), suitable initial and boundary conditions, the latter at all times t ∈ [0,t], should be defined. in addition, the grid is designed such that rg falls between two nodes, of a grid composed of 1000 nodes, unless otherwise stated; the tolerance for stopping the iterations of the newton method is set to 10−10, unless otherwise stated. validation of the numerical scheme: convergence to steady state as discussed in the numerical scheme section, the coupled non-linear transient flow and transport model (6) is solved by using the numerical scheme proposed by freeze46 and shown by facchini et al.26 to compare well with the analytical solution of the stationary counterpart of model (6). therefore, we first analyze the convergence of numerical solutions of hydrostatic and osmotic pressures to the steady-state solution obtained by facchini et al.26 the numerical solutions are obtained for a two-layer membrane with discontinuous (i.e., ε = 0) physiological parameters at the interface. the initial conditions are a linear distribution of both pressures across microvessel wall, while constant boundary conditions, equal to the initial values reported in table 1, are applied at the luminal (r = rc) and interstitial (r = ro) interfaces. since this distribution of the pressures is not consistent with the steady-state behavior, transient conditions will develop, finally converging to the steady-state solution, for which an analytical solution is available.26 the dynamics of hydrostatic and osmotic pressures varies significantly during the transient generated by imposing an unrealistic linear decline across the microvessel wall. the hydrostatic pressure declines rapidly showing a significant difference with respect to the initial condition already at t = 10−6, while no variations are observed in the osmotic pressure (figure 6). a longer time should be waited for, i.e. t = 10−2, in order to observe a similar variation of the osmotic pressure, when hydrostatic pressure is nearly in steady-state conditions. both reach steady state at t = 10−1 and the numerical solution approximates very well the analytical solution obtained by facchini et al.26 in figure 7, the l2-norm of the difference between the transient numerical solution and the steady-state analytical solution of both osmotic and hydrostatic pressure are depicted with respect to time t. note that the convergence is quick at the beginning (until around t = 10−4), but then it gradually slows down and convergence is obtained for t ≃10−1 (notice the logarithmic scale of the figure). time-dependent model since analytical solutions of equations (6) are not available, we check the accuracy of the numerical scheme as follows. first, we assume that the solutions for both hydrostatic and osmotic pressures are given by the following arbitrary expressions: no n c om me rci al us e o nly article [veins and lymphatics 2017; 6:6849] [page 109] (22) the arbitrary increase of 5 for the osmotic pressure is necessary to assure that osmotic pressure remains always positive. given their arbitrary choice, the functions (22) do not satisfy the system of equations (6), but the following modified system of differential equations, where the source terms ŝ 1 (r,t) and ŝ 2 (r,t) are obtained by substituting p (r, t) with p̂ (r,t) and π(r, t) with π̂ (r, t) into the equations (6): (23) the solution of system (23) with initial conditions p̂ (r, 0), = sin(2 π r), π̂ (r, 0) = sin(2 π r)+5 and boundary conditions p̂ (0, t) = p̂ (1, t) =sin(2 π t), π̂ (0, t) = π̂ (1, t)=sin(2 π t) + 5 should be equal to the imposed functions (22). notice that the only change in the numerical implementation lies in the right-hand sides of the discretized equations (20), which become now equal to s1(i,n)+4(δx)2 (ri+ξ) ŝ1 (ri,tn+1) and s2(i,n) +8(δx)2 (ri+ξ) ŝ 2 (ri,tn+1), respectively, where s1(i,n) and s2(i,n) are the source terms (21) of the discretized equations (20). since equations (22) are periodic in t with period equal to 1, we evaluate the accuracy of the numerical method by comparing the exact solutions (solid curves) and the numerical solutions (circles) after one period, as depicted in figure 8. the imposed and the numerical solutions of the modified system of equations (23) are barely distinguishable, thereby confirming that the implicit crank-nicolson finite-difference scheme proposed by freeze46 works well also when applied to transient equations (6). a more comprehensive analysis of the numerical error is provided in table 3, which shows the most used norms of the error at time t = 1, defined as the difference between the numerical solution and the imposed functions (22) at the grid nodes. table 4 shows the empirical order of convergence of the numerical scheme to the exact solution. as expected, it approaches the theoretical order of accuracy of crank-nicholson method, table 3. lp-norm errors at t = 1 of the two-layer model with dt = (dx)2 and ε2 = 10−2, numerically solved by varying the number of grid nodes as reported in the first column. mesh dx dt l∞-error l1-error l2-error 7 0.166667 0.0277778 0.437544 0.284086 0.276584 13 0.0833333 0.00694444 0.116974 0.0636364 0.0682671 25 0.0416667 0.00173611 0.0299723 0.0175038 0.0178583 49 0.0208333 0.000434028 0.00734658 0.00463064 0.00446781 97 0.0104167 0.000108507 0.0018257 0.00118912 0.00112179 table 4. empirical orders of accuracy at time t = 1 for the two-layer model with dt = (dx)2 and ε2=10−2, according to the lp-norm errors reported in table 3. mesh dx dt l∞-error l1-error l2-error 13 0.0833333 0.00694444 1.90324 2.1584 2.01846 25 0.0416667 0.00173611 1.96448 1.86218 1.9346 49 0.0208333 0.000434028 2.02849 1.91838 1.99895 97 0.0104167 0.000108507 2.00862 1.96132 1.99377 figure 6. hydrostatic (a) and osmotic (b) pressures for the two-layer model at given times t = {0,10−6,10−4,10−2,10−1}, obtained numerically with a spatial grid of 1000 points, dt = (dx)2, ε = 0 and tolerance equal to 10−9. the analytical steady-state solutions (thick curves) for both hydrostatic and osmotic pressures obtained by facchini et al.26 are also shown and compared with the numerical solution at time t = 10−1 (black bullets) when steady state is reached. a b no n c om me rci al us e o nly article which is second order. this occurs also for ∆t = k(∆x)2 with k larger than 1, but smaller than k = 1000. it can be shown that, for k ≥ 1000, the numerical solutions are no longer convergent to their analytical counterparts. steady-state implicit exact solutions single-layer solutions for a single-layer vessel wall with uniform physiological parameters (ℓp, ℓd, σ) and constant pressures in the lumen and the interstitium, the solution of the stationary counterpart of the system of equations (6), obtained by letting ∂p/∂t = 0 and ∂π/∂t = 0, leads to the following expressions:26 (24) for the hydrostatic pressure and (25) for the osmotic pressure, respectively. in equations (24) and (25), the integration constants assume the following expressions: (26) (27) k4=fe f ξδ (28) where f = (k1/k2)(σ − 1)πc − 1 and δ=k12 (σ-1)2/ [k2 (ℓpσ2 − ℓd)]. by imposing the osmotic pressure equal to πc at r = rc, we obtain the following expression in the only unknown k2, provided that k1 is given by equation (26): (29) two-layer solutions in this case, the physiological parameters (ℓp, σ, ℓd) and the integration constants (k1, k2, k3 and k4) are layer-specific. the need to respect continuity in both hydrostatic and osmotic pressures at the inner and outer surfaces of the microvessel walls, leads to the following expressions k3g, k4g and k4g, k4w to be substituted into equations (24) and (25):26 (30) where (31) by imposing the continuity conditions at the interface between the two layers at r = rg, we obtain the following two equations for the two remaining unknowns (k1 and k2) in equations (24) and (25):26 (32) figure 7. l2-norm of the difference between the transient numerical solution (obtained numerically with a spatial grid of 1000 points, dt = (dx)2, ε = 0 and tolerance equal to 10−9) and the steady-state analytical solution for the two-layer model of both the osmotic (dashed curve) and the hydrostatic pressure (solid curve). [page 110] [veins and lymphatics 2017; 6:6849] no n c om me rci al us e o nly article [veins and lymphatics 2017; 6:6849] [page 111] (33) where g1 and g2 assume the following expressions (34) (35) with σg ≠ σw and (36) references 1. levick jr. capillary filtration–absorption balance reconsidered in light of dynamic extravascular factors. exper physiol 1991;76:825-57. 2. levick jr. an introduction to cardiovascular physiology. boca raton, fl: crc press; 2010. 3. starling eh. on the absorption of fluids from the connective tissue spaces. j physiol 1896;19:312-26. 4. katchalsky a, curran pf. non-equilibrium thermodynamics in biophysics. cambridge, ma: harvard univ. press; 1965. 5. landis em. micro-injection studies of capillary permeability. ii. the relation between capillary pressure and the rate at which fluid passes through the walls of single capillaries. am j physiol 1927;82:217-38. 6. landis em. micro-injection studies of capillary blood pressure in human skin. heart 1930;15:209-23. 7. michel cc. starling: the formulation of his hypothesis of microvascular fluid exchange and its significance after 100 years. exper physiol 1997;82:1-30. 8. weinbaum s. 1997 whitaker distinguished lecture: models to solve mysteries in biomechanics at the cellular level; a new view of fiber matrix layers. ann biomed engine 1998;26:62743. 9. levick jr, michel cc. microvascular fluid exchange and the revised starling principle. cardiovasc res 2010;87:198-210. 10. sugihara-seki m, fu bm. blood flow and permeability in microvessels. fluid dyn res 2005;37:82-132. 11. weinbaum s, tarbell jm, damiano er. the structure and function of the endothelial glycocalyx layer. ann rev biomed engine 2007;9:121-67. 12. ebong ee, macaluso fp, spray jm, tarbell dc. imaging the endothelial glycocalyx in vitro by rapid freezing/freeze substitution transmission electron microscopy. arterioscler thromb vasc biol 2011;31:1908-15. 13. squire jm, chew m, nneji g, et al. quasi-periodic substructure in the microvessel endothelial glycocalyx: a possible explanation for molecular filtering? j struct biol 2001;136:239-55. 14. hawkins bt, davis tp. the blood-brain barrier/neurovascular unit in health and disease. pharmacol rev 2005;57:173-85. 15. formaggia l, quarteroni a, veneziani a. cardiovascular mathematics. milan: springer; 2009. 16. quarteroni a, veneziani a, zunino p. mathematical and numerical modeling of solute dynamics in blood flow and arterial walls. siam j numer analys 2002;39:1488-511. 17. prosi m, zunino p, perktold k, quarteroni a. mathematical and numerical models for transfer of low-density lipoproteins through the arterial walls: a new methodology for the model set up with applications to the study of disturbed lumenal flow. j biomechan 2005;38:903-17. 18. causin p, guidoboni g, malgaroli f, et al. blood flow mechanics and oxygen transport and delivery in the retinal microcirculation: multiscale mathematical modeling and numerical simulation. biomechan model mechanobiol 2016;15:525-42. 19. kedem o, katchalsky a. thermodynamic analysis of the perfigure 8. hydrostatic (a) and osmotic (b) pressures of the modified problem for the two-layer model after one period (t = 1), obtained numerically with a spatial grid of 49 points, dt = 5 · 10−3 and ε2 = 10−2 (circles), compared to the analytical solutions (solid curves). a b no n c om me rci al us e o nly article [page 112] [veins and lymphatics 2017; 6:6849] meability of biological membranes to non-electrolytes. biochim biophys acta 1958;27:229-46. 20. khakpour m, vafai k. a comprehensive analytical solution of macromolecular transport within an artery. int j heat mass transfer 2008;51:2905-13. 21. khakpour m, vafai k. analysis of transport phenomena within pem fuel cells an analytical solution. int j heat mass transfer 2008;51:3712-23. 22. khakpour m, vafai k. effects of gender–related geometrical characteristics of aorta-iliac bifurcation on hemodynamics and macromolecule concentration distribution. in j heat mass transfer 2008;51:5542-51. 23. ai l, vafai k. a coupling model for macromolecule transport in a stenosed arterial wall. int j heat mass transfer 2006;49:1568-91. 24. khakpour m, vafai k. critical assessment of arterial transport models. int j heat mass transfer 2008;51:807-22. 25. michel cc, curry fe. microvascular permeability. physiol rev 1999;79:703-61. 26. facchini l, bellin a, toro ef. a mathematical model for filtration and macromolecule transport across capillary walls. microvasc res 2014;94:52-63. 27. bear j. hydraulics of groundwater. new york, ny: mcgrawhill international book company; 1979. 28. charm se, kurland gs. blood flow and microcirculation. new york: wiley; 1974. 29. adamson rh, lenz jf, zhang x, et al. oncotic pressures opposing filtration across non–fenestrated rat microvessels. j physiol 2004;557:889-907. 30. michel cc, phillips me. steady-state fluid filtration at different capillary pressures in perfused frog mesenteric capillaries. j physiol 1987;388:421-35. 31. hu x, weinbaum s. a new view of starling’s hypothesis at the microstructural level. microvasc res 1999;58:281-304. 32. speziale s, tenti g, sivaloganathan s. a poroelastic model of transcapillary flow in normal tissue. microvasc res 2008;75:285-95. 33. urick rj. a sound velocity method for determining the compressibility of finely divided substances. j appl phys 1947;18:983-7. 34. carew te, vaishnav rn, patel dj. compressibility of the arterial wall. circulation res 1968;23:61-8. 35. robinson tc. arterial graft prosthesis. us patent 4731073; 1988. available from: http://www.patentlens.net/ patentlens/patent/us_4731073/en/ 36. kawamoto a, matsumori t, yamasaki s, et al. heaviside projection based topology optimization by a pde–filtered scalar function. struct multidisciplin optimizat 2011;44:19-24. 37. corless rm, gonnet gh, hare deg, et al. on the lambert w function. adv computat math 1996;5:329-59. 38. barry da, parlange jy, li l, et al. analytical approximations for real values of the lambert w-function. math comput simulat 2000;53:95-103. 39. facchini l, bellin a, toro ef. modeling loss of microvascular wall homeostasis during glycocalyx deterioration and hypertension that impacts plasma filtration and solute exchange. curr neurovasc res 2016;13:147-55. 40. müller lo, toro ef. a global multi-scale model for the human circulation with emphasis on the venous system. int j numer methods biomed engine 2013;30:681-725. 41. müller lo, toro ef. enhanced global mathematical model for studying cerebral venous blood flow. j biomechan 2014;47: 3361-72. 42. müller lo, toro ef, haacke em, utriainen d. impact of ccsvi on cerebral haemodynamics: a mathematical study using mri angiographic and flow data. phlebol 2016;31:30524. 43. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatr 2009;80:392-9. 44. talbert dg. raised venous pressure as a factor in multiple sclerosis. med hypothes 2008;70:1112-7. 45. toro ef. brain venous haemodynamics, neurological diseases and mathematical modelling. a review. appl math computat 2016;272:542-79. 46. freeze ra. a stochastic-conceptual analysis of one-dimensional groundwater flow in nonuniform homogeneous media. water resour res 1975;11:725-41. no n c om me rci al us e o nly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: great saphenous vein surgery without high ligation of the saphenofemoral junction by casoni p, lefebvre-vilardebo m, villa f, corona p. j vasc surg 2013;58:173-8. stefano ricci abstract traditional surgical treatment of varicose disease requires an invasive procedure like high ligation of sapheno femoral junction (sfj), resulting in high recurrence rates, especially in the long term. the aim of this prospective randomized study was to evaluate whether great saphenous vein (gsv) surgery without high ligation of the sfj is beneficial in terms of varicose vein recurrence. the study enrolled 120 patients with gsv reflux due to sfj incompetence, from december 2000 to may 2004, randomly allocated preoperatively to two groups undergoing gsv surgery with (group a) or without (group b) high ligation of the sfj (60 patients and 62 limbs in each group). surgery was performed under tumescent local anesthesia, continuous femoral block and kleine tumescence by a single operator. group a underwent standard gsv surgery, including high ligation of the sfj, foramen ovale plasty and infolding suture to hide the free endothelium of the saphenous stump. group b underwent gsv surgery without high ligation of the sfj. after the gsv was hooked through a small incision at lower leg level, a stripper device was inserted. invagination stripping was performed without echographic guidance. the gsv was hooked at the thigh level, 2 to 3 cm below the groin (sfj), and gsv ligature was performed in distal to epigastric and perineal veins to preserve physiologic drainage. clinical evaluation and duplex ultrasound scanning (dus) were performed at 6 months and yearly thereafter. the follow-up of the last operated-on patient ended in may 2012, so that all patients had a minimal follow-up of 8 years. the primary end point was varicose vein recurrence, defined as an operated-on limb with new minimal thigh varices at clinical evaluation (ceap c2) or venous reflux at the thigh or groin level, as assessed by dus, or both. a total of 123 limbs were followed up 8 years after surgery. the combined clinical and dus-determined recurrence rate was 24.4% (30 of 123), consisting of 32.2% (20 of 62) in group a vs 16.4% (10 of 61) in group b. long-term actuarial freedom from varicose vein recurrence was significantly higher in group b [85% than in group a (67%)]. the 1-year recurrence rate of 3.3% was lower than that achieved with endovenous laser ablation (evla) (11.6%), radio frequency ablation (rfa) (7.3%), ultrasound-guided foam sclerotherapy (ugfs) (13.8%), and conventional surgery (14.8%). at 5 years postoperatively, surgery without high ligation of the sfj resulted in a recurrence rate of 9.8%, which is significantly lower than the 25 to 47.1% reported for conventional surgery. this minimally invasive surgical approach was associated with a lower rate of treatment failure at short-term and long-term follow-up compared with conventional surgery. this could be due to the preservation of the sfj during gsv reflux treatment enabling the sparing of some normal, competent tributaries (epigastric and perineal vein) draining the residual stump. finally, this surgical technique is less invasive and is associated with a reduced risk of inflammatory reactions at the site of groin dissection, resulting in a lower grade of neovascularization. other advantages of gsv surgery without high ligation include lower costs of the procedure and earlier return to work. comment by stefano ricci this is one of the most important papers published in recent years on gsv surgery. it gives an 8-year follow up of a method based on the revolutionary idea that sfj does not have to be fully dissected. although endovenous treatments have yielded good results in terms of recurrences leaving the 2 last cm of gsv exposed, yet this aspect has barely been tackled in surgery.1,2,3,4 considering laser and rf treatments costs and the economical crisis impinging upon most of the western national health services, this new, simple and free option could become interesting if confirmed by further research. concerning the technique of saphenectomy without high ligation, no mention is made about the incision placed 2-3 cm below the groin and the method for hooking the gsv. some questions are left unanswered: how large the incision is? is the gsv found by the assistance of the stripping previously inserted? what is the management of the anterior accessory saphenous vein (one of the major causes of recurrence) when present? finally, it is a pity the authors did not cite dortu’s pioneering work published on the french journal phlébologie: dortu, a fellow countryman of dr. lefebvre-vilardebo, had the good idea. just for historical recall, dortu operated 596 patients by what he called supra-fascial crossectomy. minumum follow up was three years. over 125 cases (149 limbs) blindly chosen inside the patients list of the period 1982-1988, he could find 146 very good results, 2 recurrences on posterior accessory and 1 on anterior accessory (15 years after). not all the history is written in english. references 1. dortu j. la crossectomie sus-fasciale au corse de la phlebectomie ambulatoire du complexe saphenien interne à la cuisse. phlébologie 1993;46:123-36. 2. fays-bouchon n, fays j. une technique d’endo-eveinage de la saphéne interne en ambulatoire par micro-incisions. phlébologie 1995;48:353-8. 3. horakova ma, horakova e. ambulatory phlebectomy of incompetent great saphenous vein without flush saphenofemoral ligature: effect on the saphenofemoral junction. phlébologie 2002;55:299-305. 4. pittaluga p, chastanet s, guex j-j . great saphenous vein stripping with preservation of sapheno-femoral confluence: hemodynamic and clinical results. j vasc surg 2008;47:1300-5.[abstract] [top] fabrizio salvi letter to the editor corner does a mobbing in research exist? fabrizio salvi, md irccs delle scienze neurologiche di bologna, italy fabrizio.salvi@gmail.com pierfrancesco veroux, md s.c. di chirurgia vascolare e centro trapianti, università di catania, italy pveroux@unict.it sir, we are both fascinated and motivated in understanding the role of cerebral venous return in brain pathophysiology, as well as in the development of specific neurological symptoms. we also read with interest the editorial published by bourdette and cohen in the last issue of neurology.1 the authors invite to move in an opposite direction, and, in doing so, do not hesitate to use dishonorable appellations and examples for those who have different ideas. the science behind vascular investigation, as well as the benefits for patients achieved by the means of the modern endovascular treatment in different fields of application, does not merit being confused through mystifying comparison with historical corporal treatment cited by bourdette and cohen. the letter would comment the results of a clinical trial published on the same issue by siddiqui et al., who investigated the efficacy of internal jugular veins angioplasty in the treatment of patients with multiple sclerosis.2 safety of venous angioplasty is well known and documented in previews papers and as primary outcome measure of the study was completely achieved. unfortunately they were able to enroll only 9 and 10 patients in angioplasty and sham arm respectively. the statistical power to achieve such information was calculated for a double blinded rct actually in course (clinicaltrials.gov identifier: nct01371760), and require hundreds of enrolled patients, as well delineated in the statistical section of the study design.3 despite this, the authors draw arbitrary and definitive conclusions to suspend a multicenter randomized trial with solid outcome measures, and hundreds of recruited patients before conclusions. the level of scientific debate is usually elegant and more objective, especially when writing an editorial aimed to guide the readership in the current scientific interpretation of an article.4 we would recommend, with the aim to build a constructive debate, to bring this scientific dispute in the academic track as well to respect research activities carried out through the correct ethical and scientific pre-requirements. references bourdette dn, cohen ja. venous angioplasty for "ccsvi" in multiple sclerosis: ending a therapeutic misadventure. neurology 2014 2014;83:388-9. [crossref] [pubmed] siddiqui ah, zivadinov r, benedict rh, et al. prospective randomized trial of venous angioplasty in ms (premise). neurology 2014;83:441-9. [crossref] [pubmed] zamboni p, bertolotto a, boldrini p, et al. efficacy and safety of venous angioplasty of the extracranial veins for multiple sclerosis. brave dreams study (brain venous drainage exploited against multiple sclerosis): study protocol for a randomized controlled trial. trials 2012;13:183. [crossref] [pubmed] zamboni p, menegatti e, occhionorelli s, salvi f. the controversy on chronic cerebrospinal venous insufficiency. veins and lymphatics 2013;2:e14. [crossref] [top] hrev_master veins and lymphatics 2014; volume 3:2107 [veins and lymphatics 2014; 3:2107] [page 29] in vitro measurements of compression bandages and bandage systems: a review of existing methods and recommendations for improvement jan schuren retired from 3m deutschland gmbh, skin and wound care division, neuss, germany abstract in this article an overview is presented of identified devices that are or can be used for in vitro pressure and stiffness measurements of compression bandages and bandage systems. the performance of these devices has been evaluated on several parameters as well as the clinical relevance of the findings. in addition, recommendations for improvement and standardization of future measurements from the international compression club (icc) working group compression bandages are presented. introduction there is a variety of methods to describe the properties of bandages used for a variety of indications where compression therapy is required. often the extensibility of materials is used to determine their characteristics. the german din quality standard (deutsches institut für normung ev)1 defines the elasticity of bandages by percent elongation following the application of a force of 10 n per cm bandage width. the resulting maximal stretch percentage divides bandages in three categories: i) rigid (0-10%); ii) short stretch (10-100%); and iii) long stretch (>100%). veraart et al.2 present four categories: i) non-elastic; ii) short-stretch (<70% maximal tension); iii) medium stretch (70-140%); and iv) fully elastic (>140%). thomas3 classifies bandages into three distinct types which have fairly precise clinical indications. they are retention (class 1), light support (class 2) and the provision of varying degrees of compression (classes 3a-3d). these compression bandages are subdivided into four groups according to their ability to retain predetermined levels of tension under controlled laboratory conditions. it is this tension which governs the pressure that the various products might be expected to apply in use. thomas also recognizes that there are certain other highly specialized products available which may not fit into this classification and these should therefore be considered separately. the international compression club (icc; http://www.icc-compressionclub.com/) held a consensus meeting in 2005 on measurements of lower leg compression in vivo and published their recommendations, in which was stated that sub-bandage pressures and material stiffness characterize the elastic properties of the used materials and are the deciding parameters determining the dosage of compression treatment.4 partsch describes the method to measure the pressure at a defined position of the lower leg at rest and to repeat the measurement on the same spot, when the circumference has maximally increased by the muscles actively engaged to stand in the upright position. the pressure in the supine position is subtracted from the pressure in stance. the resulting index indicates the effectiveness of the applied system. this index is referred to as static stiffness index (ssi) and provides an indication of how well an applied compression system manages to keep forces produced by the muscle activity to stay in the upright position, inside the compressed area.5 provided that they are applied with the same resting pressure, typically short stretch bandages have higher ssi’s than long stretch bandages. following a subsequent icc meeting, another consensus document was published in which the growing trend is mentioned for the use of both multilayer bandages and bandage kits that consist of several bandaging materials, which influence sub-bandage pressure and stiffness. it is stated that it is not possible to use in vitro data to predict the influence of these parameters and therefore they need to be measured on the leg.6 mosti et al. state that the physical characteristics of bandage kits, in which different materials are combined, cannot be predicted by laboratory tests and can only be assessed in vivo by measuring the interface pressure and calculation of stiffness.7 schuren et al. conclude that although the well-established ssi in general is able to differentiate between elastic and inelastic materials, it only provides a rough estimate of the effectiveness of applied systems as interpretation is heavily influenced by the muscle forces of the person being bandaged.8 besides the mentioned variation caused by variability from the human leg, which cannot be standardized, there is the variation caused by the person applying the system. the application of bandage systems by experienced nurses to volunteers9 or on artificial legs10 shows a marked variation in applied pressure. the consequence is that making statements on the possible effectiveness of an applied system, is difficult. medical elastic compression stockings (mecs) can be divided into different classes based on pressure. however, pressure is not the only parameter that differentiates one stocking from another. just as for compression bandages, the so-called stiffness factor, the elasticity coefficient or slope value of the stocking is another important parameter. this slope value is defined as the increase in pressure when the circumference of the stocking increases by 1 cm. this slope value is determined in the laboratory.11 neumann states that it is not sufficient to determine the compression (class) of the mecs alone, also the stiffness or elasticity coefficient is of importance for the final results of compression therapy. he provides objective criteria for prescribing mecs for venous diseases in phlebology.12 currently many different bandage systems are commercially available. they all include instructions for their most optimal use. it is obvious that with so many available compression bandages and systems, there is a need to have a method that exactly determines the properties of an applied system and eventual modifications.13 two decades ago, mccollum identified the need to ensure that prescribable bandages meet acceptable standards of manufacture and specified performance in terms of elasticity, elastic range, elastic modulus, and correspondence: jan schuren, grotestraat 34, 6067 br linne, the netherlands. e-mail: jan.schuren@gmail.com key words: compression therapy, bandages, bandage systems, in vitro measurements, pressure, static stiffness index, strain index. conflicts of interest: js is a retired 3m employee and invented and co-developed the 3m coban 2 layer compression systems. members of the international compression club (icc) working group bandages who agreed with this consensus document: abel m. (germany), bender d. (usa), besse b. (germany), bichel j. (germany), charles h. (uk), convert r. (france), damstra rj. (the netherlands), hitschman g. (germany), kloeppels m. (germany), mooij m. (the netherlands), morrison t. (usa), mosti g. (italy), muldoon j. (uk), partsch h. (austria), planisek rucigaj t. (slovenia), polpot s. (france), schuren j. (the netherlands), schwidden i. (germany), will k. (germany). received for publication: 5 november 2013. revision received: 27 may 2014. accepted for publication: 28 may 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright j. schuren, 2014 licensee pagepress, italy veins and lymphatics 2014; 3:2107 doi:10.4081/vl.2014.2107 no nco mm er cia l u se on ly article [page 30] [veins and lymphatics 2014; 3:2107] durability and suggested to lay down these criteria and classify bandages according to some measure of elasticity and elastic modulus.14 clark states that simplistic descriptions of short-stretch and long-stretch bandages fail to take account of the huge variations within these two groups and, more importantly, the development of multi-layer compression systems that combine materials with different performance characteristics. he concludes that the current classification system refers to individual bandages and does not adequately reflect the physiological effects of multi-layer bandaging systems and that a european-wide standard for the testing and classification of bandage systems is required.15 schuren developed and validated a method to measure under completely controlled conditions the capabilities of an applied compression system to keep the forces inside the system, similar to the ssi. as the name ssi is well established, a different description was needed for the value from this measurement and the term strain index was selected.13 in a recent document, cornu-thenard et al. propose that the term resistance should be used in the medical compression vocabulary or that perhaps words similar to resistance or resistance coefficient could be used such as hardness, rigidity, firmness, inelasticity and others.16 as in vitro measurements can be performed over a longer period, also the effects of material fatigue on pressure and stiffness can be investigated. in an overview to highlight the differences between different compression materials, clark states that if the main in vitro and in vivo comparisons are to remain pressure and force measurement bound, then there is a need for a consistent classification system based upon the pressure measurements to mirror the agreed consensus upon how subbandage pressures are to be measured.17 figure 1 shows an overview of evaluations that can be performed on compression bandages and bandage systems, with the specific role for in vitro and in vivo research. in this article an overview is presented of identified devices that are or can be used for in vitro pressure and stiffness measurements of compression bandages and bandage systems. the performance of these devices has been evaluated on several parameters as well as the clinical relevance of the findings. in addition, recommendations for improvement and standardization of future measurements from the icc working group compression bandages are presented. materials and methods a search in the medical literature was performed in the personal database (papers 2.2.10; mekentosj.com) and using medline. next an extensive manual search was carried out in the bibliographies of identified articles. the search was focused on identifying all available methods that could be used for in vitro pressure and stiffness measurements of compression bandages and/or compression bandage systems (js). there were no restrictions on quality of identified papers. next, a patent search was performed using the united states patent and trademark office (http://patft.uspto.gov) and the european patent office (www.epo.org) and identified patents were downloaded (js). a questionnaire was developed with key questions on the method and presented in table 1. if the identified published information was sufficient to answer these questions, the questionnaire was completed (js). if this was not the case, the identified researchers were contacted with the request to provide additional information or to complete the questionnaire. the search ended on may 1, 2013. the results were presented at a meeting of the icc working group bandages in copenhagen on may 18, 2013 (js) for further discussion. results a total of seventeen devices were identified, nine of them were disclosed in the published literature, six were found in patent applications and two were brought in by members of the icc working group bandages, who used them in their commercial working environment. the oldest identified device was disclosed in a patent application from 1979, the last came from a publication from 2012. an overview of the devices is listed on date of publication, either in literature or on date of patent application and is presented in table 2.13,18-30 several devices are published in more than one publication; the one that describes the device in the highest detail is listed in the overview. figure 1. evaluation methods on compression bandages and bandage systems. table 1. questionnaire with the key questions. name of the device: .................................. resting pressure (y/n): ............................................ stiffness (y/n): ............................................ application method automated (y/n): ............................................ validation available (y/n): ............................................ available for bandages (y/n): ............................................ available for bandage systems (y/n): ............................................ is the device ready to be used (y/n): ............................................ is the method disclosed (y/n): ............................................ no nco mm er cia l u se on ly article [veins and lymphatics 2014; 3:2107] [page 31] after completion of the questionnaires, the collected information was transferred to a sheet in which each yes from the questionnaire was marked in green and each no in red. this sheet is presented in figure 2. discussion for compression bandages and bandaging systems, there is a variety of methods to look at their physical properties. measuring pressure and stiffness are only a few and in this article, only a minor number of studies describing them are referenced. the icc has published a consensus document on how the sub-bandage pressure can be measured4 and a document on the classification of bandages.6 for a variety of reasons, in vitro measurements have also been widely used, not only for stockings but also for bandages. for in vitro measurements of bandages and bandage systems for compression therapy, it is important that not only the pressure can be identified but also that information can be collected on the stiffness, a measure of the possible performance. ten of the seventeen identified devices fulfill that requirement. another important factor for in vitro measurements is that the used method is completely controlled and therefore reproducible. this implies that the application must be automated. for most of the identified systems, bandages have to be applied manually, which reduces the reproducibility. six identified devices use various automated applications. combining the positives on stiffness and automated application, leaves only two devices with a green for both parameters. one of them is still under design, which means that only one device (number 13, figure 3) has a complete green scorecard. when bandages or systems are applied with this winder, the force needed to bring each individual component to the required percentage stretch, is calculated on a tensile tester (e.g. 50% for profore layer 3; smith & nephew corp., london, uk). from this force, the weight is calculated with which each individual component of a system must be stretched with the exact amount of tension. water filled bottles are used of which the weight is controlled with 0.01 grams of precision on a calibrated scale. as can be seen on figure 3, pressure is measured with a picopress® [microlab elettronica sas, ponte s. nicolò (pd), italy] sensor and the data can be stored on a computer. the sensor is positioned on a fluid bag. the stiffness of a system can be measured by inflating another sensor underneath the fluid bag with a controlled amount of air. an example of a pressure recording with the above described roll winder is shown in the upper measurement in figure 4.13,31 however, many other identified devices have unique design features that could eventually be used to develop an optimal in vitro measuring device. e.g., where device number 16 from figure 3 only uses the small area of the fluid bag to imitate muscle enlargement, the mannequin leg developed by hirai et al.31 (device number 14, figure 5), uses the entire area of the leg to enlarge. this may have several advantages, of which probably the most important that this total enlargement reflects the natural situation in a more realistic way. the icc working group bandages discussed the findings of the review in a meeting held on may 18 2013 in copenhagen. in this and two subsequent meetings held in germany, the group agreed on a number of recommendations for in vitro measurements of compression bandages and bandage systems. these recommendations are listed in table 3. an overview of the discussed topics is provided below. leg-shaped model or cylinder? an important question for in vitro measurements of bandages and bandage systems is if the model on which the measurements are to be made, should have a leg-shape or if it can be a cylinder. twelve of the seventeen identified devices use a leg model, of which only one allows an automated application. the advantage of a cylinder is that not only exactly the number of layers can be applied that is recommended by the manufacturer but also the force of application can be evenly distributed over the entire width of the roll. the table 2. an overview of the identified devices. no. name of device disclosed in 1 hosiery testing apparatus swallow18 2 measuring apparatus wray et al.19 3 hosiery pressure measuring device pirlitescu et al.20 4 pressure measuring device testud et al.21 5 cylindrical limb model melhuish et al.22 6 wooden leg partsch et al.23 7 mannequin leg rajendran et al.24 8 leg garment test apparatus kuenzli et al.25 9 mannequin leg ghosh et al.26 10 elastically deformable limb wesp et al.27 11 test rig al khaburi28 12 mannequin leg schuren13 13 roll winder schuren13 14 mannequin leg hirai et al.29 15 air bladder mannequin leg kumar et al.30 16 wrapping unit not disclosed; concept of karl otto braun gmbh & co. kg, wolfstein, germany 17 compression model leg not disclosed; used by lohmann & rauscher gmbh & co. kg, rengsdorf, germany figure 2. the score card with the 17 devices; each green cell indicates a yes, each red cell a no. no nco mm er cia l u se on ly article [page 32] [veins and lymphatics 2014; 3:2107] recommendation of the icc working group is that for in vitro testing of compression bandages and bandage systems, cylinders should be used. concerning the material that cylinders are made of, the icc working group recommends that the friction between cylinder surface and bandaging material should be reduced to the minimal (e.g. by using polished steel). application method if in vitro pressure measurements are performed on leg-shaped models, it is difficult to have an automated application. this is not a surprising result as most of the reviewed devices were developed to perform measurements on stockings and one to perform research on the reproducibility of pressure and stiffness (device 12). the one leg model which has an application that is described as automatically (device 7), uses a manual winder to turn the fixed leg.29 although it is possible with this device to apply bandages with e.g. a 50% overlap, it is difficult to have the forces distributed evenly because of the irregularly shaped leg. the recommendation of the icc working group is that for in vitro testing of compression bandages and bandage systems, the application should be performed as recommended in the instructions for use. in addition, it is recommended that applications should be controlled, automated and reproducible. stiffness as mentioned, an in vitro assessment of stiffness of compression bandages and especially of bandage systems, the model needs a controlled and reproducible method to imitate the real life situation of measuring the ssi, the difference between the pressure in the supine and upright position. to achieve this enlargement, the mannequin leg (device 14) is cut in half lengthwise and when the lever arm is pushed down, the leg splits by 0.5 cm, leading to a 1 cm increase in circumference. this method of enlargement guarantees an easy and reproducible method. an example of a pressure recording with the above described mannequin leg is shown in the lower measurement in figure 3. ten of the seventeen devices allow stiffness recordings and use different methods of enlargement to achieve these measurements. an increase of 1 cm over the entire area used in four of them (devices 14, 15, 16 and 17). stolk et al. measured the maximum difference between the maximal dorsiflexion and maximal plantar flexion circumference at the point where the gastrocnemius muscle passes over into its aponeurosis (the so-called b1 point) in five volunteers and found a mean difference of 1.18 cm.32 enlarging with 1 cm is arbitrary but based on the findings of stolk et al., a value that reflects a real-life situation. a 1 cm increase in circumference also correlates with the stiffness measurements of elastic stockings, which is defined by the european committee for standardization (cen) as the increase in pressure per 1 cm increase in leg circumference.33 the recommendation of the icc working group is that for in vitro testing of compression bandages and bandage systems, stiffness measurements should be in line with existing methods like the cen method. as mentioned in the introduction, the name ssi is well established and recommended to be used for in vivo measurements.4,5 the recommendation of the icc working group is that stiffness measured in vitro should not be named static stiffness index. for stockings, the term dynamic index is used. for bandages and bandage systems, a new term e.g. strain index8,13 or in vitro statical stiffness index could be introduced. figure 3. the automated roll winder (device number 13). figure 4. in vitro pressure and stiffness recordings with device number 13 (upper line) and device 14 (lower line); the picture is composed with data from schuren13 and hirai et al.,31 which in the original publications are presented on a different scale. no nco mm er cia l u se on ly article [veins and lymphatics 2014; 3:2107] [page 33] radius/circumference of the cylinder on four of the seventeen identified devices in this review, cylinders are used to perform the measurements. following laplace’s law, the final pressure of an application depends on the tension with which the bandage is applied as well as the radius of the cylinder to which it is applied. the six identified devices use different radii with an average radius of 4.7 cm (range 4.0 to 6.1), which is an average circumference of 29.3 cm. schuren used cylinders with a radius of 4 and 5 cm (circumference 25.1 and 31.4 cm). in the test method validation, four different operators applied four different compression systems on both cylinders.13 the test results reveal that the pressures on the cylinders with the radius of 5 cm, are close to the expected range of pressures when these systems are used in clinical practice. however, further unpublished research of one of the group members revealed that if the method of enlargement described by hirai et al.29,31 is used on cylinders, a diameter of 4 cm is closer to the expected range.34 based on these findings, the recommendation of the icc working group is that for in vitro testing of compression bandages and bandage systems, cylinders should be used with a radius of 4 cm (circumference 25.1 cm). fatigue to have an objective measurement of the degree and duration of the compression exerted by six commonly used elastic bandages, tenman et al. tested the sustainability of pressure on healthy volunteers.35 they found pressure drops up to 63% in 4 h. partsch reports that when bandages with a high stiffness are applied, a pressure drop will occur in the first minutes and hours when the patient is walking to values that are 30-40% lower compared to the initial pressure. he states that this drop is mainly due to an immediate reduction of leg volume and that for the next few days only a mild further pressure drop occurs.36 provided that an applied system stays in place, observed pressure drops may be caused by a combination of edema reduction and material fatigue. when loss of pressure is measured on volunteers, it is impossible to identify which of the two components contributes for which part. by profiling the pressure of compression bandages by a computerized instrument, das et al. showed that in bandages with higher mass per unit area, the internal pressure applied by the bandage decreases at a higher rate than in bandages with lower mass per unit are. in addition, the authors showed that the internal pressure profile with time is different for different bandages, higher internal pressures show a higher rate of pressure loss over time.37 this implies that material fatigue and resulting pressure loss could have an effect on pressure but also on stiffness and therefore on the effectiveness of applied systems over time. schuren studied material properties in vivo on healthy volunteers and in vitro under controlled conditions (figure 6), both over a oneweek period and found significant differences between these measurements. isolating the effect of material fatigue on pressure and stiffness revealed that most of the pressure loss takes place in the first four hours and that after 48 h, the pressure stays stable for the materials under investigation.13 in vitro measurements allow pressure recordings over a longer period and in different ways. figure 6 shows that recordings can be taken at different intervals and in figure 7,38 the recordings are presented of measurements during constant motion to mimic a walking pattern. therefore the recommendation of the icc working group is that for in vitro testing of compression bandages and bandage systems, measurements are performed at specific intervals over a specific period, or e.g. to mimic a walking pattern over a certain period. as material fatigue starts immediately after the application and is further enforced by stiffness measurements, it figure 5. the mannequin lag with the lever arm, which when pushed down, guarantees a 1 cm enlargement in circumference (device number 14). table 3. recommendations of the international compression club working group bandages for in vitro measurements of compression bandages and bandage systems. topic recommendations leg-shaped or cylinder it is recommended that measurements are performed on cylinders. it is recommended that the friction between cylinder surface and bandaging material should be reduced to the minimal (e.g. by using polished steel). application method it is recommended that applications are performed as recommended in the instructions for use. it is recommended that applications should be controlled, automated and reproducible. stiffness it is recommended that stiffness measurements should be in line with existing methods like the cen method. it is recommended that stiffness measured in vitro should not be named static stiffness index; the term dynamic index used for stockings could be used or a new term like strain index could be introduced. radius/circumference it is recommended that for in vitro testing of compression bandages and of the cylinder bandage systems, cylinders should be used with a radius of 4 cm (circumference 25.1 cm). fatigue it is recommended that measurements are performed at specific intervals over a specific period or e.g. to mimic a walking pattern over a certain period. as material fatigue starts immediately after the application and is further enforced by stiffness measurements, it is recommended to first perform the measurement of pressure under tension before measuring the pressure in the relaxed position. pressure sensor it is recommended that for in vitro testing of compression bandages and bandage systems, pressure should be recorded with a picopress® transducer (microlab). it is recommended to perform further research on the reproducibility of the picopress® (microlab) device or alternative methods. cen, european committee for standardization. no nco mm er cia l u se on ly article [page 34] [veins and lymphatics 2014; 3:2107] is also recommended to first perform the measurement of pressure under tension before measuring the pressure in the relaxed position. pressure transducer in an icc consensus document with recommendations for in vivo measurements, an overview is presented of key specifications of a pressure sensor.4 partsch et al. compared three portable instruments and conclude that the best reproducibility and the highest degree of accuracy was achieved with the picopress® transducer (microlab), which in addition also allows dynamic pressure tracing in connection with a software program and which may be left under a bandage for several days, is a reliable instrument for measuring the pressure under a compression device.39 al khaburi reviewed available types of pressure measurement transducers to measure the interface pressure under compression products and states that these transducers differ in their core technology, physical dimensions, accuracy and their ability to provide dynamic measurements. he identified a total of more than thirty types that could be used. he performed a comprehensive analysis on different pressure transducers among which the picopress® transducer (microlab). one of the conclusions is that the picopress® (microlab) sensor was found to have good accuracy in terms of low nonlinearity, and hysteresis errors but that it overestimates the pressure applied to it due to its physical dimensions. the usage of a correction factor for the pressures measured by picopress® (microlab) sensors could improve the reliability of their pressure readings. however, the author states that correction factors are calculated from the radius of curvature of the leg which is very difficult to determine within a clinical environment.28 as the recommended in vitro measurements in this article are performed on cylinders with the same radius, an accurate, reliable and repeatable overestimation does not play a major role and the suggested correction is not required. based on these findings, the icc working group recommends that for in vitro testing of compression bandages and bandage systems, pressure should be recorded with a picopress® transducer (microlab). because of the reported overestimation of the pressure, it is recommended to perform further research on the reproducibility of the picopress® (microlab) device or alternative methods. next steps after the icc working group bandages meeting in copenhagen, a few members agreed to implement the recommendations to further optimize the in vitro measurement of compression bandages and bandaging systems. this work is still ongoing. in addition, the icc working group bandages agreed to perform further research to investigate the relation between in vivo and in vitro measurements. recommendations recommendations of the icc working group bandages for in vitro measurements of compression bandages and bandage systems are summarized in table 3. clinical relevance in vitro measurements of pressure and stiffness is a well known method used for the classification of medical elastic compression stockings. there are several classification systems in different part of the world, which have one thing in common, they are all based on the findings of in vitro measurements.11 for bandages or bandage systems that are used for compression therapy, there is no common language to describe the physical properties. there is only one classification system for bandages, which is based on force-elongation curves obtained in a laboratory.6,40 this system only provides pressure information on bandages used for so-called single component applications and uses light (<20 mmhg), medium (21-30 mmhg), high (31-40 mmhg) and extra high (41-60 mmhg) as pressure ranges. for single component bandages, the terms rigid or no-stretch (0-10%), shortstretch (10-100%) or long-stretch (>100%) are most often used. these definitions are based on the percent elongation of the material after application of a force of 10 n per cm bandage width.1,6 veraart et al.2 and thomas3 also described classification systems for single component compression bandages. however, many bandaging systems are commercially available for which these terms are not very useful. most of the used materials have package inserts to describe how they are best used. a validated and reproducible method to investigate the preferred application method is not available yet. it is obvious that a standard for testing and classification of bandage systems is required.15 in an earlier icc consensus document, the practical aspects of classifying compression bandages figure 6. measurement of pressure (in mmhg) and strain index over a longer period. figure 7. measurement of pressure (in mmhg) during motion mimicking a walking pattern. modified with permission from steinlechner and bernat.38 no nco mm er cia l u se on ly article [veins and lymphatics 2014; 3:2107] [page 35] was presented.6 one of the conclusions was that future descriptions of compression bandages should include the sub-bandage pressure range as well as information on the stiffness of the final bandage. the development of a validated classification system is one of the objectives of the icc working group bandages. this document presents the current status, recommendations and next steps of the development of these future descriptions. with such a descriptive system in place, specific information on the physical properties of bandages and bandaging systems can be provided on packaging and instructions for use, similar to the ones used for compression hosiery. references 1. deutsches institut für normung ev. din 61632 verbandmittel, idealbinden. berlin, wien, zürich: beuth verlag; 1985. 2. veraart jcjm, neumann ham. interface pressure measurements underneath elastic and non-elastic bandages. phlebology 1996;14:2-5. 3. thomas s. bandages and bandaging: the science behind the art. care sci pract 1990;8:56-60. 4. partsch h, clark m, bassez s, et al. measurement of lower leg compression in vivo: recommendations for the performance of measurements of interface pressure and stiffness: a consensus statement. dermatol surg 2006;32:229-38. 5. partsch h. the static stiffness index: a simple method to assess the elastic property of compression material in vivo. dermatol surg 2005;31:625-30. 6. partsch h, clark m, mosti g, et al. classification of compression bandages: practical aspects. dermatol surg 2008;34: 600-9. 7. mosti g, mattaliano v, partsch h. influence of different materials in multicomponent bandages on pressure and stiffness of the final bandage. dermatol surg 2008;34:631-9. 8. schuren j, bichel j. sub-bandage dynamics: stiffness unravelled. veins and lymphatics 2013;2:e2. 9. wertheim d, melhuish j, williams r, harding k. measurement of forces associated with compression therapy. med biol eng comput 1999;37:31-4. 10. collier m, schuren j. ease of use and reproducibility of five compression systems. j wound care 2007;16: s8-10. 11. van geest aj, veraart jcjm, nelemans p, neumann ham. the effect of medical elastic compression stockings with different slope values on edema measurements underneath three different types of stockings. dermatol surg 2000;26:244-7. 12. neumann ham. compression therapy with medical elastic stockings for venous diseases. dermatol surg 1998;24:765-70. 13. schuren j. compression unravelled. essen: margreff druck gmbh; 2011. 14. mccollum c. extensible bandages should be dispensed with more information on performance. bmj 1992;304:520-1. 15. clark m. compression bandages: principles and definitions. in: calne s, ed. emwa position statement: understanding compression therapy. london: medical education partnership ltd; 2003. pp 5-7. 16. cornu-thenard a, benigni jp, uhl jf. terminology: resistance or stiffness for medical compression stockings? veins and lymphatics 2013;2:e4. 17. clark m. what are the differences between different compression materials. j wound technol 2010;8:6-8. 18. swallow rt. hosiery testing apparatus. united states patent application 1979: us 4,137,763. 19. wray gr, vitols r, tjon wds, baker je. measuring apparatus. uk patent application 1986: gb 2,168,156/a. 20. pirlitescu m, guidici d, quaranta m, bignotti r. a device for measuring that can be exerted by a hosiery article. european patent application 2001: ep 1, 118,851/a2. 21. testud jl, sennoune m, prudhomme jp, ouchene a. device for measuring pressure points to be applied by a compressive orthotic device. united states patent application 2002: us 6,334,363/b1. 22. melhuish j, clark m, harding kg, williams rj. the effect of compression bandage application technique upon measured sub-bandage pressures. wounds 2005;17:243-6. 23. partsch h, partsch b, braun w. interface pressure and stiffness of ready made compression stockings: comparison of in vivo and in vitro measurements. j vasc surg 2006;44:809-14. 24. rajendran s, anand sc. evaluation of pressure profile of bandages using mannequin leg. in: anand sc, kennedy jf, miraftab m, rajendran s, eds. medical textiles and biomaterials for healthcare. cambridge: woodhead publishing ltd; 2006. pp 233-242. 25. kuenzli d, braun w, ruettiger m. apparatus for the testing of elastic textile leg garments. united states patent application 2007: us 0,012,120/a1. 26. ghosh s, mukhopadhyay a, sikka m, nagla ks. pressure mapping and performance of the compression bandage/garment for venous leg ulcer treatment. j tissue viability 2008;17: 82-94. 27. wesp hj, oestreicher u, jung h. device for the determination of parameters particularly for therapeutic compression means on limbs. united states patent application 2009: us 0,215,016/a1. 28. al khaburi jaj. pressure mapping of medical compression bandages used for venous leg ulcer treatment. the university of leeds, school of mechanical engineering; 2010. 29. hirai m, niimi k, miyazaki k, et al. development of a device to determine the stiffness of elastic garments and bandages. phlebology 2011;26:285-91. 30. kumar b, das a, alagirusamy r. prediction of internal pressure profile of compression bandages using stress relaxation parameters. biorheology 2012;49:1-13. 31. hirai m, partsch h. the mannequin-leg: a new instrument to assess stiffness of compression materials. veins and lymphatics 2013;2:e3. 32. stolk r, van der wegen-franken cpm, neumann ham. a method for measuring the dynamic behaviour of medical compression hosiery during walking. dermatol surg 2004;30:729-36. 33. european committee for standardization (cen). non-active medical devices; working group 2env12718: european prestandard medical compression hosiery; cen tc205. brussels: cen; 2001. 34. hitschmann g. in vitro pressure and stiffness testing of compression bandages on a roll winder using different cylinders. data on file. neuss: 3m deutschland gmbh; 2013. 35. tenman wg, park kgm, ruckley cv. testing compression bandages. phlebology 1988;3:55-61. 36. partsch h. compression therapy of venous ulcers: haemodynamic effects depend on interface pressure and stiffness. ewma j 2006;6:16-20. 37. das a, kuma b, mittal t, et al. pressure profiling of compression bandages by a computerized instrument. indian j fibre textile res 2012;37:114-9. 38. steinlechner e, bernat v. in vitro compression model leg. data on file. rengsdorf: lohmann & rauscher gmbh; 2012. 39. partsch h, mosti g. comparison of three portable instruments to measure compression pressure. int angiol 2010; 29: 426-430. 40. british standards institution. the elastic properties of flat, non-adhesive, extensible fabric bandages. bs 705 1995. london: bsi; 1995. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2017; volume 6:6630 [page 16] [veins and lymphatics 2017; 6:6630] needing more: the case for extra high compression for tall men in uk leg ulcer management alison hopkins, richard bull, fran worboys accelerate cic, mile end hospital, bancroft road, london, uk introduction this paper provides an observation on the approach taken to the use of compression therapy in the uk within the context of patient and expert experience. venous ulceration is relatively common affecting 13% of the population;1,2 it is a treatable condition but chronicity or non-healing is commonplace. many patients will have a difficult experience often because compression is little understood in practice and usage across the uk is generally inadequate with pockets of good practice across the country. this paper contends that uk guidance offers little hope of a therapeutic intervention for the complex or non-standard group; there is no ‘plan b’ if the patient does not respond favourably to standard uk high compression. the authors present 2 patients that are examples of this issue and have observed that tall men require compression greater than the uk standard; unfortunately the provision of strong compression of >60 mmhg is not promoted within the uk. variations in guidance the uk national guidance1 for the management of venous ulceration is weekly compression therapy where high compression is stated as being 23-35 mmhg; in practice clinicians and industry refer to meeting 40 mmhg at the gaiter. this is considered gold standard therapy within the uk. however, there are international variations3 and these are that compression is described as: i) mild <20 mmhg; ii) moderate 20-40 mmhg; iii) strong 40-60 mmhg; iv) very strong >60 mmhg. specialist clinicians in the uk do not promote the use of compression above 40 mmhg; there is the assumption that this is already high compression and is the upper limit. with the exception of the authors own training materials, there is no evidence that even within specialist leg ulcer modules that compression above 40 mmhg is promoted; there is plenty of anecdotal evidence that the uk consensus is that the application of strong compression is simply too strong and is seen as too high a risk for general leg ulcer management. clinicians are advised1 on the areas that need to be considered when determining the strength of the compression therapy, such as ankle width, underlying arterial status or tolerance and pain management. the standard care is promoted and is considered key to the provision of optimal care and a quality intervention. however this intervention assumes that patients are similar, require the same level of compression therapy for this to be effective and also that nursing intervention is also standard. this is clearly not the case. also guidance states that there are a number of parameters (pain, arterial status) that can be reviewed in order to provide safe but reduced compression. however only in the presence of a larger ankle circumference is the clinician advised to increase the level of compression to accommodate this feature and thereby providing a higher sub-bandage pressure and thus a therapeutic intervention. when an ulcer fails to respond to compression therapy when the use of optimal compression therapy at around 35 mmhg is failing to heal the leg ulcer, the guidance for the clinician is to use advanced dressings. if the compression therapy is not being tolerated by the patient, the guidance is to increase compression tolerance through patient education and adjustment and/or reduction of the compression level; there is the underlying belief that light compression is better than nothing. there is no guidance to review the therapeutic value of this potent intervention. it is not routine practice to question whether the standard high compression is actually adequate for that patient. there is no recommendation that improving the bandaging technique or consistency of intervention may increase its efficacy or tolerance; conversely patient experience would recognise the wide variations in application techniques. there is thus no suggestion that the patient may benefit from a higher level of compression. correspondence: alison hopkins, accelerate cic, mile end hospital, bancroft road, london e1 4dg, uk. email: alison.hopkins2@nhs.net this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright a. hopkins et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6630 doi:10.4081/vl.2017.6630 figure 1. national sales of a multilayer compression regime. figure 2. large absorbents. no n c om me rci al us e o nly conference presentation [veins and lymphatics 2017; 6:6630] [page 17] the uk picture there is a growing gap between the theory of compression therapy as a clinical intervention and the uk practice of application. compression is increasingly being taught as a task and not as a therapeutic intervention, often due to workforce capacity issues and the lack of available time for adequate training. the association of poor compression use with limb amputation has led to a risk averse approach to compression use and a culture of fear within nursing. this has meant a reduction in use of standard compression of 40 mmhg and a promotion of light or reduced compression in the uk; this can only lead to an increasing number of patients receiving inadequate compression therapy and there is certainly enough anecdotal evidence to support this. the default to light compression is becoming the norm in clinical practice; a recent report of a leg ulcer audit found that of those who would benefit from compression therapy, 16% were in high compression and 30% were in light compression.4 figure 1 demonstrates the growing use of reduced compression within one well known multilayer compression regime that has two versions: standard high compression and a reduced or light compression. it appears that the introduction of the light compression version was in response to nursing requests and the belief that patients do not tolerate high compression therapy. this assumption needs to be challenged. the authors and those clinicians who attend the icc would refute this, noting that lack of patient tolerance is predominantly down to nursing technique, skill and knowledge of this potent therapy. the impact of non-therapeutic care is significant, resulting in poor oedema and exudate management in both leg ulcers and lymphorrhea; alongside this escalation of light compression we are seeing an increase in spend on extra-large superabsorbent dressings (a pad size greater than 15x15 cm) that simply absorbs this unmanaged exudate (figure 2). unfortunately admission for cellulitis due to erosive or leg ulceration are common. the impact of height uk guidance1 does not consider the impact of height on the level of compression a patient requires for it to be therapeutic. this paper contends that tall men are a group of patients who do not respond to standard compression but experience a destructive response to its use (figure 3). it is clear that hydrostatic pressure increases with height and that ordinarily 60-90 mmhg is required to narrow and occlude the veins. it is likely that a resting pressure of greater than 60 mmhg is thus required for vein occlusion in taller men. however, in the uk where multicomponent elastic figure 3. inelastic multilayer regime. figure 4. john’s ulcer, right lower gaiter present for 4 years. table 1. john and geoff’s common experience. no post thrombotic history, duplex discounted the presence of venous reflux young and previously active (50 and 40 years) variety of standard compression systems tried (uk high) compression was not tolerated despite opioid use destructive cycle of pain, oedema and exudate labelled as rare and diagnosis unclear despite negative biopsies each responded swiftly to strong compression with a resting pressure of >60 mmhg; no medical intervention was required no n c om me rci al us e o nly conference presentation [page 18] [veins and lymphatics 2017; 6:6630] compression is common and the role of static stiffness is not appreciated, this level will rarely be achieved and is certainly not promoted. john and geoff were referred to the author’s treatment centre for assessment following significant interventions from dermatology and vascular departments (table 1). their experience of cycles of improvement, deterioration, referral to various clinicians and query over their diagnosis all took its toll on their lives. their journeys and the impact of sustained very strong compression has led us to question the gaps in current uk guidance. it is the authors’ observation that the standard high compression,1 in the presence of height greater than 180 cm, acted as reduced or light compression; this generated a destructive cycle of uncontrolled oedema, causing exudate and further erosions, additional pain and lack of tolerance for an ineffective regime. the patient’s pain also caused concern and the nurses reduced the level of compression further by applying light compression regimes. as described previously, guidelines advise the clinicians to seek alternative diagnosis or treatments; unfortunately these simply prolonged the patient’s deterioration and intractable pain. the clinical goal was to increase the level of compression to therapeutic levels alongside the provision of adequate analgesia; an inelastic multilayer regime was used. this ensured that the hydrostatic nature of the ulceration or functional venous disease was managed, delivering circa 60 mmhg resting pressures at b1 level (figure 3) and towards 70 mmhg working pressure. this approach led to healing without any additional medical interventions; management was mostly a straightforward therapeutic task once the correct level of compression was reached. it is also important to note that this strong compression helped to reduce the pain despite the fear that this would exacerbate it; their experience was that their legs felt relief at the extra stiffness this regime provided, creating confidence in this approach (figures 4-7). conclusions this brief paper has identified some of the inadequacies of the current uk guidance on the management of venous ulcers namely what constitutes high compression and the limited advice for a non-standard patient. guidelines and current uk education promote a risk aversion approach thereby limiting the treatment options for the most complex of patients. figure 5. geoff’s left leg ulceration, present for 18 months. figure 6. john’s ulcer 12 months later. figure 7. geoff’s ulcer 9 months later. no n c om me rci al us e o nly conference presentation [veins and lymphatics 2017; 6:6630] [page 19] this paper introduces 2 patients for whom their destructive ulceration was reversed using extra high or strong compression, an approach that would be considered dangerous in the uk. the authors contend that strong compression addresses the larger hydrostatic column in taller people. however, it is unclear whether bandages also behave differently in tall people. the use of light compression is on the increase in the uk and this can only have a detrimental impact on patients’ lives, the nursing workforce and the health economy. clinicians in the uk and the icc need to critique the current status of leg ulcer management and promote the international consensus opinion of what constitutes high and thus therapeutic compression. learning points clinicians in the uk need to question the level of sub-bandage pressure required in the non-healing group. that taller patients require strong or very strong compression and this is above the uk recommendations. that contrary to popular belief, strong compression can significantly reduce pain in the larger limb. references 1. scottish intercollegiate guidelines network (sign). management of chronic venous leg ulcers. clinical guideline no. 120. scottish intercollegiate guidelines network; 2010. available from: www.sign.ac.uk 2. kunimoto b, cooling m, gulliver w, et al. best practices for the prevention and treatment of venous leg ulcers. ostomy wound management 2001;47:34-50. 3. world union of wound healing societies (wuwhs). principles of best practice: compression in venous leg ulcers. a consensus document. london: mep ltd.; 2008. available from: http://www.woundsinternational.com/m edia/issues/65/files/content_25.pdf 4. king bm. leg ulcer audit report. leg ulcer forum j 2016;28:16-9. no n c om me rci al us e o nly stefano ricci comment to: spontaneous plantar vein thrombosis: state of the art by karam l, tabet g, nakad j, gerard jl. phlebology 2013;28:432 stefano ricci abstract in the last 20 years, less than 20 cases of plantar vein thrombosis were reported in the literature. current ultrasound investigation protocols for deep venous thrombosis neglect this entity which is also not specifically mentioned in therapeutic guidelines. case 1: an 82-year-old man presented for a left foot plantar pain. foot x-rays and duplex sonography of the deep venous system were unremarkable; plantar fasciitis was diagnosed and non-steroidal anti-inflammatory drugs were given. one week later, physical examination revealed swelling and tenderness of the plantar side of the foot with retromalleolar tenderness and slight redness extending below and above the medial malleolus. a new duplex sonography showed enlarged non-compressible left lateral plantar veins with a 10 cm extension of the thrombus to the posterior tibial veins. the patient was put under low molecular weight heparin and switched later to anti vitamin k for a three-month period. investigations did not reveal any malignancy however, one year later, colonoscopy was performed in the setting of a rectal bleeding and an adenocarcinomatous lesion was discovered. case 2: a 57-year-old female who presented with one-week history of spontaneous left foot plantar pain. she had no history of foot trauma, recent surgery and was not under any hormonal treatment. physical examination revealed tenderness along the lateral course of the plantar side of the left foot with a discrete swelling. a contrast-enhanced magnetic resonance imaging revealed filling defects in one of the left lateral plantar veins, confirmed by a color doppler ultrasound showing the non-compressible vein. the patient was put under low molecular weight heparin followed by anti-vitamin k therapy for a three-month period. duplex control showed complete re-permeabilization of the vein. a complete hypercoagulation investigation revealed slightly positive anticardiolipine antibodies and heterozygote mutations of the mthfr gene and the g20210a mutation of the prothrombin gene. in front of a unilateral plantar pain plantar fasciitis, described as first-step pain, is the most common cause, followed by plantar fibromatosis, morton’s neuroma, stress fractures of the metatarsal bones, tendon abnormalities and ganglion cysts, while retromalleolar redness and tenderness may suggest erysipelas, arthritis, hyperuricemia and neuroalgodystrophia. in plantar veins thrombosis cases usually predisposing factors are present, as recent surgery, trauma, infection, malignancy, airplane travel, use of contraceptive pills. thrombophilia should be highly suspected in the absence of other predisposing factors, specially the g20210a prothrombin mutation. in over 50-year-old patients with no evident predisposing factors, undiagnosed malignancy should be ruled out. for treatment, the use on anticoagulation for a three-month period is recommended. comment by stefano ricci this interesting review should be offered to all ultrasound courses participants: the problem is evident, the solution is simple. probably, foot veins thrombosis is very frequent in everyday life, due to the tortures people oblige to their feet (wrong shoes, long standing jobs, excess in sport activities, etc.) apart from predisposing factors. it could be possible that limited thrombotic occurrences could be found if currently researched, fortunately spontaneously healing most of the time. anticoagulation is recommended in agreement to dvt therapy, but no mention is made in the paper about compression treatment, that also, is included in standard dvt management. in fact, a foot firm compression, possibly with short elastic material, would rapidly eliminate edema and pain, block the thrombus and accelerate the possible re-permeabilization. [top] hrev_master veins and lymphatics 2014; volume 3:1933 [veins and lymphatics 2014; 3:1933] [page 11] ultrasound-guided sclerotherapy using liquid sclerosant after preliminary saline flush kenneth a. myers, amy may clough victoria vein clinic, melbourne, australia abstract the aim of this study is to evaluate the efficacy of liquid sclerosant with preliminary saline flush for ultrasound-guided sclerotherapy. aethoxysklerol was used in varying concentrations ranging from 1.0% to 3.0% according to the volume required. infusion of sclerosant was preceded by infusion of normal saline. occlusion rates were determined by life-table analysis. progressively lower concentrations were used as the study progressed. life-table analysis showed significantly better results for tributaries compared to saphenous veins (92% vs 65%) and for dilute concentrations (≤1.5%) compared with stronger concentrations (>1.5%) (88% vs 66%). this observational study suggests that liquid sclerosant following a preliminary saline flush may give comparable results to those obtained with foam sclerotherapy. confirmation would require a randomized controlled trial. introduction our unit has long advocated the use of foam for ultrasound-guided sclerotherapy.1 however, some four years ago we encountered increasing numbers of internet-wise patients who were aware of the findings by morrison and neuhardt that some 14-42% of patients studied with transcranial doppler showed foam bubbles passing through the middle cerebral artery.2 we emphasized to all patients that there was no evidence that foam sclerotherapy caused any form of brain damage except in a small fraction of the many patients being treated worldwide.3,4 however, we were unable to provide any evidence to reassure patients that the micro-bubbles seen in the middle cerebral artery in many patients treated with foam sclerotherapy was not a potential cause for diffuse brain damage. since increasing numbers of patients then declined treatment with foam, we elected to return to using fluid sclerosant. at about the same time, we became aware of in vitro studies by parsi and colleagues that sodium tetradecyl sulphate was 30 times more effective and aethoxysklerol 160 times more effective in saline than in blood.5 the decision to find an alternative to foam and return to a liquid-based technique resulted in changing our in vivo technique to administer liquid aethoxysklerol in veins pre-flushed with normal saline. the technique that then evolved is not new and was commonplace in many units including our own before the introduction of foam sclerotherapy. materials and methods this prospective observational study is of all patients treated by liquid ultrasound-guided sclerotherapy (ugs) by one phlebologist (km) between april 2010 and august 2013. no patient was treated with foam sclerosant during this time. the treatment policy through this period was to offer endovenous laser ablation (evla) or mechanicochemical treatment (clarivein®; clarivein occlusion catheter, vascular insights llc, madison, ct, usa) for all saphenous veins or major tributaries >4mm diameter.6 liquid ugs was used as primary treatment for saphenous veins and major varicose tributaries ≤4 mm diameter. associated smaller tributaries were not treated at the time of evla or clarivein but left for two to three weeks to further reduce in size to be then treated by secondary ugs. sclerotherapy under direct vision was used for small superficial varices, reticular veins and telangiectasias. the series required 828 treatment sessions for 634 venous systems affecting 533 legs of 354 patients. accordingly, multiple treatment sessions were frequently required (on average, 1.3 sessions per venous system). there were 81 male and 273 female patients and ages ranged from 17 to 83 (median 48) years. the clinical ceap classifications were 429 c2-3, 48 c4, 2 c5 and 14 c6. treatment sessions were required for 275 venous systems not previously treated, 63 that had recurred after previous surgery, 262 treated at approximately two weeks after evla and 34 treated at approximately two weeks after clarivein. the veins treated were 203 great saphenous veins, 41 anterior accessory saphenous veins, 47 small saphenous veins and 343 tributaries alone. tributaries were treated for primary untreated disease for 88 sessions or recurrence after past surgery for 43 sessions (38% for primary ugs), and after recent evla for 189 sessions and recent clarivein for 23 sessions (62% for secondary ugs). all patients were studied before selecting treatment by standard techniques for duplex ultrasound as described by a international union of phlebology (uip) consensus document.7 in particular, representative vein diameters were measured with the patient examined on a tilt table with the patient tilted head up at an angle of 45°. reflux was defined as retrograde flow for >0.5 s shown by spectral doppler although the reflux time was appreciably greater in most patients. studies were performed with the philips iu 22 or ge logic ultrasound machines. preparation of sclerosant in australia, the therapeutic goods administration limit a daily dose of aethoxysklerol to no more than 2 mg/kg which is 4ml of 3% aethoxysklerol in an average size patient. the sclerosant was occasionally used undiluted but usually diluted with normal saline to provide larger volumes. if disease was extensive, it was common practice to treat each leg on separate days for bilateral disease. progressively, lower concentrations were used and found to be at least equally effective so that it became frequent practice to make up 12 ml of 1% aethoxysklerol to be administered in 2 ml aliquots providing six injections. similarly, a 1.2% solution allowed five injections, a 1.5% solution allowed four injections, a 2% solution allowed three injections while a 3% solution allowed just two injections. the concentrations and volumes used for each session throughout the study are shown in tables 1 and 2. technique for injection the maximum volume at the selected concentration of aethoxysklerol is made up in a 10 ml syringe. a three-way tap is used with a 5 ml syringe containing normal saline in line with a 1½ inch 25 gauge needle and a 3 ml syringe containing a 2 ml aliquot of sclerosant to the side (figure 1). the needle is passed into the vein confirmed by ultrasound and aspiration, the vein segment is then flushed with 5 ml of normal saline confirming that the needle is in the vein. in theory, 5 ml of saline should fill an approximate 10 cm length of a 4 mm diameter correspondence: kenneth myers, victoria vein clinic, suite 506, 100 victoria pde., east melbourne, 3002, victoria, australia. fax: 61396634326. e-mail: myers.kaba@gmail.com key words: sclerotherapy, saline flush, liquid sclerosant. received for publication: 20 september 2013. revision received: 9 january 2013. accepted for publication: 16 january 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright k.a. myers and a.m. clough, 2014 licensee pagepress, italy veins and lymphatics 2014; 3:1933 doi:10.4081/vl.2014.1933 no nco mm er cia l u se on ly article [page 12] [veins and lymphatics 2014; 3:1933] segment of vein. the three-way tap is then carefully turned with the free hand to allow the sclerosant to be infused. the vein is then vigorously massaged with the ultrasound probe for one to two minutes. it was found that this immediately helped to put the treated segment of vein into spasm. a disadvantage of the technique is the need to use two hands so that an assistant nurse or sonographer is required to hold the ultrasound transducer. subsequent management after completing all injections, the treated limb is placed in a class i support garment (1019 mmhg pressure) without bandaging or other forms of compression over the treated veins. the patient is then asked to walk for 10 to 15 min. compression is maintained through the first night after treatment and then during the day for as long as it is providing comfort to the patient. daily walking is encouraged. all physical and sporting activities are allowed to be resumed after 24 h. follow-up patients were reviewed clinically and with a duplex ultrasound scan to assess occlusion or persisting patency within a week after treatment. when the venous system was satisfactorily controlled, repeat ultrasound was performed at six weeks, six months then six table 1. number of sessions relating to concentration of sclerosant. concentration number of sclerosant (%) sessions 1.0 73 1.2 49 1.5 354 2.0 319 3.0 28 table 2. number of sessions relating to volume of sclerosant. volume sclerosant number of (ml) sessions 2 237 3 105 4 170 5 41 6 126 8 76 10 12 12 27 figure 1. syringes used for injection. figure 2. concentrations according to veins treated. figure 3. concentrations according to time when treated. no nco mm er cia l u se on ly article [veins and lymphatics 2014; 3:1933] [page 13] monthly until the treated veins could no longer be seen on ultrasound or until the present time. analysis of outcome the only objective outcome measured was clinical and ultrasound occlusion of the veins. actuarial life-table analysis for occlusion rates was performed with log-rank analysis for significance of difference between curves. to allow for censored data, results are shown to 12 months beyond which the standard error for cumulative failure rates exceeded 10%. results the most frequently used concentrations were 1.5% and 2%. the 2% concentration was used more frequently for saphenous veins than for tributaries (46% vs 33%) whereas the 1.5% concentration was used more frequently for tributaries that for saphenous veins (45% vs 39%) (figure 2). the numbers of sessions using different concentrations were arbitrarily divided into three time periods. the number of sessions using more dilute concentrations progressively increased through the study. during the first year from april 2010 to march 2011, 65% of sessions used 2.0% concentration and 26% used 1.5% concentration. during the second year from april 2011 to march 2012, 33% of sessions used 2.0% concentration and 65% used 1.5% concentration. during the third period from april 2012 to august 2013, 35% of sessions used 1.2% or 1.0% concentration (figure 3). there were significantly better results for treatment for tributaries compared to all saphenous veins with 92% occlusion for tributaries and 65% occlusion for saphenous veins at 12 months (figure 4). there was significant difference for occlusion rates according to the concentration of sclerosant with better results for more dilute concentrations compared to higher concentrations (figure 5). discussion throughout the study, there were progressively increasing numbers of sessions using more dilute concentrations of sclerosant. this has the potential to confound results. it is difficult to compare the results for this study to those previously presented for foam sclerotherapy1 as it was policy then to treat larger diameter veins by ugs than at present. indeed, it is difficult to compare results for studies from different groups because of variations in techniques to prepare foam. in vitro studies have shown marked variability of foam stability according to methods of preparation.8 however, occlusion rates at one year for all tributaries was 91% in the early study compared to 92% in the present study, while occlusion rates at one year for all great saphenous veins was 68% in the early study compared to 65% in the present study. the finding of significantly better results for dilute compared to more concentrated solutions in the present study is in part due to a moderately higher proportion of saphenous veins in the latter group but is in large part unexplained, and further work will be needed to explain this apparent paradox. it is in keeping with findings in the earlier study using foam where multivariate analysis showed that failures occurred in 14% of veins treated by 1.5% concentration compared to 34% treated by 3.0% concentration independent of the veins treated. it must be again emphasized that there have figure 4. primary patency rates saphenous versus tributaries. figure 5. primary patency rates according to concentration. no nco mm er cia l u se on ly article [page 14] [veins and lymphatics 2014; 3:1933] been extremely few patients reported as suffering from stroke among the many millions of patients treated by foam sclerotherapy. however, this failed to reassure our patients that such treatment could be associated with diffuse brain damage from micro-bubbles. this will require studies using sophisticated magnetic resonance imaging techniques before and after treatment. it is also possible that other techniques to treat venous disease such as endothermal ablation or the combination of mechanical ablation and sclerosants are associated with production of bubbles or particulate matter that pass to the cerebral arteries. furthermore, adverse effects may result from other mechanisms, particularly release of chemicals from injured endothelial cells. since this is a preliminary observational study, the efficacy of the present treatment would need to be evaluated by a prospective randomized controlled trial. this would be worthwhile if it is considered that current techniques for foam sclerotherapy carry any risk of causing brain damage. references 1. myers ka, jolley d, clough a, kirwan j. outcome of ultrasound-guided sclerotherapy for varicose veins: medium-term results assessed by ultrasound surveillance. eur j vasc endovasc surg 2007;33: 116-21. 2. morrison n, neuhardt dl. foam sclerotherapy: cardiac and cerebral monitoring. phlebology 2009;24:252-9. 3. rathbun s, norris a, stoner j. efficacy and safety of endovenous foam sclerotherapy: meta-analysis for treatment of venous disorders. phlebology 2012;27:105-17. 4. guex jj. complications and side-effects of foam sclerotherapy. phlebology 2009;24: 270-4. 5. parsi k, exner t, connor de, et al. the lytic effects of detergent sclerosants on erythrocytes, platelets, endothelial cells and microparticles are attenuated by albumin and other plasma components in vitro. eur j vasc endovasc surg 2008;36:216-23. 6. myers ka, clough a, tilli h. endovenous laser ablation for major varicose tributaries. phlebology 2013;28:180-3. 7. coleridge-smith p, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs-uip consensus document. part i. basic principles. eur j vasc endovasc surg. 2006;31:83-92. 8. cameron e, chen t, connor de, et al. sclerosant foam structure and stability is strongly influenced by liquid air fraction. eur j vasc endovasc surg 2013;46:488-94. no nco mm er cia l u se on ly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: great saphenous vein diameter at the saphenofemoral junction and proximal thigh as parameters of venous disease class by mendoza e, blättler w, amsler f. eur j vasc endovasc surg 2013;45:76-83. stefano ricci abstract the aim of this study was to investigate a possible correlation of gsv diameters measured at the sfj and the proximal thigh (pt) with the importance of the venous disorder. between october and december 2009. 844 legs were screened and 182 legs included in the survey (ceap c1-c5). the criterion for patient inclusion was the presence of a gsv reflux beginning at the terminal or the preterminal valve and escaping through a mid-thigh branch vein (above knee reflux, -51 legsgroup ii) or escaping through a lower leg branch vein (above and below knee reflux-71 legs-, group iii). legs with varices but no gsv were recruited as controls (-60 legsgroup i). vein diameters were measured holding the probe transversely with no pressure at the sfj distal to the terminal valve and 15 cm below the junction. measurement of gsv vein diameter at the sfj is challenging for the curvature of the inguinal gsv, the presence of epigastric, pudendal and accessory veins and eventual aneurysmatic dilatations. the pt site 15 cm below the sfj, chosen by chiva group members, is located in the truncal portion of gsv where the vein is cylindrical and largely devoid of joining branches, so well accessible, and diameter measurements can be taken reliably. gsv diameters in all groups, measured at both sites, were not related with patients’ age and sex or calf muscle-pump function. modest correlations were found with body weight and bmi but not with height. gsv diameters in controls (group i) measured 7.5 mm (±1.8) at the sfj and 3.7 mm (±0.9) at the pt. in patients with gsv reflux (groups ii and iii), they measured 10.9 mm (±3.9) at the sfj and 6.3 mm (±1.9) at the pt, respectively. vein diameters were larger in the presence of reflux, compared with its absence, by an average of 3.4 mm at the sfj and 2.6 mm at the pt. no difference in diameters was found between group ii and group iii. thus, the degree of vein dilatation was independent of the length of reflux above knee only versus above and below knee. a gsv diameter above the 2 sd margin of group i legs was found in 2% in group i at either point of measurement. in groups ii and iii, a significantly different prevalence was observed when measurements made at the sfj and pt, respectively. the 2 sd margin was exceeded by 43% of patients when measured at the sfj and by 62% when measured at the pt. a mathematical formula was developed to mutually convert measurements taken at the sfj and the pt, used to revise published data. conversion pt to sfj (95% ci 1.698–1.836): diameter sfj (mm) = 1.767 × diameter pt (mm) conversion sfj to pt (95% ci 0.544–0.548): diameter pt (mm) = 0.566 × diameter sfj (mm) measurement at the pt as compared to measurement at the sfj demonstrated higher accuracy and both higher sensitivity and specificity for venous disease class as well as for prediction of reflux. gsv diameter, venous hemodynamic (ppg refilling times) and clinical disease class did not differ whether reflux was above knee only or above and below knee. diameter assessment at the pt seems suitable for stratification of patients allocated to future interventional trials as well as for outcome evaluation. comment by stefano ricci obtaining the greatest result with the lowest effort is the ideal research objective. this paper could be a good example of this concept. as nothing simpler than gsv diameter measurement may be done during ultrasound examination, this measurement reveals indirectly the presence of pathology, being a possible outcome evaluation method, and (in the future, as said by the authors) becoming an argument in the discussion of treatment options. although the diameter measurement is a simple measurement, no consensus exists on where the measurement should be done. the authors suggest studying the proximal thigh (15 cm below the junction) following the experience of chiva group members, as this gsv tract is the more constant, the more involved, and usually free from tributaries. according to the study results, a diameter of 3.7 mm (from 2.8 to 4.6 mm) indicate reflux absence, a diameter of 6.3 (from 4.4 to 8.2) means reflux present. if this observation will be confirmed by other studies, a great diagnostic contribution will be offered. however some details may be discussed: i) although simple, the diameter measurement should be described in details, because inter-observer differences are common; considering that 2 mm of difference may change the score, a precise measuring method should be created, for example performing multiple observations, using multiple observers, using maximal magnification, choosing the diameter orientation when the section is not circular, considering time of day, patient positioning, room temperature, etc.; ii) the caliber of the gsv, when incontinent, is related to the flow in the diastolic phase, particularly to reflux velocity; when the sfj terminal valve is incompetent, the reflux volume is much more important than in cases in whom the terminal valve is competent, like demonstrated by cappelli in a paper of paramount importance.1 this author, using the same pt measurement, showed that in incompetent gsv, diameters below 5 mm belong in 70% of cases to competent terminal valve legs; while diameters over 6 mm belong in 70% of cases to incompetent terminal valve legs, showing an interesting diameter difference related to the terminal valve. why did you choose to ignore this important criterion, giving more importance to the length of the gsv reflux? iii) reflux in gsv of small caliber (3-4mm) is not so rare in every day experience, and in papers reports. how do you explain so few cases in your observation? us machine setting? patients’ selection? what else? reply by the author (mendoza) thank you for your comments and the opportunity to reply. i) diameter measurement point: the locations of the sites of measurement used in this survey are shown in figure 1. we agree that intraand inter-observer comparisons have to be carried out as for any diagnostic test. this, however, was not our aim. the study argues for the 15 cm proximal thigh site because of its good correlation with clinical findings. thus, the required assessment of accuracy can be limited to this site; ii) caliber of refluxive veins in relation to competent or incompetent terminal valve (cappelli): our paper compared diameters with clinical findings and examined its potential use for decision-making. we assessed the criteria published by cappelli as well: 30% of patients had a competent and 70% an incompetent terminal valve. correlation between diameter and competence of terminal valves in refluxive gsv was high (pearson’s r 0.594, p iii) the extension of gsv reflux down the leg was studied because the criterion is attributed a high predictive value for clinical disease severity in germany; iv) prevalence of small gsv diameters: 5% of our patients had a diameter references 1. cappelli m, molino lova r, ermini s, zamboni p. hemodynamics of the sapheno-femoral junction. patterns of reflux and their clinical implications. int angiol 2004;23:25-8.[abstract][pubmed]   [top] hrev_master veins and lymphatics 2017; volume 6:6646 [veins and lymphatics 2017; 6:6646] [page 35] primum non nocere erika mendoza venenpraxis, wunstorf, germany dear editor, thank you for the editorial pointing out the possibility of sparing saphenous veins in phlebology.1 you are right pointing out, that the innovation in phlebology goes ahead and looking at the last 20 years one could think, that everything might be possible to deal with varicose veins. of course, surgical ablation of great saphenous veins (gsv) has the longest history and so the procedure is carved in stone in many national health services (nhs) as the gold standard (so still in germany!!) and in many brains of lots of honorable chiefs of department. but there is another point to be taken into consideration: other than in spain and italy, where department chiefs and surgeons are employed by the nhs and earn their money independently of the sales – in lots of countries the health professionals’ income depends on their performance. the higher the income for a procedure, the higher the personal financial benefit. in poorer countries foam sclerotherapy is the best option. in high sophisticated places, the more the cost, the better the treatment, the better the income. endoluminal heat treatments were introduced as a way to do stripping without a knife. so the idea from the very beginning included heating the complete refluxive segment of the saphenous vein. in the recently published study, chiva with endoluminal procedures: laser versus vnus,2 it could be demonstrated, that the short term results of chiva with both methods (laser or vnus closurefast) were identical and both methods showed no statistical differences to another cohort of surgically treated chiva patients: 104 patients were investigated before and 3-6 months after the treatment of gsv with chiva strategy using enoluminal heat techniques to close the groin segment [vnus closurefast or laser (1470 nm, intros radial)]. general data (age, sex, bmi) and phlebological data (qol as reflected in vcss, clinics as c(ceap), diameters of gsv at the groin and proximal thigh, as well as diameters of the common femoral vein were not different among both groups. as a result, we found a significant reduction of diameters of gsv at proximal thigh from 6.5 +/-1.6 to 3.7 +/-1.1 and vfc from 15.2 +/-2.3 to 14.8 +/-2.2 were recorded, as well as reduction of clinical scores (vcss from 5.6 +/-3.1 to 2.2 +/-2 and c(ceap) from 3.2 +/-1 to 2.1 +/-1.1. results are comparable to those achieved after surgical crossectomy and published in other series. in this publication, we do not only open chiva to other techniques, but we also show that even applying high technology (endoluminal heat and possibly glue) it is not necessary to sacrifice the complete length of the saphenous vein. if those patients with reflux in gsv but competentterminal valve would be treated withouth high ligation but with chiva (flush ligation of the tributary) or müller/asval and in those with incompetent terminal valve only a short segment would be closed with endoluminal devices, we could spare far more than 50% of saphenous veins. as a bypass? as a drainage path? as an option to treat the vein in the future – when possibly even more gentle techniques are available? as a tribute to our maximal objective in medicine: primum non nocere? references 1. zamboni p. 2016: the year of phlebological olympic games. veins and lymphatics 2016;5:6249. 2. mendoza e. chiva performed with endoluminal heat technique: laser versus vnus cross treatment of the great sapenous vein. phlebologie 2017;46:5-12. correspondence: erika mendoza, venenpraxis, speckenstrasse 10, 31515 wunstorf, germany. tel.: 05031.912781. e-mail: erika.mendoza@t-online.de conflict of interest: the author declares no potential conflict of interest. received for publication: 13 february 2017. accepted for publication: 27 february 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright e. mendoza, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6646 doi:10.4081/vl.2017.6646 no n c om me rci al us e o nly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: less invasive ultrasonography-guided high ligation of great saphenous vein in endovenous laser ablation by okazaki y, orihashi k. ann vasc dis 2013;6:221-5. stefano ricci abstract endovenous laser ablation (evla) has two pitfalls: endovenous heat-induced thrombosis (ehit) and great saphenous vein (gsv) recanalization. trying to avoid these pitfalls, the authors developed a novel method of ultrasonography-guided high ligation (ughl) as an adjunct to evla. after positioning a 5-f introducer sheath over a guidewire by a venous catheter above or blow the knee, the gsv at 2 cm distal to the sfj was located by us, and 2 small 2–3-mm skin incisions were made next to the gsv under local anesthesia. the bilateral aspects of the gsv were dissected using mosquito forceps under duplex scanning guidance. the dorsal aspect of the gsv was then dissected using a deschamps aneurysm needle, appearing as a strong echo behind the gsv. the needle, advanced to the other incision hooked a 2-0 silk thread which was pulled through to the first incision, encircling the dorsal aspect of gsv. the deschamps needle was then advanced on the anterior aspectof the gsv for dissection, and led to the other incision carrying the thread, encircling the gsv. after evla of the gsv was completed the thread was tied around the gsv. skin incisions were closed with steri-strips.the procedure was performed in 20 patients who were scheduled for evla for incompetent gs. the mean gsv diameterat 2 cm distal to the saphenofemoral junction (sfj) in the standing position, was 5.1–11.5 mm. the ceap clinical class was c2–c5. evla and ughl were performed without complications. the time needed for ughl was 191–853 s). ughl took longer than 360 s (6 min) in 4 patients in the first 10 cases and in 1 patient in the last 10 cases. in the case with a deeply located gsv, encircling of the gsv was fairly difficult, and surrounding tissue could be caught during ligation. successful gsv ligation was immediately confirmed by us. the postoperative courses were uneventful in all cases. comment by stefano ricci this is a very interesting method for gsv ligation with a limited surgical action. probably not all the cases are simple, in particular when subcutaneous tissues are particularly thick or peri venous layers are sclerotic for inflammation. excessive dilatation may cause difficulties too. however, considering the reduced rate of the two pitfalls reported in evla outcome, it may be questioned whether such approach to the gsv terminal part is really necessary in association to evla or not, if we consider the possible (although rare) occurrence of complications of this same procedure (vein rupture, hematomas, infection), when performed by non skilled surgeons. much more interesting, instead, could be the use of this kind of gsv obstruction in association with gsv sclerotherapy, to guarantee a higher rate of gsv closure, or in association with saphenous vein sparing methods (chiva), in order to avoid the gsv surgical high ligation. [top] 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2014; volume 3:4428 [page 42] [veins and lymphatics 2014; 3:4428] ultrasound assisted great saphenous vein ligation and division: an office procedure stefano ricci, leo moro, raffaele antonelli incalzi centro di flebologia, area di geriatria, università campus bio medico, roma, italy abstract the aim of this proof of concept study is to describe an ultrasound (us) assisted simplified surgical procedure for pre-terminal great saphenous vein (gsv) high ligation/division avoiding groin dissection and tributary interruption, in an office setting, in association to varices phlebectomy and saphenous vein foam occlusion treatment. inclusion criteria: primary gsv reflux due to terminal valve, vein diameter >6 mm. by ultrasonography in standing position, the point gsv passing over the adductor longus muscle (about 3 cm from the junction) is identified. this e (easy) point, relatively superficial, free from tributaries and other structures, allows an easy grasping and extraction of the gsv vein through a 3 mm stab incision provided an ultrasonography assistance. the vein is divided/ligated about 2 cm distal from the ostium, the distal stump is cannulated and foam is injected on the distal segment from the e-point incision in a retrograde fashion, varices are avulsed by phlebectomy. twenty procedures in 18 patients (venous clinical severity score: mean 3.15 gsv diameter: mean 7.34) were performed, all the cases without inconveniences, with a duration not exceeding 10 min in addition to the phlebectomy procedure time. no complications as hemorrhage, infection, nerve lesion, lymphatic leak or thrombosis have been registered. at one month the residual saphenous stump length was in average 2.16 cm with complete closure of gsv in all. three patients have been controlled at 6 months showing gsv complete closure. the procedure described is a simple office us assisted method for gsv ligationdivision, leaving the 2 last cm of the saphenofemoral junction. it could be associated to most of the procedures in use with limited additional time and resources required. introduction several methods are in use for achieving great saphenous vein (gsv) exclusion [high ligation, high ligation + stripping, endovascular heat occlusion-laser/radio frequency (rf), chemical occlusion-sclerotherapy, glue occlusion-cyanoacrylate, steam occlusion, and others] in varicose veins treatment. laser and rf, in particular, have achieved efficient gsv stem occlusion at 1 year (91%-95%)1 and even at 5 years long term follow up (73-86%),2,3 with sparing of the proximal part (2-3 cm) of the gsv. indeed, leaving this part patent and drained through the sapheno-femoral junction (sfj) allows the saphenous tributaries to maintain their physiological drainage. in fact recurrence after surgery is frequently associated to groin neovascularisation which is possibly triggered by tributaries dissection/ligation,4 one of the proposed pathophysiological mechanisms. avoiding both groin dissection and tributary interruption could explain the lower incidence of groin reflux recurrence referred by endovascular procedures,5,6 but confirmatory long term randomized studies are still lacking. furthermore, there is some evidence7 that a detailed ultrasound (us) sfj investigation could avoid the need of dissection in almost the half of cases, while for the remaining ones a minimally invasive approach like the proposed one could lead to a decrease in the recurrence rate. this view is at variance with the traditional belief that the junction need to be fully dissected and all the tributaries interrupted.8,9 isolated gsv surgical high interruption, as an alternative to traditional saphenectomy can be useful in several selected conditions (summarized in table 1). while treating varicose disease in an office setting, we conceived an us assisted simplified surgical procedure for high ligating/dividing the gsv, avoiding tributary interruption. this proof of concept study summarizes our initial experience with this method. it provides technical details of the method, the solutions we found to overcome some difficulties and the main indications. materials and methods patients eighteen patients underwent 20 gsv preterminal interruptions (pti) from october 2013 to april 2014 [12 female, 6 male; meanage: 46 (from 28 to 70); mean-body mass index: 24.23 (from 16.6 to 31.8]. selection and exclusion criteria are reported in table 2. candidates were selected from the patients scheduled for primary varicose vein treatment in our dedicated office based surgical activity (ambulatorio flebologico, area di geriatria, campus bio-medico, roma, italy). all patients were c2sepaspr2,3,5 of the clinical class of ceap (clinical-etiology-anatomicpathophysiologic) classification,10 symptomatic and with evident and extended bulging varicosities with a gsv stem >6 mm (reflux cutoff value ≥1 s). in two cases the procedure was bilateral. written informed consent was obtained from every patient. methods in our practice varicose disease is treated by office based stab avulsion phlebectomy of varicosities, associated to us assisted foam sclerotherapy (46 ml, 3% polidocanol 1:4 of air tessari method11) of the saphenous stem when the sfj is incompetent, provided that gsv diameter, measured avoiding isolated dilatations at 15 cm below the junction, exceeds 6 mm.12-14 for gsv <6 mm only the varicosities avulsion is made. indeed, gsv treatment likely is not indicated due to possible residual efficiency of ostial/femoral valves.7,15 in the planning phase, the gsv is initially studied in standing position by echography during the preoperative veins marking phase. the vein is followed distally, starting from the junction, and the point passing over the adductor longus muscle (about 3 cm from the junction) is identified (figure 1a). this site, that we call the easy (e) point, the gsv stem is relatively free from other structures contact (collateral branches, lymph nodes, deep veins and arteries, nerves), lies over a muscular plane and is only covered by a thick, highly echogenic superficial fascia (figure 1b). the overlying skin is marked at this point. then, all the veins to be avulsed are marked on the skin and the patient is prepared for the procedure. local infiltration anesthesia (mepivacain 0.4% solution prepared with correspondence: stefano ricci, corso trieste 123, 00198 roma, italy. tel.: +39.327.5405566. e-mail: varicci@tiscali.it key words: great saphenous vein ligation, ultrasound guidance, office procedure. contributions: sr, study design, data analysis, writing, final approval; lm, data collection, data analysis, critical review, final approval; rai, data analysis, critical review, final approval. conflict of interests: the authors declare no potential conflict of interests. received for publication: 11 june 2014. revision received: 29 july 2014. accepted for publication: 31 july 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s. ricci et al., 2014 licensee pagepress, italy veins and lymphatics 2014; 3:4428 doi:10.4081/vl.2014.4428 no n c om me rci al us e o nly article [veins and lymphatics 2014; 3:4428] [page 43] bicarbonate 1.4%16 is done over the markings but is made only superficially at the groin marked site to avoid hiding of the gsv by the subcutaneous infiltration. after varicosities phlebectomy is completed, us assistance is prepared at the groin using a probe sterile covering and sterile gel; a 3 mm transversal incision is made at marked site; by blunt dissection of the superficial subcutaneous tissue, a mosquito forceps is progressively advanced till the fascia layer over the gsv, observed in a transverse section. the fascia is repeatedly grasped by the forceps, possibly pulled out of the incision and sectioned to achieve a true opening of the structure: this will facilitate the vein’s extraction. a right angle tiny forceps (figure 2) is then advanced in the deeper space between the gsv and the adductor longus muscle and passed below the vein, under direct echo-visualization. further anesthetic is then injected to obtain complete painless procedure, pushing the infiltration both towards the groin and over the distal part of the vein. (this will allow pulling the vein out in both directions). the gsv is then gently extracted from the skin incision (figure 3a), freed from residual connective adhesions, sectioned between two forceps. the distal lower end is cannulated (jelco optiva® 2, i.v. catheters, 20g; smiths medicals, st. paul, mn, usa) and foam (4-6 ml) injected, until foam comes out of the distal phlebectomy stab incisions (for this reason performed previously), and ligated. the proximal upper end is gently pulled out and transfixed with 3/0 vycril suture without occluding the tributaries. few drops of sclerosing agent are dripped in the residual part of the ligated stumps to eliminate all the endothelium remnants. the two ends are actively repositioned under the fascia layer, to avoid adhesions to the skin. the incision edges are approached by a steri-strip. a compressive adhesive bandage is applied on the entire limb starting from the groin, to be worn for a week. patients are invited to walk immediately and actively during the following hours; no anticoagulation prophylaxis is prescribed unless in presence of hyper coagulation status. figure 1. a) about three cm far from the ostium the great saphenous vein (gsv) lies over the adductor longus muscle, in a point (e point *) free from collateral branches, lymph nodes, nerves, deep veins and arteries (modified from: bardeleben kh, haeckel e. atlas of applied (topographical) human anatomy for students and practitioners. new york, ny: rebman company; 1906). b) at the e point (*) the gsv lies over the muscle plane and is covered by a well visible superficial fascial plane. table 1. indications of sapheno-femoral junction isolated interruption. traditional saphenectomy not suitable (patient aged, co-morbidity, ulcers) to obtain a more efficient sclerotherapy of the saphenous stem when sclerotherapy has failed or is contra-indicated (pfo + neurologic symptoms, thrombophylia, allergy, non acceptance) when a saphenous conservative method is preferred (chiva) ascending gsv thrombosis needing to be arrested or avoided sfj interruption associated to endovascular treatments pfo, patent foramen ovale; chiva, conservative hemodynamic correction of venous insufficiency; gsv, great saphenous vein; sfj, sapheno-femoral junction. table 2. inclusion and exclusion criteria. inclusion criteria primary gsv reflux due to terminal valve incompetence (valsalva and compression/release positive over the junction, reflux >1 s, in standing position) vein diameter >6 mm measured at 15 cm distal from the groin length of the incompetence >30 cm (continuous, non interrupted) competent junction tributaries exclusion criteria clinical state not suitable for office surgery depth of gsv (skin-vein us distance) >3 cm previous gsv sclerotherapy gsv, great saphenous vein; us, ultrasound. no n c om me rci al us e o nly article [page 44] [veins and lymphatics 2014; 3:4428] clinical and duplex monitoring for these first cases are scheduled at 7 and 30 days, and then at 6 and 12 months. results twenty cases in 18 patients have so far been operated. the mean venous clinical severity score17 was 3.15 [from 1 to 5; standard deviation (sd): 1.04]. the mean-diameter of gsv at 15 cm distal from the groin was 7.34 mm (610.5 mm; sd: 1.12). the duration of the specific procedure, as part of a phlebectomy session (lasting in average 45 min), has never exceeded 10 min. in no case the procedure has been interrupted. no complications as hemorrhage, infection, nerve lesion, lymphatic leak or thrombosis have been registered; one patient presented an asymptomatic edema around the groin incision lasting 15 days, treated by compression and antibiotics. incision healing resulted very satisfactory (figure 3b). in one case skin retraction at the scar was registered, in treatment with massaging. all the patients have been clinically and us controlled at 7 days and 30 days. at one month the residual saphenous stump length was in average 2.16 cm (1.18-3; sd: 0.52) with complete closure of gsv in all. in all the cases the stump was patent without reflux. eight patients have been controlled at 6 months showing gsv complete closure; one case presents at valsalva a stump filling due to a pelvic reflux (table 3) feeding the stump through a pudendal vein (not to a reflux from the ostium). discussion this proof of concept study suggests that the proposed gsv pti is easy to be performed and safe. it lends support to the current propensity to spare the last 2 cm of the gsv, to allow sfj tributaries physiological drainage. it is effective at short term when associated to foam sclerotherapy, due to the wash out effect elimtable 3. demographic, clinical characteristics and results of participants. demographic and clinical characteristics all procedures, no. 20 patients, no. 18 gender, no. (% women) 12 (66.6) age mean 46 (28-70) bmi mean; ds 24.23; 3.99 gsv vein diameter at 15 cm distal from the groin mean (ds); mm 7.34 (6-10.5); 1.12 vcss mean; ds 3.15 (1-5); 1.04 results saphenous stump length mean (ds); cm 2.16 (1.18-3); 0.52 patent stumps, no. 20 reflux by valsalva maneuver, no. 0 results at 6 months (8 controls) saphenous stump length mean (ds); cm 1.65 (1-2.5); 0.52 patent stumps, no. 8 reflux by valsalva maneuver, no. 1 (pudendal) bmi, body mass index; sd, standard deviation; gsv, great saphenous vein; vcss, venous clinical severity score. figure 2. through a fascia opening a right angle tiny forceps is advanced in the deeper space between the great saphenous vein and the adductor longus muscle and passed below the vein, under direct echo-visualization. figure 3. a) the great saphenous vein extracted from the skin incision will be divided and ligated. b) at one month the incision healing is usually very satisfactory. no n c om me rci al us e o nly article [veins and lymphatics 2014; 3:4428] [page 45] ination. longer outcome evaluation will need considering possible bias due to the state of the related superficial vein network (possible recurrence, perforators hemodynamic, phlebectomy outcome). indeed, traditional flash to femoral vein high ligation has been universally considered as the gold standard operation to achieve gsv interruption.18 however, suspect is rising that junction recanalisation due to neo-vascularisation could be secondary to junction wide dissection19 and tributary interruption.5 indeed, several authors performing saphenectomies without junction dissection reported favorable outcome, with apparently better results compared to traditional junction dissection.20-22 endovascular venous closure treatments meanwhile show that gsv closure leaving the junction’s last 1-2 cm open to allow tributaries physiological drainage is associated with limited recurrence rates.1,23-26 although gsv high ligation seems to be unnecessary when associated to modern procedures, still gsv interruption could be useful in some specific clinical and anatomical situations other than traditional gsv stripping (table 1). however, traditional groin dissection is a true surgical procedure, even when performed in local anesthesia, requiring surgical skill and a protected, dedicated setting. for this reason a simple technique of gsv interruption like the one we suggest could fit all described situations, but with a limited cost, limited surgical experience required, good efficacy and safety. this technique being pre-terminal, i.e. sparing the junction tributaries and avoiding dissection, it could create lesser stimuli to neo-vascularisation, provided that the neovascularization reaction theory will be definitively confirmed.5,6 the residual 2-3 cm long saphenous stamp does not substantially differ from that left in place by the endovascular techniques. about 15 % of the saphenous stems treated by sclerotherapy may recanalise at 1 year follow up,27 up to about 50% at 5 years,1 requiring further foam sclerotherapy. trying to avoid recanalisation we began to perform pre terminal gsv ligation/division during the same phlebectomy/sclerotherapy session to obtain a more complete and durable foam sclerosis. our 6 months control shows no recanalization, but the numbers are limited and long-term patency needs to be evaluated. our gsv pti takes inspiration from the dortu’s experience dating back to 199328 followed by fays-bouchon in 199529 and recently resumed by others20,21,30 suggesting a stab avulsion method of the saphenous stem with preterminal junction ligation. the gsv at the groin was found by pulling the distal gsv progressively extracted and feeling the saphenous stem under the skin28 or a stripper previously introduced in a distal approach.29 in our experience, the modern habit of us observation revealed that the gsv becomes more superficial at 2-3 cm from the sfj, when passing over the adductor longus muscle. in that site, the e point, the vein has its medial side in contact with the muscular fascia, while its lateral side is free from any other dangerous structure, allowing an easy blunt dissection guided by us imaging. interestingly, this part of the gsv is usually free from tributaries and is easily pulled out for 1-2 cm due to its elasticity. two recently published papers31,32 describe a gsv interruption technique by passing a tread below the gsv by us assistance, as a complement of endovenous laser ablation, with the purpose of avoiding risk of thrombosis and recurrence keeping the thermal energy away from the saphenofemoral junction. these authors simply apply a tread to close the vein in association to the laser treatment. the method that we suggest, at the opposite, allows gsv interruption, possible vein resection, vein cannulation for foam or endovenous ablation. furthermore, a better visualization of the vein is accomplished avoiding the risk of femoral vein involvement.32 finally, gsv pti could perfectly fit the office based chiva (conservative hemodynamic correction of venous insufficiency) protocol33 or similar34 where the gsv interruption is done in the perspective of gsv stem sparing strategy. compared to the other gsv interruption options (laser, rf, steam, glue) the pti technique seems simpler, cheaper (no technology is needed) and, in particular, more precise in terms of anatomical positioning. attention should be drawn to assess the competence of the junction tributaries (particularly the anterior accessory sv) destined to drain in the residual gsv part. in case of one or more tributary incompetence, a reflux of the sfj would be maintained active by the reverse flow in the same tributary, with possible fast recurrence. at the opposite, reflux absence in the residual stump is assured by the tributary valve competence. finally, attention to the giacomini vein (gv) hemodynamic should always be deserved, avoiding gsv proximal interruption when gv is the prevalent drainage of the small saphenous vein. limitations some limitations of the described method should be underlined: obese patients may be particularly cumbersome, especially if groin anatomy is unfavorable (deep skin creases); previous sclerotherapy may cause fibrous adhesions and gsv fragility; gsv diameter dilatation or aneurysm at the e point may suggest more traditional surgical techniques. finally, a good us experience is needed in the preoperative and operative phase. some technical points also will need to be analyzed in the future studies: should we shorten the proximal/distal stump surgically in order to make the neovascularization less probable? should we do a simple ligature/titanium clip positioning on the gsv? conclusions gsv pti is a simple office surgical technique allowing a gsv ligation-division leaving the 2 last cm of the sfj, possible thanks to us assistance. it could be associated to most of the procedures in use, if definite pre-terminal gsv interruption is wished, with limited additional time and resources required. however, only a long-term follow up will definitively prove its efficacy. references 1. rasmussen lh, lawaetz m, bjoern l, et al. randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins. br j surg 2011;98:1079-87. 2. nicolini p; closure group. treatment of primary varicose veins by endovenous obliteration with the vnus closure system: results of a prospective multicentre study. eur j vasc endovasc surg 2005;29: 433-9. 3. winterborn rj, corbett cr. treatment of varicose veins: the present and the future: a questionnaire survey. ann r coll surg engl 2008;90:561-4. 4. disselhoff bc, der kinderen dj, kelder jc, moll fl. 5-year results of a randomised clinical trial comparing endovenous laser with sfl ligation and stripping for great saphenous varicose veins. br j surg 2011;98:1107-11. 5. chandlerj g, pichot o, sessa c, et al. defining the role of extended saphenofemoral junction ligation: a prospective comparative study. j vasc surg 2000;32: 941-53. 6. theivacumar ns, darwood r, gough mj. neovascularisation and recurrence 2 years after varicose vein treatment for sapheno femoral and great saphenous vein reflux: a comparison of surgery and endovenous laser ablation. eur j vasc endovasc surg 2009;38:203e7. 7. zamboni p, gianesini s, menegatti e, et al. varicose vein surgery without saphenofemoral junction disconnection. br j surg 2010;97:820-5. 8. bradbury aw. varicose veins. in: beard hd, gaines pa, eds. vascular and endovasno n c om me rci al us e o nly article [page 46] [veins and lymphatics 2014; 3:4428] cular surgery. 2nd ed. london, uk: w.b. saunders; 2001. pp 498-513. 9. blomgren l, johansson g, dahlbergakerman a, et al. recurrent varicose veins: incidence, risk factors and groin anatomy. eur j vasc endovasc surg 2004;27:269-74. 10. bergan jj, eklof b, kistner rl, et al. classification and grading of chronic venous disease in the lower limbs. a consensus statement. vasc surg 1996;30:5-11. 11. tessari l. nouvelle technique d’obtention de la scléromousse. phlebologie 2000;53: 129. 12. mendoza e, blättler w, amsler f. great saphenous vein diameter at the saphenofemoral junction and proximal thigh as parameters of venous disease class. eur j vasc endovasc surg 2013;45:76-83. 13. mendoza e. diameter reduction of the great saphenous vein and the common femoral vein after chiva long-term results. phlebologie 2013;42:65-9. 14. cappelli m, molino lova r, ermini s, et al. hemodynamics of the sapheno-femoral complex: an operational diagnosis of proximal femoral valve function. int angiol 2006;25:356-60. 15. cappelli m, molino lova r, ermini s, zamboni p. hemodynamics of the sapheno-femoral junction. patterns of reflux and their clinical implications. int angiol 2004;23:25-8. 16. moro l, serino fm, ricci s, et al. dilution of a mepivacaine-adrenaline solution in isotonic sodium bicarbonate, for reducing subcutaneous infiltration pain in ambulatory phlebectomy procedures: a randomized, double blind, controlled trial. j am acad dermatol 2014 [in press]. 17. rutherford rb, padberg ft jr, comerota aj, et al. venous severity scoring: an adjunct to venous outcome assessment. j vasc surg 2000;31:1307-12. 18. bergan jj. surgery of the veins of the lower extremity. philadelphia: wb saunders; 1985. 19. glass gm. neovascularization in recurrence of the varicose great saphenous vein following transaction. phlebology 1987; 2:81-91. 20. pittaluga p, chastanet s, guex j-j. great saphenous vein stripping with preservation of sapheno-femoral confluence: hemodynamic and clinical results. mdj vasc surg 2008;47:1300-5. 21. casoni p, lefebvre-vilardebo m, villa f, corona p. great saphenous vein surgery without high ligation of the saphenofemoral junction j vasc surg 2013;58: 173-8. 22. mariani f, bucalossi m, mancini s, mancini s. selective vs radical crossectomy of the great saphenous vein in primitive venous insufficiency: results at 5 years. acta phlebologica 2009;10:5-10. 23. pronk p, gauw sa, mooij mc, et al. randomized controlled trial comparing saphenofemoral ligation and stripping of the great saphenous vein with endovenous laser ablation (980 nm) using local tumescent anaesthesia: one year results. eur j vasc endovasc surg 2010;40:649-56. 24. min rj, khilnani n, zimmet se. endovenous laser treatment of saphenous vein reflux: long-term results. j vasc interv radiol 2003;14: 991-6. 25. ravi r, trayler ea, barrett da, diethrich eb. endovenous thermal ablation of superficial venous insufficiency of the lower extremity: single-center experience with 3000 limbs in a 7-year period. j endovasc ther 2009;16:500-5. 26. merchant rf, pichot o; closure study group. long-term outcomes of endovenous radiofrequency obliteration of saphenous reflux as a treatment for superficial venous insufficiency. j vasc surg 2005;42: 502-9. 27. winterborn rj, corbett cr. treatment of varicose veins: the present and the future:a questionnaire survey. ann r coll surg engl 2008;90:561-4. 28. dortu j. la crossectomie sus-fasciale au corse de la phlebectomie ambulatoire du complexe saphenien interne à la cuisse. phlébologie 1993;46:123-36. 29. fays-bouchon n, fays j. une technique d’endo-eveinage de la saphéne interne en ambulatoire par micro-incisions. phlébologie 1995;48:353-8. 30. horakova ma, horakova e. ambulatory phlebectomy of incompetent great saphenous vein without flush saphenofemoral ligature: effect on the saphenofemoral junction. phlebologie 2002;4:pages? 31. okazaki y, orihashi k. less invasive ultrasonography-guided high ligation of great saphenous vein in endovenous laser ablation. ann vasc dis 2013;6:221-5. 32. zhu h-p, zhou y-l, zhang x, et al. combined endovenous laser therapy and pinhole high ligation in the treatment of symptomatic great saphenous. ann vasc surg 2014;28:301-5. 33. passariello f, ermini s, cappelli m, et al. the office based chiva. j vasc diagn 2013;2013:13. 34. gianesini s, menegatti e, zuolo m, et al. short endovenous laser ablation of the great saphenous vein in a modified chiva strategy. veins and lymphatics 2013;2:e21. no n c om me rci al us e o nly hrev_master veins and lymphatics 2014; volume 3:4150 [veins and lymphatics 2014; 3:4150] [page 71] the bassi historical international library of phlebology at the ferrara university hospital marco bresadola dipartimento studi umanistici, university of ferrara, italy abstract this year we celebrate the centenary of the birth of the italian phlebologist glauco bassi, who played a principal role in the development of phlebology as a discipline, as well as in the foundation of the union internationale de phlebologie (uip). moreover, bassi is not only a founding father of phlebology, but he represents an inspiring model for a medical teaching and practice centered on the doctor-patient relationship. in compliance with the will of neso onorina, the bassi fund heir, and of dr. lorenzo tessari, her emissary and bassi's pupil, the glauco bassi foundation donated the bassi fund to the university of ferrara. following those principles of advanced research in the venous restoration rather than abolition that were transmitted from glauco bassi to lorenzo tessari, this last one identified in the prof. paolo zamboni's academic vein centre the right environment in which letting the research and innovation grow. in turn, to make the bassi fund scientific literature treasure available to the public community, with the hope of increasing the general awareness on venous restoration, prof. paolo zamboni, world-wide recognized pioneer in the venous hemodynamics field, donated the bassi fund to the library of the health sciences of the university hospital of ferrara, constituting a scientific committee of which he became president. the bassi library now lives at the cona hospital and is daily attended by students, residents, phd, and people interested in phlebology as well. the centenary of glauco bassi’s birth and the international historical library of phlebology this year we celebrate the centenary of the birth of the italian phlebologist glauco bassi, who was born in feltre, a village in the northeast of italy, on 19th of december 1914 (figure 1). while most physicians know his name after some small veins of the calf (bassi’s perforators), not so many know his role in the birth of phlebology as a discipline and still fewer know his scientific contributions and personality in detail. this is really unfortunate, as bassi is not only a founding father of phlebology, but he represents an inspiring model for a medical teaching and practice centered on the doctorpatient relationship. in compliance with the will of neso onorina, the bassi fund heir, and of dr. lorenzo tessari, her emissary and bassi's pupil, the glauco bassi foundation donated the bassi fund to the university of ferrara. following those principles of advanced research in the venous restoration rather than abolition that were transmitted from glauco bassi to lorenzo tessari, this last one identified in the prof. paolo zamboni's academic vein centre the right environment in which letting the research and innovation grow. in turn, to make the bassi fund scientific literature treasure available to the public community, with the hope of increasing the general awareness on venous restoration, prof. paolo zamboni, world-wide recognized pioneer in the venous hemodynamics field, donated the bassi fund to the library of the health sciences of the university hospital of ferrara, constituting a scientific committee of which he became president. the bassi library now lives at the cona hospital and is daily attended by students, residents, phd, and people interested in phlebology as well (figure 2). in the library there are also documents and letters testifying the first contacts among the fathers of phlebology immediately after the second world war. they are either political contacts about the organization of the first meeting in europe and foundation of the union international de phlebologie, or scientific contacts regarding articles and first textbooks on venous disorders. the library has been recently visited by the union internationale de phlebologie (uip) president elect nick morrison, md, and by many other leading people in phlebology such as b.b. lee, md, and joseph raffetto, md (figure 3). the legacy of glauco bassi, a founding father of phlebology as robert stemmer, a former secretary of the uip, wrote in a eulogy composed on the occasion of bassi’s seventieth birthday, visiting a patient with bassi is a medical delight. and jean van der stricht, a former president of the uip, strongly suggested that young phlebologists follow bassi’s recommendations in their daily practice and study his views before undertaking their research on the physiology and pathology of the veins. but the best portrait of bassi is perhaps the one he himself wrote in his own obituary, composed some months before his death, which occurred in december, 1987: those who knew bassi personally say that he had a good disposition but a difficult character. he easily lost his temper, and lacked tact and diplomacy. he was too honest and rigorous to be appreciated by most, but he never missed the esteem and friendship of the most eminent among his foreign colleagues. in fact, bassi was an international medical figure. he was much more appreciated by french and german physicians than by his italian colleagues, and he himself looked beyond the alps to develop a new conception of the functioning of the venous system and to establish more efficient therapeutic methods. bassi’s international standing is testified by his publications in many different languages and by his strenuous activity in european societies and worldwide conferences. his book le varici degli arti inferiori (the varicose veins of the inferior limbs) published in 1962 and with a new french edition in 1967, was considered the bible of the phlebologist by raymond tournay, the inventor of the term phlebology. bassi published two other fundamental books on phlebology and more than a hundred articles in the major international journals. he spent more than thirty years treating patients in his medical practice in trieste, and was also very interested in the teaching and popularization of medicine. he even produced a movie to communicate new views on the treatment of varicose veins. last but not least, he actively participated in the construction of international networks of phlebologists, being one of the founders of the union internationale de phlebologie and its vice-president for many years. bassi’s multifarious and international activity is reflected in his medical library and archive, which is now kept in the library of the sant’anna hospital in ferrara, italy. bassi’s library contains all the main journals and books on angiology and phlebology published correspondence: marco bresadola, dipartimento studi umanistici, university of ferrara, via paradiso 12, 44100 ferrara, italy. tel.: +39.0532.293412. e-mail: marco.bresadola@unife.it key words: bassi foundation, glauco bassi, international union of phlebology. received for publication: 22 may 2014. accepted for publication: 22 may 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright m. bresadola, 2014 licensee pagepress, italy veins and lymphatics 2014; 3:4150 doi:10.4081/vl.2014.4150 no nco mm er cia l u se on ly technical note [page 72] [veins and lymphatics 2014; 3:4150] until the end of the 1980s. his archive preserves his clinical notebooks, the texts of his conference papers, reviews, articles, and books, about three thousand pages of notes taken from his readings and reflections on phlebology, and his correspondence with the major phlebologists of his time. it is a real treasure, which allows reconstructing how phlebology emerged as a discipline and developed in his early four decades of life, from the 1950s to 1980s. but it is also an archive of phlebological knowledge which today’s physicians and researchers may consult to find fundamental information and original ideas on the physiology, pathology, and treatment of the venous system. in what follows we shall give just two examples of the richness and interest of bassi’s archive, as well as of the fundamental role played by his activity in the emergence and development of phlebology. the first example concerns bassi’s role in the organization of the first world conference of angiology, which took place in paris in 1952. in previous years bassi had spent long periods of study in the french capital, where he had met some of the main angiologists of the time such as louis gerson, the organizing secretary of the 1952 conference. in a letter of october 1951, gerson asked bassi to give him a list of the italian physicians active in the field and to set up an italian committee of angiology. bassi accepted the task, participated in the conference and established the first italian association of phlebology with marcello comel and a few others. some years later, in 1959, this group joined the french and german phlebological societies to form the uip, which is still the most important medical association in the field. a second example from bassi’s archive concerns the publication of his compendio di terapia flebologica published in 1985, a compendium of phlebological theory to which nearly all the major phlebologists of the time gave their contribution. as had happened with his book on varicose veins, which had been translated into french, bassi wanted to make his compendium accessible to an international audience. he wrote to jean van der stricht and andré davy, at the time president and secretary of the uip, to propose them a spanish edition of the compendium under the aegis of the society. here is what van der stricht answered in a letter of december, 1986: you do not ignore that uip has planned the publication of a treatise aimed at the teaching of the fundamental aspects of phlebology, a work addressed to those figure 1. glauco bassi, md. he lived in trieste, italy, close to the lighthouse, and according to robert stemmer, this was the symbol of his position in the international phlebology world. figure 2. the bassi clinical cases and the pioneering hypertext are consulted by medical students. figure 3. the international union of phlebology elected president nick morrison (fourth from left) visits together marco bresadola (second from left) and sergio gianesini (second from right) the bassi international library in ferrara with members of joseph raffetto’ family. no nco mm er cia l u se on ly technical note [veins and lymphatics 2014; 3:4150] [page 73] who want to learn phlebology rather than to expert specialists. now i am glad that you have preceded us. your project meets the uip’s purpose. it is thus convenient that we abandon our project and bring it together with yours. i am very pleased to collaborate personally to this useful work and to give the official support of the union’s president. in the following months the project developed, as bassi’s correspondence and other material kept in his archive testify. unfortunately, however, the publication of this new edition of the compendium promoted by the uip and written in english, never saw the light due to bassi’s death in december 1987. some months before dying bassi published an article on the teaching of phlebology. he reviewed the state of the art in the three main fields of phlebological therapy that is surgery, sclerotherapy, and compression therapy. he acknowledged the advancements made in the previous three decades, but remarked that these progresses affected the practice of just a small number of physicians, while the majority of them still relied on wrong conceptions and outdated methods. bassi called for the establishment of phlebology not only as a medical specialty but also as an autonomous discipline, with its own doctrinal body and teaching positions. he also stressed the fundamental role of the patient’s attitude in the success of phlebological therapy, as the cure of veins’ diseases needed prolonged times and the active collaboration of the patient. in his paper on the teaching of phlebology bassi stressed the importance for an efficient therapy of treating the patient with psychology, tact, and perseverance, three fundamental qualities of the phlebologist but we may add of any physician. he then concluded his paper with the following words: our generation has created phlebology. next generation must educate phlebologists. in the last twenty-five years since bassi’s death, phlebology has undergone many changes and its importance has been recognized in many countries. once a specialty cultivated mainly in europe, it has become a body of knowledge and therapeutic methods developed by physicians working in many other countries, and especially in the united states. today there are phlebological societies established in all continents, but the unifying core of all these scientific and promotional initiatives is still the international union of phlebology. the present conditions of phlebology, and its future development, are thus rooted in its history, which has been made by great figures of physicians, scientists, and organizers. there is no doubt that glauco bassi was one of these great figures. documents available at: the bassi international library of phlebology, c/o biblioteca delle scienze della salute, azienda ospedaliera universitaria di ferrara, via aldo moro 8, 44124 loc. cona, ferrara, italy. tel.: +39.0532.236257 fax +39.0532.236392. email: biblioteca@ospfe.it open from monday to friday; 9 a.m. 4 p.m. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2017; volume 6:6817 [veins and lymphatics 2017; 6:6817] [page 61] vascular anomalies in the mesenteric circulation of patients with crohn’s disease: a pilot study matilde zamboni,1 maria grazia sibilla,2 roberto galeotti,3 massimo pedriali,4 simona ascanelli2 1department of thoracic, cardiac, and vascular sciences, post graduated school in vascular surgery, university of padua; 2department of surgery, unit of translational surgery, universityhospital of ferrara; 3unit of vascular and interventional radiology, university-hospital of ferrara; 4unit of anatomy, histology and pathological citology, university-hospital of ferrara, italy abstract crohn’s disease (cd) is a chronic inflammatory bowel disease and its pathogenesis is still not well understood. previous studies suggested the possibility of the involvement of vascular system, but, todate, the mesenteric circulation has poor been investigated, especially in complicated cd cases requiring colectomy. we investigated the mesenteric circulation in a case-control pilot study, including 19 controls and 7 patients affected by complicated cases of cd. cases and controls underwent selective angiography of both superior and inferior mesenteric district. transit time was found either significantly shortened in 2/7 cases (29%), or prolonged 5/7 (71%) (p=0.0034 in the superior mesenteric district; p=0.0079 in the inferior mesenteric district), respectively due to the presence of a-v malformations and of a miscellaneous of venous abnormalities, which included thrombosis, hypoplasia and extra-truncular venous malformations. our study demonstrates the presence of congenital or acquired vascular anomalies in a small sample of cd patients not responder to current treatment and with severe complications. the present pilot study warrants further investigations. introduction crohn’s disease (cd) is an inflammatory bowel disease and its pathogenesis is still unknown. so many have been the hypothesis: viral and bacterial infections, hereditary factors, disregulation of the immunitary system, enviromental factors etc.1-6 cd is clinically characterized by both bowel and extrabowel symptoms. the first are abdominal pain, diarrhea, meteorism, loss of weight, anorexia; the second and less frequent are tipically rheumatological: erythema nodosum, pyodherma gangrenosum, anklylosing spondylitis, arthropathy, uveitis, episcleritis.1 in the majority part of the population cd does not remain steady but it progresses into a serious of dramatic and surgical situations such as bowel obstruction/perforation, recurrent fistulas (enterocutaneous, enteroenteric, enterocolic, enterovaginal) which affect on the quality of life of this population.1-6 old and recent studies seems to indicate the possible involvement of the vascular system in the pathogenesis of the disease.6-12 the first big chapter concernes deep venous thrombosis (dvt). during years it has been noticed and confirmed that dvt is highly increased in cd (2-4 times more respect to healthy controls).10 this phenomenon could be explained by a series of organic situations which are usually present in cd patients: systemic inflammatory, loss of water, stillness, surgery, steroid therapy.8-10 the second chapter looks after vascular abnormalities and cd. there are just a few studies conducted in the 70’s by some swedish groups. they investigated celiac and mesenteric arteries with angiographies and demonstrated that the majority part (90%) of population with cd or ulcerative colitis exhibited different angiographic anomalies.11-12 we hypothesized that an aggressive cd clinical course could be related to acquired and/or congenital mesenteric circulation pathology. aim of the present study was to investigate patients with aggressive and complicated clinical course of cd studying selective angiographies of the mesenteric circulation. ethical approval our study is a pilot case-control study, approved by our ethical committee and registered at number #140686. all procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. informed consent was obtained from all individual participants included in the study. materials and methods patient populations the control population was selected from 109 patients who underwent a mesenteric angiography in the last 5 years and none was affected by cd. selection was based on the availability of a complete superior and inferior mesenteric study, with both arterial inflow and venous outflow, until the opacification of the portal trunk. the final control population was consisted of 19 patients, 12 males and 7 females and the reason why they underwent angiography includes a miscellaneous of digestive pathology (9 tumors, 2 visceral artery aneurysms, 4 bleedings, 2 angina abdominis, 1 vasculitis). the case patients were 7 cd patients with one or more complications mentioned before. they were 5 men and 2 women with an average age of 45 years old. they all underwent to a selective angiography study. they were all acquainted about the procedure with risks and benefits and they all signed an informed consent. case population and its demographic characteristics are shown in table 1. selective catheter angiography standard angiography was performed selectively to show mesenteric arteries, superior and inferior, and their outflows. angiography was performed by a pretreatment with one butylscopolamine vial i.v. followed by seldinger’s technique and record of both arterial and venous time. we used a 5 french introducer and a cobra correspondence: matilde zamboni, department of thoracic, cardiac, and vascular sciences, post graduated school in vascular surgery, university of padua, italy. e-mail: wambazamba@icloud.com key words: crohn’s disease; mesenteric circulation; angiography; av malformations. conflict of interest: the authors declare no conflict of interest. received for publication: 25 may 2017. revision received: 13 july 2017. accepted for publication: 14 july 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright m. zamboni et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6817 doi:10.4081/vl.2017.6817 no n c om me rci al us e o nly article catheter to study superior mesenteric district (25-30 ml at a flow rate equal to 3 ml/sec) and a simmons catheter for the inferior one (15-20 ml at a flow rate equal to 2 ml/sec). the iodinated contrast medium concentration was equally 400 mgi/ml. we studied angiographies in both cases and controls, specially we looked after the vascular morphology and the transit time (tt) evaluation. tt was calculated from the beginning of the automated injection until the portal vein appeared opacified by the contrast dye. in one case we performed a selective angiography on the resected sigma soon after the surgical procedure. statistical analysis data were summarized as mean ± standard deviation (sd). ordinary anova test was used to estimate tt; two sided fischer exact test was used to estimate differences in the frequency of vascular abnormalities in both populations. statistical significance was set with p<0.05. results firstly tt was evaluated in the control population: 12.5±0.9 sec in the superior mesenteric circulation and 17.9±1.4 sec in the inferior one. this functional result permitted to compare the mesenteric circulation in complicated cd respect to controls. comparing tt results and angiography morphology we noticed that every cd patient had an altered tt accompanied by a vascular anomaly. cases with av malformation/fistulas in case #2 we documented an a-v malformation (avm) by the means of selective angiography of the inferior mesenteric artery at the level of the superior haemorrhoidal artery (figure 1). the patient clinically presented multiple not healing digestive fistulas, topographically corresponding to the bowel segment with low perfutable 1. patients’ cohort demographics and clinical characteristics. patients age m/f smoke time to disease site of disease bowel anorectal surgery therapies complication complication l.z. 55 m yes 22 yrs ileum colon obstruction fistulas 3 metronidazole abscess c.d. 60 m yes 17 yrs colon obstruction fistulas 2 mesalazine abscess f.m. 55 f yes 14 yrs jejunum obstruction fistulas 3 infliximab ileum abscess n.m. 32 f yes 7 yrs ileum perforation abscess 2 steroids colon d.m. 48 m yes 24 yrs ileum obstruction fistulas 1 none colon c.r. 62 m yes 10 yrs colon perforation no 1 steroids p.m. 46 m yes 22 yrs ileum perforation no 2 none colon table 2. transit time evaluation, mean and standard deviation, in the superior and inferior mesenteric district. controls crohn’s disease vs av shunt other crohn’s disease cases transit time superior meseneteric district 12.5±0.9 sec 10.5±0.7 sec 14.8±3.0 sec transit time inferior mesenteric district 17.9±1.4 8.5 ± 4.9 sec 22±4.8 sec figure 1. av malformation. figure 2. extratroncular av fistulas. [page 62] [veins and lymphatics 2017; 6:6817] no n c om me rci al us e o nly article sion due to the a-v shunt. tt was reduced in the inferior mesenteric artery: 5 sec. the preoperative angiographic assessment permitted to regulate the margins of bowel resection. the relative bowel ischemia is well apparent in the post-operative selective angiography of the operatory specimen. in case #5 catheter arteriography of the superior mesenteric artery demonstrated the presence of multiple extratroncular av fistulas (figure 2) with an evident overload of the iliac veins, which appeared abnormally dilated. cd lesions corresponded to the intestinal areas of relative ischemia. also in case #5 tt was decreased (11 sec.) in the superior mesenteric district. so, in these two av shunt cases tt was significantly shorter: 10.5±0.7 in the superior district and 8.5±4.9 in the inferior one. cases with prolonged mesenteric transit time in case #1, #3, #4, #6, #7 tt was significantly increased: 14.8±3 sec in the superior mesenteric district and 22±4.8 sec in the inferior one. the reason of a slower circulation was represented by a series of venous anomalies: in case #2 and in case #7 we observed small sized mesenteric and/or iliac veins compatible with venous hypoplasia (figure 3); dysplasia and varicosities of the parietal veins, compatible with extra-troncular venous malformation, were observed in case #3 and #4; and finally a mesenteric dvt was detected in case #6 (figure 4). overall tt was significantly different in the cd population: p=0.0034 in the superior district and p=0.0079 in the inferior one (tt are shown in table 2). finally, the presence of anomalies in the mesenteric circulation was significantly higher in complicated cd respect to controls (or=25, 95% ci 1.2-504; p=0.0064). discussion the original idea of this study has been to observe bowel from a circulatory point of view. indication to vascular study was given by the treating physician to understand more about the continuous development of severe complications in this group of patients. we have found a set of vascular anomalies and malformations, which are frequently observed in other districts of the human body. particularly, out of the case of mesenteric dvt, the other six cases, according to a recent consensus statement, can be classified among the venous malformations.13 the iup classification divides the vascular malformations according to the flow rate and the stage of the vascular system development. in our survey we found two cases of high flow malformations and 5 of low flow rate. the latter could be extratruncular, whether the arrest of the development happens during the first three months of pregnancy, and truncular whether it occurs in later stages (5th-7th months).13 both arterial and venous side were involved, potentially contributing to the patho-physiology of the disease: hypoperfusion, venous stasis, oedema and inflammation. the second exclusive finding has been to calculate tt in both populations and find them significantly changed. this result reflects a pathological vascularization of bowel tissues and, possibly, a vascular contribution to the pathogenesis. for instance, the case of the avm clinically corresponded to multiple not healing digestive fistulas, topographically in the bowel segment with low perfusion due to the shunt. the relative bowel ischemia is well apparent in the post-operative selective angiography of the operatory specimen (figure 5). moreover, cases with venous hypoplasia and/or venous thrombosis corresponded to biopsy where histology documented oedema and chronic inflammation. limitations of this preliminary study are the followings: i) angiographies in the control population have been performed mostly in bleeding patients, so tt could be distorted by haemodynamic adaptations of the body (blood loss and autonomic nervous system disregulation); ii) cd patients were complicated patients, which means people who underwent a bowel resection. this fact is so important because it means that angiographies do not show completely the original vascularization; iii) we do not have a tt evaluation in healthy cd patients without complications; iv) a small casuistry. furthermore, our data cannot clarify whether the vascular condition is a cause or a product of the bowel disease. however, our findings and results are very impressive and need to be amplified in a structured and wider case control study, including complicated patients before bowel resection. figure 3. troncular venous malformation. figure 5. avm after bowel resection. [veins and lymphatics 2017; 6:6817] [page 63] figure 4. deep venous thrombosis. no n c om me rci al us e o nly article [page 64] [veins and lymphatics 2017; 6:6817] references 1. sands be, siegel ca. crohn’s disease. in: feldman m, friedman l, brandt l, eds. sleisenger and fordtran’s gastrointestinal and liver disease. philadelphia, pa: saunders; 2010. chapter 111. 2. balfour sartor r. bacteria in crohn’s disease: mechanism of inflammation and therapeutic implications. j clin gastroenterol 2007;41:s37-43. 3. chiodini rj, chamberlin wm, sarosiek j. crohn’s disease and the mycobacterioses: a quarter century later. causation or simple association? crit rev microbiol 2012,38:52-93. 4. frolkis a, dieleman la, barkema h, et al. environment and the inflammatory bowel diseases. can j gastroenterol 2013;27:18-24. 5. geremia a, biancheri p, allan p, et al. innate and adaptive immunity in inflammatory bowel disease. autoimmun rev 2014;13:3-10. 6. deban l, correale c, vetrano s, et al. multiple pathogenic roles of microvasculature in inflammatory bowel disease: a jack of all trades. am j pathol 2008;172:1457-66. 7. de franco a, di veronica a, armuzzi a, et al. ileal crohn disease: mural microvascularity quantified with contrast-enhanced us correlates with disease activity. radiology 2012;262:6808. 8. morasch md, ebaugh jl, chiou ac, et al. mesenteric venous thrombosis: a changing clinical entity. j vasc surg 2001;34:680-4. 9. hatoum oa, spinelli ks, abu-hajir m, et al. mesenteric venous thrombosis in inflammatory bowel disease. j clin gastroenterol 2005;39:27-31. 10. danese s, papa a, saibeni s, et al. inflammation and coagulation in inflammatory bowel disease: the clot thickens. am j gastroenterol 2007;102:174-86. 11. erikson u, fagerberg s, krause u, olding l. angiographic studies in crohn’s disease and ulcerative colitis. am j roentgenol radium ther nucl med 1970;110:385-92. 12. brahme f, hildell j. angiography in crohn’s disease revisited. am j roentgenol 1976;126:941-51. 13. lee bb, baumgartner i, berlien p, et al. consensus document of the international union of phlebology (iup): 2013 xvii uip world meeting, september 8-13, 2013, hynes convention center, boston ma. no n c om me rci al us e o nly hocaoglu c. clozapine-induced rabbit syndrome: a case report one hundred years since the discovery of heparin, not so long ago. the story of a loser stefano ricci, giovanni agus this article is part of an issue appeared in the journal acta phlebologica 2006 august; 7(2): 91-7 (by kind permission). introduction the discovery of heparin dates back to 1916. in 2016, there will be the hundredth anniversary since this event which was initially considered as a curious physiological phenomenon, but subsequently became the basis for the evolution of vascular and cardiac surgery, haemodialysis, blood conservation, and prevention and treatment of thrombo-embolic disease. heparin discovery, its subsequent understanding, production, experimental and clinical application, and its final introduction into clinical use like a major pharmacological aid in many treatments almost resemble the script of a drama, full of joys and tears. jay mclean is credited (see photo and biographic reference of g. agus elsewhere in the journal) to the first description of a natural substance acting as inhibitor of coagulation (1916). this was done in the occasion of a relatively simple biological research on the pro-coagulation activity of cephalin, a phosphatid compound of many body tissues, mostly in the brain. mclean was a 2nd year medicine student eager to satisfy his pretension of independence and his self esteem: the discovery of heparin came as a result of my determination to accomplish something by my own ability.1 the observation of an anti-coagulating function of a fraction of a heart and liver phosphatid was mainly a serendipitous event, even if associated to logic procedures. later on, mclean underlined that the common opinion that he discovered this by chance was not correct. it was discovered serendipitously in the course of a problem, but not merely by chance.2 this to explain that chance, when displaying its effects must be guided in some ways by a human contribution. subsequently, heparin was divulgated and studied by w.h. howell (1918), chief of the physiology department where the research was accomplished; it was licenced for production by c.h. best (1931), a canadian physiologist; it was clinically employed for the first time by murray, in canada, and by crafoord in sweden at the same time (1936). more than 30 years were needed before passing from discovery to clinical use, though. all the characters of this story achieved fame and honor for their contribution in developing heparin, except for poor mclean, a real born-to-lose guy. in fact, he rapidly followed a diverting career (1917), and realized only a long time after (1940) that he had been part of an historical event, though only skimming over it. his battle for achieving recognition as heparin discoverer had a minor result only after his death, when a bronze plaque was placed at the department of pharmacology of the johns hopkins medical school.1 this is what the plaque reads: jay mclean, md, 1890-1957. in recognition of his major contribution to the discovery of heparin in 1916, as a second-year medical student in collaboration with professor william h. howell. this plaque is presented to johns hopkins medical school at the conference on bleeding in the surgical patient, held by the new york academy of sciences. may 3, 1963. biography of jay mclean jay mclean was born in san francisco in 1890. his childhood was unfortunate, scarred by tragic events like his father’s death when he was 4, the re-marriage of his mother five years later, and the the earthquake fire in san francisco in 1906. also, he had a bad relationship with his stepfather, who stopped supporting his studies when he was 22. this notwithstanding, he managed to obtain his bachelor of science degree in 1914 at the university of california. recalling those days he wrote:2 my argument was that johns hopkins offered me more preparation in the field of academic surgery, that is, research and teaching, for a lifetime career. also i felt deeply the responsibility of being a physician. i doubted if i possessed the qualifications to become one; and i deliberately chose the fiercest student competition, as johns hopkins' matriculants were meticulously chosen. he entered johns hopkins university in 1915 and met william h. howell, chairman of the department of physiology, already famous at that time, with a long-lasting experience in blood coagulation research. indeed, in 1910 he had found a way to isolate thrombin and his textbook of physiology published in 1905 would have gone through 14 editions. dr. howell gave me the problem of determining the value of the thromboplastic substance of the body. he thought this to be kephalin (cephalin),..... it was kept in a glass vessel with ground glass cover (vaselined), as it was observed that access of air decreased its ability to accelerate clotting. in three months it was decayed. my problem was to determine what portion of this crude extract was the active accelerator of the clotting process and to that end, to prepare cephalin as pure as possible and determine if it had thromboplastic action. i was also to test the other components of the crude ether-alcohol extract. i was assigned a sink and attached table-drain board with a shelf over the sink in a large student physiology laboratory (not used as such then) across the hall from dr. howell's office and private laboratory.2 after one year (1916), he could send for publication to the american journal of physiology the following paper, below reported only in those parts concerning the findings of an anticoagulating substance. the thromboplastic action of cephalin3 in 1912, howell reported the results of a study of the thromboplastic action of the tissues in which he showed that the active substance is a phosphatid having the general properties of cephalin. at the suggestion of dr. howell i have undertaken a re-examination of this subject to determine if possible whether the thromboplastic effect may be attributed to an impurity, or is a property of the cephalin itself, and also to determine in how far a similar property is exhibited by other related phosphatids. the phosphatids which have been examined in regard to their thromboplastic action are cephalin, lecithin, sphingomyelin, cuorin and heparphosphatid. the cuorin, when purified by repeated precipitation in alcohol at 60”, has no thromboplastic effect-indeed it possesses an anticoagulating power as may be illustrated by the following experiment. dog’s oxalated plasma and dog’s serum using-plasma, 8 drops; phosphatid, 3 drops; serum, 3 drops. control-plasma, 8 drops; water, 3 drops; serum, 3 drops. heart cephalin.. . . . . . . . . . . . . . . . . .;.. . . . . . . . . . . . . . .solid clot 3 min. cuorin.. . . . . . . . . . . . . . . . . . . . . . . .;.. . . . . . . . . . . . . . .not clotted in 6 hours. control.. . . . . . . . . . . . . . . . . . . . . . .;.. . . . . . . . . . . . . . sliding clot in 9 min. cuorin added to blood fresh from the artery will delay its coagulation remarkably. baskoff in his work on the phosphatids of the liver, succeeded in isolating a phosphatid which resembles cuorin. to this phosphatlid he gave the name of heparphosphatid. the heparphosphatid on the other hand when purified by many precipitations in alcohol at 60” has no thromboplastic action and in fact shows a marked power to inhibit the coagulation. the anticoagulating action of this phosphatid is being studied and will be reported upon later. conclusions: cephalin when prepared as pure as possible exhibits marked thromboplastic activity, as indicated by it’s effect, in increasing the thrombic action of fresh serum. the other phosphatids that have been described, lecithin, cuorin, heparphosphatid and sphingomyelin have no thromboplastic action. in the conclusions, no mention is found about the discovered properties of cuorin and heparfosphatid to inibit coagulation. in a letter written 24 years later, in 1940, he explained to dr. best in toronto:4 […] the professor thought the findings were tentative and should not be included in an article on the clotting properties of cephalin, but rather should be studied further and written about in a separate paper. he finally agreed to permit its inclusion in the body of the paper, but not in its conclusions. mclean completed his work and at the end of the year moved to philadelphia for a fellowship at the university of pennsylvania, further studying purification of the coagulant cephalin (1917). he graduated in 1919, had a surgical training till 1924 in new york, when he entered private practice. thereafter (1939 at the age of 49 years), he moved from new york to columbus, ohio, working as an assistant in private pathology laboratories and becoming involved in the use of radiation for cancer. his sporadic research efforts with heparin did not obtain any important results. in 1940 heparin was already universally recognized as a fundamental pharmacological progress and now in worldwide use. mclean, finally aware of the importance of heparin, began a campaign based on letters to the most important physiologists and on literature harvesting, with the aim of publishing a monograph and achieving recognition as the discoverer of heparin. this useless and sad campaign was vigorously pursued for 7 years. his collection of reprints grew to monumental proportions, but the article on the discovery of heparin was never completed. this material referred to more than 1300 numbered, abstracted, and cardboard mounted reprints, collected in an index and abstracts of the heparin literature, as well as his notebooks from 1916. the collection was sent to toronto, where it remained for many years in the library of the best institute.1 his recollection of the events of 1916, although written and rewritten during the next 17 years, was published only two years after his death, in 1959.2 ironically, the heparin of 1940 had nothing to do with the liver and was not a phosphatid: it was extracted from beef lung and was a complex carbohydrate containing sulfur, but this was not the real problem for mclean. in his last paper – more similar to a will than a scientific paper (it was published after his death) – we can feel the atmosphere of those days and the details of that discovery.2 in this very personal report we can understand a substantial polemical position toward howell. he also underlined his personal initiative in the research development and in finding the anticoagulant effect of some substances (although incidental): by this time, what little cephalin remained from my former studies with brain tissue was deteriorated by the process of extraction plus air and time....i had saved batches of cuorin and heparphosphatide and from time to time tested these in serum plasma to determine whether or not the cephalin from the heart and liver deteriorated and lost its thromboplastic power as did that from the brain. if i had not saved them, i would probably not have found heparin. this was a fortuitous decision. all i was trying to prove was that an ether-soluble, alcoholinsoluble extract of cephalin would accelerate coagulation of blood, and it did. i became interested in the deterioration of cephalin (an unsaturated fatty acid), which i assumed became saturated on exposure to air (and ether-alcohol purification. the various batches were tested down to the point of no thromboplastic activity, but two of those first prepared appeared not only to have lost their thromboplastic action, but actually to retard slightly the coagulation of the serum-plasma mixture. i had in mind, of course, no thought of an anticoagulant, but the experimental fact was before me; and i retested again and again until i was satisfied that an extract of liver (more than heart) possessed a strong anticoagulant action after its contained cephalin had lost its thromboplastic action. after more tests and the preparation of other batches of heparphosphatide, i went one morning to the door of dr. howell's office, and standing there (he was seated at his desk), i said, dr. howell, i have discovered antithrombin. he smiled and said, antithrombinis a protein, and you are working with phosphatides. are you sure that salt is not contaminating your substance? i told him i was not sure of that, but it was a powerful anticoagulant. he was most skeptical.* *(we arbitrarily underlined the sentences related to the discovery of the anticoagulation effects) however, in 1940, in a letter to dr. best,5 he recalled: while i was in philadelphia, dr. howell wrote me and offered to place my name on his 1918 paper in consideration of the intravascular injection work we had done. i declined and told him i had participated to such a small extent in this later work that i did not feel i was entitled to the privilege offered; also that the work which i had done in discovering the anticoagulant action of the substance was already published in my paper of 1916 and that future work, such as the chemical purification and mechanism of its action, etc., i should be content to leave in his laboratory.6 in 1947, mclean moved from columbus to become director of the bureau of cancer control of the district of columbia. in 1957, dr. irving wright, who was organizing a historic symposium on heparin, asked him to write his recollection of the events of 1916. ironically, jay mclean was unable to complete his story before he died of myocardial ischemia on nov. 14, 1957, at 67 years of age. his unfinished autobiographic paper was published in circulation in january 1959 with the title the discovery of heparin, and is partially reported above. although initially sceptical, professor howell was strongly interested by the new anticoagulating substances and, with the assistance of another medical student, l. emmett holt jr., he continued to work on the subject trying to achieve its purification. in april 1917, he delivered the prestigious harvey lecture in new york on the topic of the coagulation of the blood.7 he stated: in some work done in my laboratory by j. mclean and published in 1916, an investigation was made of the action of the various phosphatids in regard to their influence on the process of coagulation. it was found that phosphatids from the heart and liver.., have a marked inhibiting effect upon coagulation.7 heparin was named by howell for the first time in two new factors in blood coagulation. heparin and pro-antithrombin (1918), submitted to the american journal of physiology:6 the first new factor is a phosphatid not previously described, which exists in various tissues but is found in greatest abundance in the liver. this phosphatid is designated as heparin to indicate its origin from the liver. it inhibits coagulation partially or completely, according to the concentration... attention was first called to this substance during some work done in this laboratory by jay mclean in the course of his work. in 1923, the product was no more an ether but an aqueous extraction, 5 times more effective than the initial. it was licensed for commercial production by hynson, westcott and dunning (h, w & d) not for clinical use, but [...] as an aid to laboratory workers who need an effective anticoagulant in their experimental work.8 nevertheless, some clinical thoughts were already in the air at the johns hopkins hospital. although no patient had ever received a direct injection of heparin, it was used as an anti-coagulant for blood transfusions to six patients, two of whom developed toxic reactions. howell continued to work on dog liver trying to obtain a purified heparin and retired in 1930 at the age of 70 years, leaving the research activities, but very busy in revising the fourteenth edition of his famous textbook. he died of a myocardial infarction at 85. a clinically useful form of heparin was introduced in canada and sweden in 1937. simultaneously, crafoord9 and murray10 published their first clinical experiences. heparin became available in the usa only in 1940, 34 years after its descovery. references 1. baird rj. "give us the tools...": the story of heparin as told by sketches from the lives of william howell, jay mclean, charles best, and gordon murray. j vasc surg 1990;11:4-18.[pubmed] 2. mclean j. the discovery of heparin. circulation 1959;19;75-78.[pubmed] 3. mclean j. the thromboplastic action of cephalin. am j physiol 1916;41:250-7.[full-text] 4. best ch. preparation of heparin and its use in the first clinical cases. circulation 1959;19;79-86.[pubmed] 5. best ch. collected papers and correspondence. toronto: university of toronto. cited by ronald j. baird 6. howell wh, holt e. two new factors in blood coagulation--heparin and pro-antithrombin. am j physiol 1918;47:328-41.[full-text] 7. howell wh. the coagulation of the blood. harvey lect 1916-1917;12:272-323. 8. howell wh. heparin, an anticoagulant, preliminary communication. am j physiol 1923;63:434-5. 9. crafoord c. preliminary report on postoperative treatment with heparin as a preventive of thrombosis. acta chir scand 1937;79:407. 10. murray dwg, jaques lb, perret ts, best ch. heparin and the thrombosis of veins following injury. surgery 1937;2:163. [top] battista agus ancestors’ corner giovan battista agus correspondence: giovan battista agus, e-mail: giovanni.agus@unimi.it the paper sclerotherapy of varicose veins-utilization of an intravenous air block. am j surg 1944;lxvi(3):362-6 by egmont james orbach, is probably the ancestor of the foam sclerotherapy. more visibility on orbach’s technique derived from the chapter in the samuels book diagnosis and treatment of vascular disorders (angiology) by the williams and wilkins company, baltimora, usa, translated in various languages included italian in 1958 (figure 1). we will remember how saul s. samuels was one of the founders of the first international society of angiology in 1951, after international cardiovascular society, for the united new complex specialty, medical and surgical together. the drawing of the technique is really interesting for the past and also the present of sclerotherapy (figure 2). finally, to explore this development of one of basic treatments in phlebology, we mention wollmann j-c gr. the history of sclerosing foams. dermatol surg 2004;30:694-703. figure 1. figure 2 [top] hrev_master veins and lymphatics 2015; volume 4:2230 [page 2] [veins and lymphatics 2015; 4:2230] elastic compression treatment of chronic superficial venous insufficiency of the lower limbs based on doppler venous pressure index measurements leonardo corcos,1 daniele pontello,2 tommaso spina3 1vascular laboratory, prosperius institute, firenze; 2s. maria maddalena private hospital, rovigo; 3asp cosenza, italy abstract ineffectiveness or discomfort from graduated elastic compression stockings (ges) in patients with chronic venous insufficiency (cvi) and/or varicose veins of the lower limbs (vvll) can depend of inappropriate counter pressure applied. counter pressure was calculated by doppler venous pressure index (vpi). the aim of this study was to verify the value vpi in the choice of ges. a total of 1212 ll of 606 patients subjected to vpi measurements vpi correlated with the various sites of reflux (r) and c of clinical-etiology-anatomy-pathophysiology (ceap) classification. the difference between standing vpi the and normal values=counter pressure to be applied by ges. questionnaire to 96 patients with cvi/vvll wearing ges. mean vpi values: greater saphenous (gsv)>smaller saphenous; gsv with isolated venous reflux (r) at the leg>gsv at the thigh; additional r in perforators increases vpi in all the districts; superficial r increases vpi in pt. relation between vpi/c of ceap: p<0.05-0.0001; 81/83/96 (97.5%) patients improved; 0 complained. r in gsv at the leg and in perforators increases vpi in deep veins. few discrepancies vpi/ceap can be expected. standing vpi is highly predictive. the best choice of ges can be based on the vpi measurement. introduction elastic compression treatment (ect) of chronic venous insufficiency (cvi) and varicose veins of the lower limbs (vvll) by the application of various kinds of bandages and graduated elastic stockings (ges) has been strongly recommended in the past for conservative and invasive treatments of almost every phebological condition and still is being evolved by more recent studies.1-9 the stockings were divided in classes of various pressure degrees, from prevention ges up to the 4° class2-4 and the indications for the class of compression were mainly based on clinical criteria, especially in the treatment of chronic venous ulcers; the related positive results were clearly demonstrated by clinical and instrumental investigations.5,6 however, as it is well known, many patients complain with discomfort and pain by ges and they often refuse the treatment. the more frequent explanation are obesity, skeletal and joints alterations, kind of work, physical behavior, intolerance to the ges tissues and mainly to a wrong size of ges. in spite of more accuracy in measuring all the clinical and physical parameters recommended for the appropriate choice of the ges class of compression still some patients complain with pain or, at the opposite, do not improve their clinical condition. the problem is still unclear and the debated is still open.7-9 therefore we supposed that the main factor influencing the clinical results from ges could be represented by a wrong counter pressure applied which could not be able to improve the subjective symptoms when too low or, at the opposite, being a main cause of discomfort and pain when too high. the only way for detecting the appropriate counter pressure to be applied seems to be the venous pressure measurement (vpm) of the affected limbs and the comparison with mean normal values. invasive vpm belong to the past of phlebology,10 and were more recently,11,12 nor could be actually proposed to the patients. the non invasive doppler method described by gayliss and bartolo13,14 was statistically validated in 198315 and it seems to represent the more acceptable procedure in the daily practice. since the 1985 we systematically measured the venous pressure index (vpi) by noninvasive doppler method and compared the exceeding vpi, measured in standing position and after 10 tip-toeing exercises (ambulatory) of patients affected with venous disease in both the limbs, with the mean vpi detected in normal limbs. the difference obtained should correspond to the counter pressure and therefore to the appropriate class of compression. the modern haemodynamic evaluation of cvi and vvll is mainly based on duplex ultrasound (dus) and advanced technological imaging.13 further haemodynamic investigations, as vpm and plethysmography, are systematically performed only in few specialized centers.16-18 the majority of the authors do not consider the invasive vpm as an essential systematic clinical investigation,11,12 nor they trust in doppler vpm. both the methods are not recommended in the international guidelines for the diagnosis and treatment of venous disease.2-4 while the invasive vpm correspond to hydrostatic pressure in mmhg, it must be supposed that many different anatomical, functional, mechanical and/or environmental factors of variation, most of them still unknown, can influence the doppler vpm, therefore the value resulting will be different by the hydrostatic one and should be better defined as vpi. since 1996 we introduced into our vascular laboratory the use of a new phlebologic software for the informatic filing of all the cases studied which has been presented in 1999.19 the emerging data and the experience acquired clearly demonstrated that the vpi measurements can give useful information concerning the severity of cvi, it is pathophysiology and the therapeutic implications. during our experience we applied the above-mentioned principles for the choice of the ges for the ect of cvi and/or vvll and we observed a relevant decrease of unsatisfied patients. aims the aim of this study was to verify the value of vpi measurement in the choice of ges compression class and the preliminary results of ect chosen on these bases. materials and methods in the period comprised between 1996 and 2002, 2098 ll of 1049 patients affected with cvi and/or other pathologies of the ll were studied by clinical and dus (sonoscape 1.000®; sonomed bio, inc., bayamon, puerto rico) investigations and the time of reflux (r) was determined. the r was considered pathological when the time of duration was more than 1 second.19-21 in 1212 ll of 887 patients with cvi and 162 free from cvi, which were observed in our vascular laboratory by dus examination, the vpi measurements were systematically performed. correspondence: daniele pontello, via damiano chiesa 22, 33038 san daniele del friuli (ud), italy. mobile. +39.328.3266613. e-mail: ciuto77@virgilio.it key words: venous, pressure, elastic, compression, limbs. acknowledgments: this study was supported by cz medicali, cuggiorno (mi), italy. received for publication: 5 january 2014. revision received: 23 august 2014. accepted for publication: 26 august 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright l. corcos et al., 2015 licensee pagepress, italy veins and lymphatics 2015; 4:2230 doi:10.4081/vl.2015.2230 no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:2230] [page 3] limbs affected with venous malformations, deep venous thrombosis, superficial phlebitis were excluded. the vpi were detected by doppler method (dop 2.000®; cardioline milano, italy) in standing position and after 10 tip-toeing exercises (ambulatory vpi) and the differential values were calculated.14,15,19 patients affected with deep venous insufficiency were also examined in the same period and by the same investigations, but owing to the small number they were not included in the study. the distribution of the cases is reported in table 1. the vpi measurement is performed as follows. the patient is placed over a platform with banister in order to facilitate the standing position and the tip-toeing exercise. a pneumatic cuff of a sphygmomanometer is located at the middle calf and fixed with plaster. a doppler 8 mhz flat or cylindrical probe is placed at the ankle level on the skin above the great saphenous vein (gsv), the small saphenous vein (ssv) and the posterior tibial (ptv). the patient is kept in standing position, the cuff is inflated up to 120 mmhg. the venous sound that can be heard during the cuff deflation and the vpi expressed in mmhg. corresponding to the reapperance of that sound is recorded. the same measurement is performed three times during the diagnostic session in order to verify the reproducibility of the values.15 now the patient is asked to perform 10 tip-toe movements by lifting the body on the forward feet, one every second. the inflating-deflating and doppler detection maneuvers are repeated according with the previous description upon the three districtis: gsv, ssv, ptv. all the data were collected by the phlebologic software.19 the clinical-etiologyanatomy-pathophysiology (ceap) of every single limb was automatically calculated by the software and the c of ceap was correlated with the site of reflux and the mean vpi values. the mean values obtained were analyzed by student test and standard deviation. the correlations of the vpi values with the c of ceap were analyzed by the bayesian test. the mean difference of the standing vpi detected after 3 separate measurements in the gsv, ssv and ptv was calculated and compared with the mean normal values. in the patients with only one limb suffering with vvll and/or cvi the comparison was done with the normal limb. a linear correlation between the differences of the vpi of the examined limbs compared with the mean normal values indicated the value of the counter pressure to be applied expressed in mmhg. on these bases the corresponding class of compression of the ges was chosen for every single limb (figure 1). the proper size of the ges was carefully measured in the limb of every patient. a simple questionnaire was submitted to 96 patients affected with cvi/vvll (from c2 to c6) which were previously subjected to the above described selection for ect in order to know how ges were tolerated after 60 days. the main questions were the following: i) did you suffer with symptoms from cvi? ii) did the application of ges improve your symptoms? iii) did you suffer with pain or discomfort from ges? results the mean vpi values of limbs affected with extended reflux in the whole gsv or limited to the leg were significantly higher (mean: 90 mmhg; range 67-113) than the ones detected in normal limbs (mean normal value: 77 mmhg; range 44-108) (p<0.01). the standing vpi in the gsv measured in the limbs with incompetent pvs were significantly higher (mean 96 mmhg; range 76-116) in comparison with the ones free from pvs incompetence (mean 84 mmhg; range 58-109) (p<0.01). the mean vpi values in the ptv of limbs affected with extensive reflux in the gsv were significantly higher (mean 76 mmhg; range 54-97) than in normal limbs (mean normal value: 71 mmhg; range 43-99) (p<0.01). the mean vpi values appeared to be significantly higher in the cases with incompetent pvs, with or without segmental gsv reflux (mean 81 mmhg; range 61-100) (p<0.01). in these cases the segmental gsv reflux was not related with increased vpi into the ptv. the mean values of vpi measured into the incompetent ssv were higher of the 58.3% (mean 71 mm hg; range 46-100) if compared with normal limbs (mean normal value: 47 mmhg; range 16-82) (p<0.01) while the combination with pvs incompetence did not change the values. all the mentioned districts were subjected to the ambulatory vpi measurements in every single limb and the differential pressure gradient, corresponding to the difference between vpi in standing position and after exercise, was calculated. no significant variation of the differential vpi in the various gsv/ssv segments and conditions, with or without pv incompetence, was found, except for the combination of gsv and pv incompetence. in these cases the differential vpi in the ptv was significantly higher (mean 30 mmhg; range 1446) than in the normal limbs (mean normal values 26 mmhg; range 26-41) (p<0.01). table 1. distribution of the cases affected with chronic venous insufficiency/varicose veins of the lower limbs and subjected to the doppler venous pressure index measurements. parameter value no. patients examined 1049 no. patients without cvi 162 no. patients with cvi 887 average age 52.4±16.2 male 26% female 74% right 554 left 74 cvi, chronic venous insufficiency. figure 1. criteria for the selection of the counter pressure of graduated elastic compression stockings necessary in the different clinical classes related to the ceap classification, and venous pressure index (vpi). a linear correlation can be drawn. gsv, great saphenous vein; ssv, small saphenous vein; ptv, posterior tibial vein. no n c om me rci al us e o nly article [page 4] [veins and lymphatics 2015; 4:2230] all the data were analyzed by the student’s t test. the distribution of the vpi in the various districts of pathological and normal limbs were compared and analyzed by the bayesian test. in the gsv a low prevalence (0.48), a high specificity (0.99) combined with high negative predictive value (0.88) were found. in the ssv the prevalence was 0.77, while specificity and the negative predictive value were high (1.00). so it was also observed into the ptv (prevalence 0.69, specificity 0.98, negative predictive value 0.92). the severity of the disease classified by c of ceap appeared to be strictly related with the mean vpi measured in standing position in all the districts. however it must be noted that the range of variation measured in the limbs of the different c classes comprised a small number of cases characterized by quite low or high pressure which certainly required different classes of ges compression the data were examined by student’s test (p<0.01) (figures 2-4). the mean value of the standing vpi, which appeared to be the most significant measurement, observed in the 162 normal subjects the gsv’s, ssv’s and ptv’s corresponded to the mean value of 65 mmhg (range 37.6-93). such values were used further on for a comparison with the ones detected in every single patient for clinical purposes. the differences observed were taken into consideration as they should correspond to the counter pressure to be applied for the ect of cvi and/or vvll. the counter pressure needed by every single limb was calculated on the basis of the linear correlation between the different pressure gradient and the pressure of the ges related with the class of compression (figure 1). few patients of the whole casuistry, none belonging to the group of 96 who answered to the questionnaire, complained with pain or severe discomfort form ges. three cases over the 96 (3.12%) developed an allergic intolerance to the ges tissue after few days and interrupted the treatment. six patients (6.25%) which have been wearing the ges mainly suffered with burning leg/s owing to the eastern period of the treatment but kept on wearing ges and improved their symptoms from cvi. ten elder patients, some of them affected with combined skeletal and/or joints pathology (10.4%), encountered difficulties in wearing the ges, did not wear them continuously and did not improve. eighty-one over the 83 who have been wearing ges (97.5%) were satisfied for the total or partial relapse of the symptoms from cvi and did not complain with discomfort or pain from ges. two c6 cases shown a relevant improvement of the healing process of ulcers and one was completely healed. the most frequent classes of compression applied were the 2nd (n 46=47.7%) and the 1st (n 33=34.3%), while the so called preventive ges of less than 18 mmhg were prescribed in 15 cases (15.6%) and the 3d class in 2 cases only (2.08%). a vpi gradient which could indicate the application of ges of the 4th class has never been found in this group. discussion ect is a fundamental primary or complementary method for reducing symptoms from cvi and vvll, for preventing superficial and deep venous thrombosis, for the conservative treatment of chronic venous ulcers and for reducing the worsening trend of venous disease, ulcers and complications.1-9 it is well known that in the clinical practice it is sometimes impossible to obtain full cooperation from patients who refuse the use of ges, because of the reasons exposed in the introduction of this paper. this inconvenient is more frequent that the persistence of symptoms from cvi due to a too low counter pressure applied. the present study seems to confirm on one hand the importance of the vpi measurements in phlebologic patients, on the other hand the advantages obtained by the appropriate choice of the ges class of compression on the basis of physical parameters and not simply of clinical subjective and objective criteria.1-9 many efforts were done in the past and in the present for correctly defining the concept of cvi of the ll. many descriptions of the pathophysiological mechanisms which lead to cvi were also discussed and one of them was venous hypertension. however no indications for a systematic haemodynamic instrumental evaluation nor any statistically analyzed data can be found in the literature except for the noninvasive doppler method13-15,19 and photoplethysmography performed in specialized centers.16-19 noninvasive vpi measurement can be proposed in the daily practice without encountering any difficulty from patients, who need a second level16 vascular diagnostics that we perform by noninvasive investigations:19 a detailed dus examination, vpi measurement and, when necessary, photo-plethysmography. this approach made possible to have full cooperation from our patients and acquire a large experience which has shown how useful is a complete morphologic and functional information concerning the pathophysiological condition of every single case. a further advantage of the non-invasive doppler vpi measurement is represented by information concerning the gsv, ssv and ptv districts separately, which can furnish interesting data concerning the balance between the superficial and deep venous function.13-15,19 such detailed examination is not allowed by the invasive methods.11,12,16 the results of the study demonstrate the big advantage of taking significant data from the vpi examinations performed only in standing position and thus avoiding the dynamic evaluation, which is difficult especially for the elder patients or others who are affected with combined skeletal and/or joints pathology. the ambulatory vpi measurements were helpful in the few cases affected with deep cvi and occlusive venous disease, however they could not be figure 2. correlation between the standing venous pressure index (vpi) of the great saphenous vein (gsv) and the c (of ceap classification) class of severity. statistical analysis performed by student’s test. no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:2230] [page 5] taken into consideration owing to the low number of cases. such dynamic measurements in combination with photoplethysmography seemed to give some useful data in patients affected with superficial cvi/vvll and skeletal and/or joint’s pathology. these additional findings were not analyzed in the present work. until the statistical analysis of our data were completed we used to compare with the mean normal values of both the standing and post-exercise (ambulatory) vpi. it has been always a complex calculation and very often it left some perplexities concerning the indication to ges. since we understood that only the vpi measured in standing position was statistically significant in the evaluation of superficial cvi/vvll, the calculation of the counter pressure gradient to be applied became more simple and the clinical results improved. during our previous experience, which is still in progress, many advantages in the prophylactic and therapeutic project of every single patient were found. the extension and surgical strategies can be more precisely planned. in cases affected with early superficial venous disease, with initial reflux and limited varicose veins, for those who are affected with cvi and/or vvll but, in spite of our suggestions, refuse or have absolute exclusion criteria for any kind of invasive treatment, the vpi measurement can also represent a useful parameter for monitoring the progression of the disease, while the patient is subjected to conservative treatments. it can be easily affirmed that the more proper indication for ect and prevention of cvi and/or vvll can be found by the simple evaluation of the counter pressure necessary in every single case. our experience demonstrates that only few patients of the whole casuistry and only 2/83 (2.5%) patients who have been wearing ges for 60 days complained with disadvantage or pain, when selected by the method above described. allergies from elastic tissues and intolerability by the eastern climate are well known side effects of ect and do not appear significant in the evaluation of the results; so do the difficulties encountered in wearing the ges mainly by the elder patients and those affected with various kinds of skeletal and joints infirmities. in addition to the demonstration of the increased tolerability of ges in patients selected by means of vpi measurements some other new information emerged from this work. on one hand we found a significant relation between the mean vpi and the c of ceap of the three venous districts examined. this correlation indicates that the clinical criteria for deciding the appropriate ges compression class is still advisable. on the other hand it must be noted that the range of variation measured in the limbs of the different c classes comprised a small number of cases characterized by too low or too high pressure which certainly did not correspond to the simple clinical criteria and required different classes of ges compression in order to be effective and for avoiding the side effects from ges. it is possible to detect high vpi in cases affected with c2 and c3 vvll and some low pressure in the more severe c (figures 2-4); the indication to class 2 ges treatment appears to be more frequent than expected if compared with simple clinical criteria. the study performed and the results observed clearly demonstrate that discrepancies figure 3. correlation between the standing venous pressure index (vpi) of the small saphenous vein (ssv) and the c (of ceap classification) class of severity. statistical analysis performed by student’s test. figure 4. correlation between the standing venous pressure index (vpi) of the posterior tibial vein (ptv) and the c (of ceap classification) class of severity. statistical analysis performed by student’s test. no n c om me rci al us e o nly article [page 6] [veins and lymphatics 2015; 4:2230] between the clinical class of ceap and venous hypertension are to be expected in every single limb and this should be the main cause for some inappropriate indications of the ges compression class followed by discomfort of patients. we feel that the low number of the cases studied does not represent striking scientific documented evidence, but it can be easily verified by further research. the only disadvantage observed is that the vpi measurement by doppler method is the high operator-dependency and the need for a learning period. conclusions vpi measurements can represent the basis for a more precise selection of patients affected with venous disease of the lower limbs. standing vpi is the most significant evaluation characterized by a high specificity and negative predictive value, it is the expression of the peripheral result of the valvular function in the various venous districts and it can be performed by a simple procedure. the doppler vpi measurement is a highly predictive diagnostic and prognostic investigation and gives a great help for monitoring and treating all the patients affected with cvi and vvll. r in gsv at the leg and in incompetent pv increases vpi and the severity of the disease. extensive r into gsv and pv can lead to secondary deep venous hypertension and it can be interpreted as an overload syndrome. the above described experience seems to demonstrate that the best and selective choice of the ges can be performed on pathophysiological bases rather than on simple clinical criteria, which some times do not exactly correspond to the functional condition of the diseased limb. the clinical results of conservative physical treatment of superficial cvi and vvll seem to be potentially improved by the choice of ges on the bases of vpi measurements. references 1. bassi g, stemmer r. traitements mecaniques fonctionelles en phlebolgie. padova: ed. piccin; 1983. pp 67-153. 2. stemmer r. theoretical and practical bases of compression. j mal vasc 1992;17: 329-32. 3. italian college of phlebology. guidelines on compression therapy. acta phlebologica 2000;1:11-6. 4. collegio italiano di flebologia. linee guida diagnostico terapeutiche delle malattie delle vene e dei linfatici. acta phlebologica 2003;4:14:10-2. 5. o'meara s, cullum n, nelson ea, dumville jc. compression for venous leg ulcers. cochrane database syst rev 2012;11: cd000265. 6. partsch h, flour m, smith pc. international compression club. indications for compression therapy in venous and lymphatic disease consensus based on experimental data and scientific evidence. under the auspices of the iup. int angiol 2008;27:193-219. 7. palfreyman sj, michaels ja. a systematic review of compression hosiery for uncomplicated varicose veins. phlebology 2009; 24:13-33. 8. cataldo jl, de godoy jm, de barros n. the use of compression stockings for venous disorders in brazil. phlebology 2012;27:33-7. 9. lattimer cr, azzam m, kalodiki e, et al. compression stockings significantly improve hemodynamic performance in post-thrombotic syndrome irrespective of class or length. j vasc surg. 2013;58:158-65. 10. hojensgard ic, stürup h. static and dynamic pressures in superficial and deep vein of the lower extremity in man. acta phys. scandinav 1952;27:49-67. 11. neglen p, raju s. ambulatory venous pressure revisited. j vasc surg. 2000;31:1206-13. 12. meissner mh, moneta g, burnand k, et al. the hemodynamics and diagnosis of venous disease. j vasc surg 2007;46:4s-24s. 13. gayliss h. some observations on peripheral venous pressure using a non-invasive technique: a preliminary report. br j surg 1975;62:259-63. 14. bartolo m. phlebodopplertensiometry, a non-invasive method for measuring venous pressure. folia angiol 1977;25:199-203. 15. bartolo m, nicosia pr, antignani pl, et al. noninvasive venous pressure measurements in different venous diseases. angiology 1983;34:717-23. 16. nicolaides an. investigation of chronic venous insufficiency: a consensus statement. circulation 2000;102:e126-63. 17. fronek a. noninvasive diagnostics in vascular disease. new york: mcgraw-hill book; 1989. pp 11-85. 18. schultz-ehremburg u, blazek v, fronek a, et al. venous photophlethysmography and invasive venous pressure measurement a multicentric comparative study. part 2: results. in advances in computer-aided noninvasive vascular diagnostics. proceedings of the 9th international ymposium cnvd 2000. january 21-23, 2000. bratislava, dusseldorf: vdi-verlag gmbh; 1994. pp 45-52. 19. spina t, corcos l, peruzzi g, et al. the value of doppler venous pressure index in the diagnosis of chronic venous insufficiency of the lower limbs. int angiol 2009;28:92. no n c om me rci al us e o nly hrev_master veins and lymphatics 2017; volume 6:6636 a new compression pressure measuring device yung-wei chi vascular center, university of california, davis, ca, usa introduction the sine qua non of compression therapy is interface pressure yet it is rarely measured in the routine care of patients. in 2006, the first international compression club consensus on an ideal sensor to measure interface pressure was published.1 in 2008, the international union of phlebology (iup) published a consensus document stating the lack of interface pressure measurement was a knowledge gap in compression therapy.2 the 2014 society for vascular surgery and american venous forum (svs-avf) clinical guideline on venous ulcer care reiterated the lack of pressure measurement as a deficiency in the evidence to compression therapy.3 moreover, in the 2015 iup response to the svs-avf guideline, targeted pressure ranges were recommended for specific disease state.4 yet interface pressure is seldom measured in routine ulcer care leaving most if not all compression therapy, arbitrary. after a decade from the initial call to action, manometer based devices such as picopress® (microlab, padua, italy) and kikuhime® (meditrade, soro, denmark) are commercially available. unfortunately, neither was widely adopted or used. the fact is the lack of this rudimentary information has raised concern from many healthcare and scientific entities including the agency for heathcare research and quality (ahrq), the think-tank for u.s. healthcare policy. in the jun 2016 ahrq draft on technology assessment report on treatment strategies for patients with lower extremity chronic venous disease, it clearly indicated two deficiencies related to compression therapy i) optimal pressure dosing and ii) duration of compression therapy. all existing and future interface pressure measuring devices will need to satisfy these two paucities. materials and methods from a technological stand-point, the mechanical properties of manometer, piezoresistive and capacitive based sensing characteristics are vastly different with pros and cons to each. in our work, a novel patented microfluidic capacitive (iontronic) sensor was developed, and was compared to the mechanical performance of picopress®5 according to pressure cuff based cylinder model described previously by partsch et al.6 results after 10,000 cycle runs, the iontronic sensor demonstrated stability in both mechanical response and repeatability. in sensing characterization, both the iontronic sensor and picopress® showed complete overlap of pressure graphs against the standard pressure cuff model, p>0.05 (figure 1).5 in other words, the 2 sensors had the same sensing performance or efficacy. conclusions manometer based interface pressure measuring devices are available but future device innovation should focus on accuracy, versatility, user-friendliness, wireless communication and data collection including compliance tracking to ensure seamless adoption by healthcare providers and patients. references 1. partsch h, clark m, bassez s, et al. measurement of lower leg compression in vivo: recommendations for the performance of measurements of interface pressure and stiffness: consensus statement. dermatol surg 2006;32:224-32; discussion 33. 2. partsch h, flour m, smith pc; international compression c. indications for compression therapy in venous and lymphatic disease consensus based on experimental data and scientific evidence. under the auspices of the iup. int angiol 2008;27:193-219. 3. o’donnell tf jr, passman ma, marston wa, et al. management of venous leg ulcers: clinical practice guidelines of the society for vascular surgery (r) and the american venous forum. j vasc surg 2014;60:3s-59s. 4. mosti g, de maeseneer m, cavezzi a, [veins and lymphatics 2017; 6:6636] [page 31] correspondence: yung-wei chi, vascular center, university of california, davis, ca, usa. e-mail: ywchi@ucdavis.edu this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright y.w. chi, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6636 doi:10.4081/vl.2017.6636 figure 1. iontronic sensor versus picopress® performance characterization. no n c om me rci al us e o nly conference presentation et al. society for vascular surgery and american venous forum guidelines on the management of venous leg ulcers: the point of view of the international union of phlebology. int angiol 2015;34:202-18. 5. li r, nie b, zhai c, et al. telemedical wearable sensing platform for management of chronic venous disorder. ann biomed eng 2016;44:2282-91. 6. partsch h, mosti g. comparison of three portable instruments to measure compression pressure. int angiol 2010;29:426-30. [page 32] [veins and lymphatics 2017; 6:6636] no n c om me rci al us e o nly hrev_master veins and lymphatics 2018; volume 7:7069 [page 2] [veins and lymphatics 2018; 7:7069] ultrasonographic, quantitative comparison of lower extremity lymphedema versus normal control. technical note with case reports vanessa lôbo de carvalho,1 sergio xavier salles-cunha,2 filipe amorim braga,3 rita de cássia dos santos moreira,4 joyce annenberg araújo dos santos,4 thayná lucilla santos de araújo,4 guilherme benjamin brandão pitta5 1state university of health sciences of alagoas (uncisal); and biotechnology and health, northeast network in biotechnology (renorbio), maceió, al, brazil; 2visiting professor, ultrasonographer, maceió, al, brazil; and research consultant, itanhaém, sp, brazil and jacksonville beach, fl, usa; 3vascular surgeon, ultrasonographer, arapiraca, al, brazil; 4physiotherapy, university center tiradentes, maceió, al, brazil; 5northeast network in biotechnology (renorbio); federal university of rio grande do sul (ufrgs); and state university of health sciences of alagoas (uncisal), maceió, al, brazil abstract characterization of tissue by ultrasonography (catus) is a modern-day research endeavor intended to improve visual perception and image quantification. visual perception increases with color. quantification focuses on pixel echo brightnesses. a previously presented case report demonstrated reappearance of lymphatic channels a few days after manual drainage. ultrasonographic images (us) of lymphatic leg and foot were quantitated and compared to a normal extremity based on proportions of pixels in specific brightness intervals. anatomy evaluated included control-subcutaneous and lymphatic compartments. us with 256 brightness levels were obtained at the proximal, mid and distal leg and foot. control and lymphatic gray scale medians (gsm) and histograms were compared using t-test and chi-square statistics. average gsm was 97±9 (sd) (82-114, n=12 images) for control, greater than 51±15 (24-69, n=12) for lymphedematous leg/foot (p<0.001). control had >99% of pixels with brightness in the muscle-fiber range (41-196), in contrast to 62% for the lymphatic extremity (p<0.001). lymphedema averaged 7%, 3%, 15% and 14% of pixels in blood, blood/fat, fat and fat/muscle-like regions (0-4, 5-7, 8-26, 2740 brightness intervals). such regions were visually interpreted as lymphatic channels or lakes. visual perception by colorization is subjective, but most people perceives details better, for example, during the day than at night. furthermore, us images have 16 times more shades of gray, 256, than that perceived by the human visual system, 16 on average. colorization improved perception of lymphatic channels and lakes by transforming blood echoes into red and lymphatic liquid with echoes similar to fat into yellow. pixel proportions in low brightness intervals were higher in the lymphatic than in the normal extremity. lymphedema severity was quantified. the catus technique may be used to monitor treatment effects or disease evolution. introduction the utility of ultrasonography (us) to describe lymphedema, in particular of the lower extremity, has been demonstrated in a variety of ways.1-8 we have shown the short duration of manual drainage by using a technique being known as characterization of tissue by ultrasonography (catus).9 catus is an expansion of lal’s pixel distribution analysis of the carotid plaque.10 bmode echogenicity intervals were defined for blood, fat, muscle, fiber and calcium, according to levels 0-4, 8-26, 41-76, 112196 and 211-255 for an us image having 256 brightness amplitudes. the gray scale median (gsm) is a single number used to represent an anatomic region. a multi-center study demonstrated, for example, that carotid plaques with gsm < 25 have a high risk of stroke during stenting.11 catus has been applied to analyze: i) venous thrombi;12-15 ii) normal, abnormal and transplanted kidneys;16-18 iii) aneurysms;19 iv) peripheral arterial disease;20 and v) lymphedema,9 in addition to the carotid plaques.21,22 this manuscript is a fundamental description of the technique applied to a comparison between us images of: i) the leg and foot of a traditional lymphedematous lower extremity versus; ii) a control type, normal limb (figure 1). materials and methods us images were obtained at the medial aspect of the leg and dorsum of the foot. the proximal-upper, mid and distal-lower aspects of the leg were imaged. a mindray 5 instrument and a 8-12 mhz linear transducer were employed. a peripheral vein set up used to study superficial venous reflux was employed for all images. the original leg venous set-up of the instrument was adapted by one of the authors. usually, a instrumental venous set-up is designed to image femoropopliteal veins. the co-author re-selected items such as frequency range (8-12 mhz), shallow depth, gain according to his visual perception (g60 for his instrument), frame rate at 16, and dynamic range at 70 to optimize his imaging of peripheral, superficial veins. such peripheral veins included saphenous veins and related tributaries and perforating veins. another coauthor selected this set-up for this investigation to image subcutaneous, superficial compartments in the leg. practically, the correspondence: vanessa lôbo de carvalho, state university of health sciences of alagoas (uncisal); and biotechnology and health, northeast network in biotechnology (renorbio), rua professor manoel coelho neto 201, jatiúca, maceió, al, cep 57036710, brazil. e-mail: ftvanessa1981@gmail.com key words: lymphedema; ultrasonography; brightness quantification. acknowledgments: we thank arthur ramos hospital personnel, maceio, al, for allowing patient recruitment and ultrasound testing in hospital premises. contributions: vlc, design, patient recruitment, data collection, data analysis, manuscript writer-reviewer; sxsc, design, data collection, ultrasonographer, data analysis, manuscript writer; fab, design, medical consultant, ultrasonographer, vascular laboratory director, manuscript reviewer; rcsm, jaas, tlsa, patient recruitment, patient-care, ultrasound assistance, data collection, manuscript comments; gbbp, design, laboratory director, research director, manuscript reviewer. conflict of interest: the authors declare no potential conflict of interest. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright v. lôbo de carvalho et al., 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7069 doi:10.4081/vl.2018.7069 no n c om me rci al us e o nly article [veins and lymphatics 2018; 7:7069] [page 3] set-up used was acceptable to two ultrasonographers among the authors. depths were distinct1 between control, 1.5 cm, and lymphatic leg, 4.5 cm, due to the larger volume of the lymphedematous tissue. recalibration for uniformity was performed for each catus analysis using black as zero and similar fascial echoes or focus arrow as 200. the software program required redefinition of the 0 and 200 brightness levels. lal’s original version used blood and arterial adventitia for a 0190 scale.10 this application was not arterial and did not have standard arterial blood or adventitia as references. a distinct brightness had to be selected for the new 200 brighness. the author performing the catus analysis trusted the original images as representatives of the subjects’ conditions and opted for references that did not alter significantly the original images. catus was performed in anatomic compartments according to the analyst decision-making. normal control images represented the subcutaneous tissue. the depth interval 0.1 to 0.6 cm encompassed all but one image analyzed. patient´s image represented regions with lymphatic channels and/or lakes. average depth of a rectangular region analyzed was 0.5 cm to 2.2 cm. the width encompassed most of the transducer imaging width available. figure 2 demonstrates the versatility of a personalized program showing: i) lal’s criteria; ii) an equal interval-based echo subdivision; and iii) an expanded lal-based tissue subdivision with 14 intervals: non-echogenic, hypoechogenic i, ii, iii and iv, echogenic i to iv, hyper-echogenic i to iv and saturated. the later was used for control-lymphedema comparison. artificial colors were selected based on the analyst’s perspective. percentages of pixels were calculated for each interval. continuous brightness histograms, gsm, bar histograms and color imaging were part of the report. data from 12 images were available for analysis both of the control subject (right and left) and the lymphedematous extremity. gsm were compared by student’s t-test and histogram pixel percentage data were compared using chi-square statistics available with excel. results in general, average gsm was 97±9 (sd-standard deviation) (minimum=82maximum=114) for control, greater than 51±15 (24-69) for the lymphedematous leg/foot (p<0.001). control had >99% of pixels with brightness in the muscle-fiber range (41-196), in contrast to 62% for the lymphatic extremity (p<0.001). lymphedema averaged 7%, 3%, 15% and 14% of the pixels in blood, blood/fat, fat and fat/muscle-like regions (0-4, 5-7, 8-26 and 27-40 brightness intervals). the lowest gsm values were obtained in the foot of either subject. as a technical note, the new brightness 0, based on a black region of the image, was the same for all 24 images. the new 200 brightness averaged 4% higher for the control images, 203, versus 194 for the lymphedematous extremity. discussion this report described how the catus technique can be useful to distinguish echogenic differences between a lymphedematous extremity and a control limb. this initial analysis suggested that additional research could be performed to quantitate lymphedema and to follow lymphedema treatment or progression of disease. it also opened the opportunity to study other types of edemas in the leg or even in the upper extremity. in particular, differences were demonstrated based on the presence or normal absence of lymphatic channels or lakes as shown in figure 3. our poster suggested that manual drainage sequence could be optimized by ultrasound observations.9 a reviewer, however, also commented that fibrosis and hyper-echogenicity should be better to quantitate lymphedema worsening. indeed, figure 4 probably indicates that the upper leg of this patient is in worse condition than the lower leg or foot. our yet to be reported experience has raised some hypotheses that deserve catus investigation such as: i) channels and lakes are more common in the foot than in the leg; ii) lymphedematous legs also have hyperechogenic regions; and iii) presence versus absence of channels may determine better or worse response to treatment. fibrosis in cutaneous, subcutaneous and superficial or deep compartments without regional lymphatic channels should represent worst-case condition. volumetric changes of the subcutaneous and subfacial, muscular compartments have been demonstrated long time ago.1 us images of dilated lymphatic channels have been published for conditions such as lymphatic flow obstruction.2 worms moving in us images of the lymphatic tract, the filaria dance sign, has been an impressive finding.3 visual impressions by experts allowed semi-quantitative analysis of skin and superficial compartments.4-6 elastography figure 1. photographies of control and lymphedema extremities and corresponding ultrasound images. the continuous histograms show differences in echogenicity among two large anatomic regions. actual comparative analysis was restricted to subcutaneous control compartment and lymphatic compartment with channels and lakes. no n c om me rci al us e o nly article [page 4] [veins and lymphatics 2018; 7:7069] has been applied to lymphedema.7-8 catus performed under compression conditions could provide data comparable to elastographic information. echogenicity and artificial colorization of edematous conditions may be a tissue research trend in the following decade.23 gray scale analysis, in general, is a growing field, particularly in research.24 as an example, a peripheral venous thrombus with a hyperechogenic rock at the tip may be a more dangerous embolus than a hypoechogenic thrombus.12 also, hyperechogenic chronic venous obstruction may be permeated with trapped blood or hypoechogenic new thrombi causing localized symptoms for years. these opinions corroborate investigations that recommend ultrasound as an figure 2. examples of characterization of tissue based on ultrasound (catus). from reader’s left to right: i) lal’s pixel distribution based on blood, fat, muscle, fiber and calcium; classification default occurred in 32% of pixels with brightness in between such intervals; ii) pixel distribution in intervals with 20 brightness values; and iii) expanded lal’s classification showing default intervals and subdivision of muscle and fiber intervals. artificial colorization was arbitrary and may vary according to the observer’s visual preferences. brightness intervals may be defined for each individual application. no n c om me rci al us e o nly article [veins and lymphatics 2018; 7:7069] [page 5] figure 3. normal control (reader’s left) and lymphedematous leg comparison. from top to bottom: i) original ultrasound image; ii) artificial colorization; iii) bar graph histogram representing proportions of pixels according to brightness intervals; iv) table with percentages of pixels according to color intervals. brightness associations: red-blood, yellow-fat, green-muscle, brown-muscle/fiber, light purple-fiber. lymphedema presented enlarged lymph channels supposedly filled with blood plasma and/or fatty liquids. no n c om me rci al us e o nly article [page 6] [veins and lymphatics 2018; 7:7069] indicator of treatment postures.25 catus was programmed to provide the user with alternatives and knowledge on how the analytical process works. it permits specific analysis of a measurement in question. data collection, however, must avoid variability. similar set up and similar us knobs must be uniform for comparisons. re-scaling does not compensate for all variability issues. a simple application would be to follow the same patient with the same technique. catus is a subset of catim, characterization of tissue by imaging. photographic catim of diabetic and venous ulcers have been published.26,27 catus improves perception by artificial colorization and permits quantitative analysis based on percentages of pixels in specific brightness intervals. the physiological logic behind catus-catim is that the human brain perceives color better than gray, like the expression night and day. furthermore, the human eye only distinguishes, on average, 16 gray levels while an ultrasound image usually have 16 times more tons of gray, 256.28 conclusions the catus technique allowed quantitative comparison showing lower echogenicity in the lymphatic extremity as compared to control. lower echogenic regions were perceived as channels and/or lakes. research is still evolving in several areas including edema. artificial colorization may improve perception pending individual tendencies. pixel distribution percentages upgrade imaging analysis by quantification. consistent us knobology and patient follow-up under similar conditions are recommended. references 1. doldi sb, lattuada e, zappa ma, et al. ultrasonography of extremity lymphedema. lymphology 1992;25:12933. 2. drinan kj, wolfson pm, steinitz d, et al. duplex imaging in lymphedema. j vasc technol 1993;17:23-6. 3. amaral f, dreyer g, figueredo js, et al. adult worms detected by ultrasonography in human bancroftian filariasis. am j trop med hyg 1994;50:753-7. 4. suehiro k, morikage n, murakami m, et al. significance of ultrasound examination of skin and subcutaneous tissue in secondary lower extremity lymfigure 4. lymphedematous leg. from reader’s left to right: original ultrasound image, artificial colorization and continuous histogram based on pixel brightness. brightness associations: red-blood, yellow-fat, green-muscle, brown-muscle/fiber, light purple-fiber. upper leg image had a higher gray scale image (gsm) value. image at the bottom demonstrates worst case condition, or most hypo-echogenic region, observed in the foot. no n c om me rci al us e o nly article [veins and lymphatics 2018; 7:7069] [page 7] phedema. ann vasc dis 2013;6:180-8. 5. suehiro k, morikage n, murakami m, et al. subcutaneous tissue ultrasonography in legs with dependent edema and secondary lymphedema. ann vasc dis 2014;7:21-7. 6. suehiro k, morikage n, murakami m, et al. a study of increase in leg volume during complex physical therapy for leg lymphedema using subcutaneous tissue ultrasonography. j vasc surg venous lymphat disord 2015;3:295-302. 7. suehiro k, morikage n, murakami m, et al. skin and subcutaneous tissue strain in legs with lymphedema and lipodermatosclerosis. ultrasound med biol 2015;41:1577-83. 8. suehiro k, kakutani h, nakamura k, et al. immediate changes to skin and subcutaneous tissue strains following manual lymph drainage in legs with lymphedema. ann vasc dis 2016;9:30-4. 9. salles-cunha sx, silveira saf, menezes fh. case report: ultrasound virtual histology to grade treatment of lower extremity lymphedema. poster presented at the 36th society for vascular ultrasound annual meeting, washington, dc, june 7-9, 2012. 10. lal bk, hobson rw ii, pappas pj, et al. pixel distribution analysis of bmode ultrasound scan images predicts histologic features of atherosclerotic carotid plaques. j vasc surg 2002;35:1210-17. 11. biasi gm, froio a, diethrich eb, et al. carotid plaque echolucency increases the risk of stroke in carotid stenting: the imaging in carotid angioplasty and risk of stroke (icaros) study. circulation 2004;110:756-62. 12. salles-cunha sx. duplex scanning for acute venous thrombosis. in: peter gloviczki, ed. handbook of venous disorders, guidelines of the american venous forum, 3rd ed. london: edward arnold, publisher; 2009. pp 129-41. 13. cassou-birckholz mf, engelhorn ca, salles-cunha sx, et al. assessment of deep venous thrombosis by grayscale median analysis of ultrasound images. ultrasound q 2011;27:55-61. 14. barros fs, sandri jl, prezotti bb, et al. pulmonary embolism in a rare association to a floating thrombus detected by ultrasound in the basilic vein at the distal arm. rev bras ecocardiogr imagem cardiovasc 2011;24:89-92. 15. salles cunha sx, varjão de oliveira guimaraes af. complementary role of thermography in the diagnosis of subclavian vein thrombosis: case report. poster presented at 40th congress of the brazilian society of angiology and vascular surgery, florianópolis, sc, september 30 to october 5, 2013. 16. valiente engelhorn al, engelhorn ca, salles-cunha sx. initial evaluation of virtual histology ultrasonographic techniques applied to a case of renal transplant. j vasc ultrasound 2015;39:142-4. 17. valiente engelhorn al, engelhorn ca, salles-cunha sx, et al. ultrasound tissue characterization of the normal kidney. ultrasound q 2012;28:275-80. 18. valiente engelhorn al, engelhorn ca, salles-cunha sx. ultrasonographic tissue characterization of kidneys in patients with unilateral renal artery stenosis. j vasc ultrasound 2016;40:705. 19. salles-cunha sx. technical note: ultrasonographic evaluation of aortic aneurysms treated with endoprosthesis. j vasc bras 2012;11:150-3. 20. marks na, ascher e, hingorani ap, et al. gray-scale median of the atherosclerotic plaque can predict success of lumen re-entry during subintimal femoral-popliteal angioplasty. j vasc surg 2008;47:109-16. 21. menezes fh, silveira tc, silveira saf, et al. preliminary comparisons between in vivo ultrasonographic virtual histology and histopathological findings of endarterectomized carotid plaque. j vasc bras 2013;12:193-201. 22. barros fs, pontes sm, prezotti bb, et al. floating thrombus in the internal carotid artery: surgical planning defined by vascular ultrasound. arq bras cardiol: imagem cardiovasc 2013;26:335-40. 23. ueda-luchi t, ohno n, miyati t, et al. assessment of the interstitial fluid in the subcutaneous tissue of healthy adults using ultrasonography. sage open medicine 2015;3:2050312115613351. 24. harris-love mo, seamon ba, teixeira c, ismail c. ultrasound estimates of muscle quality in older adults: reliability and comparison of photoshop and imagej for the grayscale analysis of muscle echogenicity. peer j 2016;4:e1721. 25. prandoni p, prins mh, lensing aw, et al. aesopus investigators. residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. ann intern med 2009;150:577-85. 26. pereira vhh, costa filho em, santos fta, et al. photographic image tissue characterization of the ulcerated diabetic foot during treatment: technical note. j vasc bras 2013;12:303-7. 27. santos fta, rocha ca, salles-cunha sx, et al. tissue characterization by photographic imaging during treatment of chronic venous ulcer: technical note. j vasc bras 2015;14:177-81. 28. beach kw, paun m, primozich jf. principles and instruments of diagnostic ultrasound and doppler ultrasound. in: aburahma af, bergan jj, eds. noninvasive vascular diagnosis: a practical guide to therapy, 2nd ed. london: springer-verlag; 2007. pp 27. no n c om me rci al us e o nly hrev_master veins and lymphatics 2012; volume 1:e10 [veins and lymphatics 2012; 1:e10] [page 43] hot topics in venous ulcer treatment: an international survey stefano ricci,1 francesco maria serino,1 moro leo,1 fausto passariello2 1department of geriatrics, university “campus bio-medico”, roma; 2centro diagnostico aquarius, napoli, italy abstract compression is the most effective treatment to promote skin ulcer healing, although there are as many different methods of performing a leg compression as the number of phlebologists, each one having personal tricks, solutions, habits. conversely, though dressings may be done in different ways, none is considered the standard solution. we asked few (18) questions to physicians involved in this field, in italy and abroad, looking for some common feature. the analysis of 100 replies indicated the average treatment: compression made by multilayer bandage when edema is present, knee long stocking when edema is removed, mostly based on patient’s agreement. escharectomy should be done when ulcer bed is covered by necrotic tissue. advanced wound care is used, with dressing changed several times a week. for highly exuding ulcers, a specific dressing is used or frequent changing is performed. the treatment in early stage of disease is done by the physician while subsequently the dressings may be performed by the patient himself, nurses or doctors. usually no medical treatments are associated. the cost of a single dressing is often lower than 10 euro, without any reimbursement. the compression devices aren’t reimbursed as well. the expected compression pressure is 30/40 mm hg. daytime compression is not reduced at night-time. the patient is always invited to walk. the same compression is used if the abpi is <1. however the survey shows that several variations in the cookbook may occur, sometimes even contradictory. introduction there are many patients with venous ulcer and, at the same time, a relatively high number of practitioners taking care of these patients. many cases are treated by nhs services, but a great number are very well managed in private practice setting. for such a socially relevant problem, the italian heath care system does not provide reimbursement for compression hosiery and dressings easily leading to an under treatment of this disease. furthermore, this topic is particularly neglected in schools of medicine, being committed to teachers’ good willing. these are some of the reasons for the extreme variability of venous ulcer treatments in our country. although compression is considered the most effective therapy to achieve ulcer healing all over the world, there are probably as many different methods of performing a leg compression as the number of phlebologists, each one having personal tricks, solutions, habits. conversely, although dressings may be done according to different modalities, none is considered the standard solution. guidelines and consensus papers concerning compression for ulcers treatment suggest generic principles but confirm the lack of a common management of the different aspects of treatment (level and methods of compression, ulcer dressing, medical treatment, frequency of dressing, etc.). trying to find some common features of ulcer treatment we asked few (18) short questions to some physicians involved in this field, in italy and abroad, with particular attention to costs and reimbursements. materials and methods a questionnaire was submitted by vasculab mailing list in occasion of the international vasculab event compression 2012, sorrento, italy and successively sent by email to 500 doctors involved in the field. ninety-nine replies have been considered as valid: 63 from italy, 9 from usa, 3 from united kingdom, 2 from brazil, france, germany, hungary venezuela, 1 from argentina, australia, belgium, chile, colombia, el salvador, india, moldova, poland, romania, spain, sweden, switzerland, turkey (appendix). while the number of italian respondents may be considered sufficient to represent a sample of italian caregivers, the number of international participants is obviously insufficient to be representative of their countries, but may still be useful for a general comparison of the different habits in the cookbook. questions and answers question 1: how is the compression performed when the leg affected by an ulcer has an edema? a. by a long stretch bandage (elastic bandage) b. by a short stretch bandage (ideal type bandage) c. by a multi layers bandage d. by an adhesive bandage e. by a knee lenght stocking (k1,k2,k3) f. other a shown in figure 1, 52% of responders perform a multilayer bandage; 20% prefers a short stretch bandage; 4% use adhesive bandages, 3% unna boot and 1% a cohesive bandage. 12% of physician prefers elastic compression (stockings 4%, long stretch bandages (8%). short stretch compression is the most employed compression when an edema is present for its high working pressure.1,2 multilayer bandage is widely appreciated for its adaptability to any shape, well fitting to the progressive volume reduction of the leg and highly effective.1 these systems generally combine padding and elastic or inelastic materials and are widely accepted as being effective in achieving strong compression. also a short stretch bandage may be very effective (high working pressure), with the advantage of being washable and reusable but with disadvantage of loosing quickly its strength as the edema reduces, thus requiring more frequent repositioning, in order to prevent bandage slippage.2 the adhesive bandage loose pressure as well but do not slip, even if they cannot be reutilized. three responder prefer unna boot correspondence: stefano ricci, corso trieste 123, 00198 roma, italy. tel. +39.06.8551523. e-mail: varicci@tiscali.it key words: compression, venous ulcers, wound healing, treatments survey. contributions: sr, concept and design, manuscript final approval; fs, data acquisition and analysis, manuscript revision; lm, manuscript revision; fp, data acquisition, manuscript revision. conflict of interests: the authors declare no potential conflict of interests. conference presentation: the results of this survey were shown at the international vasculab event “compression 2012”, held in sorrento, italy in may 11th, 2012. “vasculab” is a phlebology forum (www.vasculab.it) organized by one of the authors (fp). received for publication: 31 october 2012. revision received: 19 december 2012. accepted for publication: 7 january 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s. ricci et al., 2012 licensee pagepress, italy veins and lymphatics 2012; 2:e10 doi:10.4081/vl.2012.e10 no nco mm er cia l u se on ly that has similar behavior.2 the long stretch bandage, although elastic (i.e. able to adapt to the volume reduction) is less effective for its reduced stiffness and for possible skin damage if applied with strong pressure;2 knee stockings are probably preferred as easy to use, but they cannot adapt to the circumferential reduction of the limb unless using progressive smaller sizes, with disproportioned costs. question 2: how is the compression performed when edema is reduced? a. by a long stretch bandage (elastic bandage) b. by a short stretch bandage (ideal type bandage) c. by a multi layers bandage d. by an adhesive bandage e. by a knee long stocking (k1, k2, k3) f. other (specify inside the final open space) after edema resolution, the preference is in part transferred from inelastic compression (still used by about 40% b+c+b+some of f) to knee stocking (49%) or other elastic tools (2% a +2% f) (figure 2). question 3: if you replied “e”, please specify the rationale of your choice... a. ease for putting on b. efficacy c. costs d. comfort e. patient’s agreement f. absence of exudates g. absence of edema h. other (specify inside the final open space) for responders favoring of a compression performed by a knee stocking (figure 3), the choice is mostly due to patients compliance (40%) and comfort (6%) or, secondarily (15%), because easier to put on (thus considered more comfortable), and only 15% because more effective. in consensus papers, hosiery is not considered the first choice even if some studies have claimed elastic stocking being as effective as inelastic bandages.2,3 due to the lack of padding it is not considered a practical option for patients at high risk of pressure damage, with large ulcers or high amount of exudates.2 strong compression hosiery is indicated as a first-line treatment for patients with small, uncomplicated ulcers, who wish to self care requiring daily skin care, or find bandages too hot or bulky; self application using an application device is an advantage but can be occasionally difficult.2 the reply: easier to put on (15%) seems not considering the fact that a compression stocking needs to slip over on a painful area compared to apply a bandage. a two-layer system, chosen by two responders, may be the good idea: usually the first stocking (10-24 mmhg) holds the dressing in place and the second one (20-30 mmhg) can be removed at night, with a total pressure that may go up to 40 mmhg.2 multi layer bandaging exerting strong compression is generally suggested for the treatment of venous leg ulcers.4 according to a cochrane review in ulcer treatment the higher the pressure the higher the ulcer healing rate.5 this seems best achieved in our survey by short stretch bandages (18%), adhesive bandages (9%) or multi layer bandages (6%) elastic (long stretch) bandaging (2%) seems the less suitable for achieving high pressures for long periods due to the risk of pressure skin damage and for the higher resting pressure when the patient is laying down.2 question 4: an escharectomy should be done… a. always b. when necrotic tissue is present c. when an infection is present d. when pain is present e. other (specify inside the final open space) in our survey 93% of responders make a debridement, but 20% who does always a debridement shows a quite aggressive attitude (figure 4). it would have been interesting to study the general setting (hospital versus doctor’s office) of these practitioners and also their relationship with the private practice. interestingly, some few colleagues never find necessary to perform the ulcer debridement providing that compression is sufficiently effective. one colleague suggests eliminating the bacterial biofilm by laser 808 after coloring the wound by methylen blue. necrotic tissue over the wound is rare in venous ulcers, more frequent in case of ischemic pathophysiology. initial debridement is required to remove necrotic tissue, excessive bacterial burden, and dead and senescent cells burden that can all inhibit wound healing.6 care givers can choose among several debridement methods including sharp, enzymatic, mechanical, biological, or autolythic. more than one debridement method may be appropriate.6 sharp debridement often is the preferred. however, the method debridement may depend on the status of the wound, the ability of the care giver, the general condition of the patient, and the professional licensing restrictions.6 excessive debridement can result in a reactivation of the inflammatory process with a consequent influx of inflammatory cytokines.6 to our best knowledge, there are no studies, which compare debridement with no debridement in the management of venous ulcers. there is a lack of data to clarify whether mechanical, chemical or bio-surgical methods are most appropriate in this patient group.4 question 5: which is your treatment approach to the wound care? a. advanced wound care b. normal saline solution c. antibiotics d. antiseptics e. steroids f. other (specify inside the final open space) as shown in figure 5, 60% of responders (a+f) use advanced wound dressings or an empirical mixture of topical agents suggested by anecdotal experience (e.g. silver ions, colloidal gels, sugar or honey, vaseline, zinc oxide, soap washings), often citing time principles.7 normal saline is used by about 30% of caregivers. local antibiotics, antiseptics and steroids are not frequently employed. from the patients perspective the local ulcer treatment, more than bandaging, is the most important aspect of venous ulcer treatment, as they see the ulcer dressing the real source of healing. often the same attitude may be found in practitioners, believing that some specific dressing may accelerate healing. this may explain the variety of topical agents suggested. guidelines and reviews for wound treatments6-10 suggest that in any case dressing should be cost effective. cost-effectiveness must be taken into maximal consideration; the risk could be that patients or nurses preferences push into using dressings slightly more effective but much more expensive.9 a modern dressing should maintain a moist wound environment to promote autolythic debridement, cell migration and matrix synthesis so accelerating the wound.6 moist wound environment also reduces pain, while dry dressings are considered harmful and can cause dehydration of the wound.7 a wide variety of dressings is available, but the evidence for their effectiveness is controversial so that the use of dressings is not always recommended.9,10 sugar or honey, suggested by three respondents could deserve some interest, since it combines efficacy and low cost.11,12 question 6: how frequently is the dressing changed on the average? a. when required b. every day c. several times a week d. once a week e. other (specify inside the final open space) about 60% of responders change the dressing quite frequently (a+b+c, + some e), usually because of exudation, pain or smell. most of those who chose the open answer (e) seems to prefer a long change interval when possible; about 1/4 of the responders prefer weekly dressing change interval. interestingly, about 20% (b+e) chose a daily changing (figure 6). article [page 44] [veins and lymphatics 2012; 1:e10] no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e10] [page 45] figure 1. methods of compression when the leg affected by an ulcer has an edema. figure 4. cases in which an escharectomy should be performed. figure 5. treatment approaches to wound care. figure 6. average frequency of changing dressing. figure 2. methods of compression when edema is reduced. figure 3. response in favor of compression with knee stocking. no nco mm er cia l u se on ly article [page 46] [veins and lymphatics 2012; 1:e10] peri-wound maceration and continuous skin contact with wound exudates can enlarge the wound and impede healing, requiring dressing change; however, when granulation tissue is achieved, the frequency of dressing change can be reduced to one per week (or even more) to allow a faster wound re-epithelization.6 in fact, the dressing changing causes a temperature fall of the wound, hampering cellular mitosis for at least 16 h. this imply that frequent dressing change will favor debridement but long intervals between dressings will favor granulation tissue and re-epithelization.6 furthermore, daily medication is hardly managed in an office wound healing setting, due to excessive patients travelling costs.5 on the other hand, patients can be treated at home, but with higher costs for the community or the patients itself. question 7: when heavy exudation is present, what is the best therapeutic option? a. bed rest b. frequent changes of dressing c. specific dressing d. medical therapy e. other (specify inside the final open space) this question is partly related to the previous one (no. 6) since the frequent dressing change may be a method to control wound exudation (45% b+e); a special dressing is proposed by 32% of responders (presumably alginate based dressings). bed rest is the best choice for about 18% of respondents, most in association to the other methods (figure 7). frequent dressing is obviously the simplest solution; however in some cases bed rest (with leg elevation if possible) may be prescribed, especially during early phases. even if bed rest may be considered inappropriate in a patient affected by venous insufficiency (due to stasis, limited muscle pumping, slow metabolism, limited breathing, etc.), it helps to eliminate liquid from the distal limb, reducing the need of frequent dressing change and accelerating the wound healing process.13 question 8: who performs the initial treatment… a. the patient (or a relative) b. a doctor c. a nurse usually the initial treatment is done by a doctor (90%), rarely by a nurse (6%), but curiously, also by patients (4%), probably meaning that patients do the first attempts (figure 8). question 9: who performs the successive treatment… a. the patient (or a relative) b. a doctor c. a nurse successive treatment is done by doctors only in 40% of cases, while nurses take over doctors in 43% of cases and patients in 17 % of cases (figure 9a). nurses can do a great job in systems where a good nursing wound care management is organized, which is not frequent in italy. patient’s self treatment (or by his/her relatives) is recommended only when ulcer is nearly healed, and only when the patient has shown a good compliance (figure 9b). a british survey reported that 71% of practitioners are the only responsible for determining the patient’s venous ulcer treatment plan.14 question 10: which medical treatment is usually associated? a. antibiotics b. nsaids c. supplements d. lmwh e. none f. other (specify inside the final open space) as shown in figure 10, 32 % of responders avoid association of a general and a local treatment. antibiotics are the most frequent medical association for 25% (a+f). current prescribing guidelines recommend that antibacterial preparations should only be used in cases of clinical infection and not for bacterial colonization.4 dietary supplements are suggested by 10% of responders, although there is still insufficient evidence to recommend them; lmwh reported by 8%, is generally suggested for microangiopatic ulcers (necrotic angiodermatitis, atrophie blanche).15 question 11: what is the cost of a single dressing (in euro), not including the compression items a. <10 b. <20 c. <30 d. <40 e. ≥50 for most of the responders, the cost of a single dressing is under 20 € (67%) and for 41% even under 10 €, but more than 12% of replies report costs higher than 30 € (figure 11). saline solution and not adhesive gauze seem to be the lowest cost dressings. question 12: is this charge reimbursed or supplied by the sanitary system of your country at a. 100% b. 80% c. ≤50% d. 0 low cost is important when we consider that venous ulcers require several dressing renewal during three months (that is the average the time required to achieve healing in most of cases) and it’s even more important if we consider that more than half of replies report no reimbursement rates, and strongly limited in other 21%. it is amazing that more than 12% of replies report costs higher than 30 € for a single dressing (figure 12). question 13: compression devices (bandages, stockings) are reimbursed by the nhs of your country? a. yes b. yes but… (specify inside the final open space) c. no compression devices reimbursement is reported by 20% of the responders and appears to be possible but with some limitations in 16%. italian responders reported no reimbursement in more than 80% of cases (figure 13a, b). only the bolzano local health system reimburses compression bandages, zinc oxide bandages and compression stockings. moreover, the reimbursement for a compressive bandage in italy is only 8 €..16 it is curious how so an important social problem, involving many subjects (0.1-0.3% of the general population, 1% at 60 years of age, till 5% at 90 years), prevalently belonging to the socially most deprived population, it is so poorly considered by italian nhs, that spends a great amount of resources on venous related diseases (1% of the entire health system budget) without a coherent program.17-19 question 14: what value of pressure (mm hg) at the ankle is expected from your compression treatment? about: a. 20 b. 30 c. 40 d. 50 mm hg the following standard has been suggested recently: mild (<20 mmhg), moderate (≥20-40 mmhg), strong (≥40-60 mmhg), very strong (>60 mmhg).20 pressures ≥40 mmhg are generally recommended for the treatment of venous leg ulcers.21 our survey indicates that 40% of care providers use a strong level of pressure exerted by compression tools. forty-seven percent of responders use a moderate pressure; only 14% of caregivers employ mild compressions, most likely those using knee stockings (figure 14). a sufficient compression pressure seems to be used by the majority according to some consensus and meta-analysis,1-10,16,20 however pressure value is mostly theoretical as is very no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e10] [page 47] figure 7. best therapeutic options in case of heavy exudation. figure 8. who performed the initial treatment. figure 10. associated medical treatments. figure 11. cost of a single dressing (euro), not including compression items. figure 9. who perform the successive treatment. no nco mm er cia l u se on ly article [page 48] [veins and lymphatics 2012; 1:e10] figure 12. percentage of reimbursements by different national health systems. figure 13. percentage of reimbursements of compression devices (bandages, stockings) by different national health systems. figure 14. expected pressure (mm hg) at the ankle from the compression treatment different national health systems. figure 15. differences between day-time and night-time compression treatments different national health systems. figure 16. cases in which the patient is invited to walk. a b no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e10] [page 49] rarely measured.4 furthermore, while compression stockings have a pressure declared by manufacturing company (which correspond to an approximate value on the leg), the pressure of the bandages can be extremely variable only depending on the stretch applied to the bandage itself.3 question 15: is the day-time compression treatment different from the night-time compression treatment? a. yes (specify inside the final open space) b. no as shown in figure 15, 62% of respondents maintain the same compression day and night. of those suggesting a lower compression at night, about half use a double layer ulcer kit, leaving only the inner layer at night (about 1518 mmhg); the same for those using a multilayer bandaging. two replies suggest the use of anti thrombus stockings at night. if the same compression is used day and night without giving discomfort during resting it is presumably made by a short stretch bandages (that have a high working pressure, but a lower resting one) or, alternatively by a low pressure compression with limited effect at rest.20 curiously, this problem has been rarely considered in consensus papers, till now. question 16: is the patient invited to walk? a. always b. if pain less c. in absence of exudation d. never as expected, 90% of survey responders always invite ulcer patients to walk. at the opposite, 10% of caregivers indicate some exceptions, finding that bed rest may be useful to reduce pain (5%) and exudation (5%) when they are particularly intense and can’t be reduced by proper compression (figure 16). patients with chronic venous insufficiency should walk a truism that do not need to be discussed (provided that an adequate compression is administered). muscular venous pumps activation assisted by bandages or stockings, limits venous pooling and normalizes walking pressure, allowing the physiological healing mechanisms. bed rest seems to be a very simple treatment modality for the initial stage of painful or heavily exudating ulcers, allowing reducing the frequency of dressing renewal and the assumption of pain killing medications. according to bassiit was the oldest traditional method for treating ulcers when compression was not available.22 although this option doesn’t fit the modern way of life and consequently it’s rarely practiced, it is very efficient and may still be indicated in specific instances. question 17: when an abi (winsor index) <1 is present, do you apply the same compression? a. yes b. no (specify inside the final open space) when an arterial impairment occurs (abpi<1) 74% of respondents do not change compression methods. most of those (26%) who change compression system suggest abpi<0.5 as cut-off for compression treatment, while few others chose a higher cut-off (<0.7). three participants suggest paying attention to absolute pressure (80-90 mmhg the limit) at the ankle instead of using abpi; another respondent suggests considering post effort abpi. two suggest using only short stretch bandages. some use a lower pressure of 20 mmhg in case of arterial disease. most respondents do not follow traditional scholastic contraindication for compression treatment in limbs with arterial disease. according to a ‘92 consensus document, only critical limb ischemia (ankle systolic pressure ≤50 mmhg and/or a toe systolic pressure of ≤30 mmhg + necrotic lesions or recurrent rest pain) should contraindicate a priori the compression therapy.23 short stretch bandages applied without tension and providing moderate pressure,4 working only during ambulation could probably help even in extreme cases, by elimination of edema, allowing a better oxygen availability to tissues so enhancing arterialvenous gradient.24 question 18: did you like this survey? the last question was: did you like this survey? over 105 forms received 75% replied yes; 16% absolutely yes; 9 % no. like always in these case, the most interesting aspect is the analysis of the reasons why some respondents did not like: 3 responders criticized that the etiology is not specified but the indication venous ulcers was already present in the title; 4 thought that questions were too much generic but this is not easily avoidable in this kind of surveys (2 without comment). conclusions organizing a survey, we tried to cover the most important aspects asking for average behaviors, and in a specific field (the venous ulcer), in a foreseen time of 5 min. the analysis of the respondents is not an indication to how to treat ulcers, but rather to how ulcers are treated in italy, with a small international sample for comparison. experience-based evidences (namely those provided by consensus conferences) give so variable indications on venous ulcers treatment that it is impossible to state which replies are adequate and which are questionable; however some contradictions have been pointed out commenting the respective survey answers. the only solid conclusion is the lack of interest of the italian nhs to the ulcer problem revealed by the limited reimbursements offered for ulcer care, bandages and hosiery, that could be at the origin of an under treatment of the venous insufficiency and its consequences in our country. the research main weakness is related to the small number of participants particularly of other countries that is related to the traditional difficulty of this kind of researches. moreover, few more precise and specific questions could have been of some help (private activity, office versus hospital practice, pressure measurement, etc). this study could be useful as a base in case larger and more accurate surveys should be undertaken. references 1. o‘meara s, tierney j, cullum n, et al. four layer bandage compared with short stretch bandage for venous leg ulcers: systematic review and meta-analysis of randomised controlled trials with data from individual patients. bmj 2009;338:b1344. 2. world union of wound healing societies (wuwhs). principles of best practice: compression in venous leg ulcers. a consensus document. london: mep ltd; 2008. 3. mosti g. elastic stockings versus inelastic bandages for ulcer healing: a fair comparison? phlebology 2012;27:1-4. 4. management of chronic venous ulcers [database on the internet]. scottish intercollegiate guidelines network; 2010. available from: http://www.sign.ac.uk/pdf/ sign120.pdf 5. o’meara s, cullum na, nelson ea. compression for venous leg ulcers. cochrane database syst rev 2009:cd 000265. 6. robson mc, cooper dm, aslam r, et al. guidelines for the treatment of venous ulcers. wound repair regen 2006;14: 649-62. 7. schultz gs, sibbald rg, falanga v, et al. wound bed preparation: a systematic approach to wound management. wound repair regen 2003;11 suppl 1:s1-28. 8. kahle b, hermanns hj, gallenkemper g. evidence-based treatment of chronic leg ulcers. dtsch arztebl int 2011;108:231-7. 9. palfreyman s, nelson ea, michaels ja. dressings for venous leg ulcers: systematic review and meta-analysis. bmj 2007; 335:244. 10. the royal college of nursing (rcn). clinical practice guidelines. the nursing management of patients with venous leg no nco mm er cia l u se on ly article [page 50] [veins and lymphatics 2012; 1:e10] ulcers. london: the royal college of nursing; 2006. available from: http://www. rcn.org.uk/development/practice/clinicalguidelines/venous_leg_ulcers 11. molan pc, betts ja. clinical usage of honey as a wound dressing: an update. j wound care 2004;13:353-6. 12. franceschi c, passariello f. low cost medication for venous ulcer. sugar-honey: an online vasculab survey. acta phlebologica 2009;10:41-4. 13. mancini s. manuale di flebologia. colle val d’elsa: laris editrice; 2009. 14. ertl p. how do you make your treatment decision? prof nurse 1992;7:543-52. 15. ramelet a-a, monti m. phlebology: the guide. amsterdam; new york: elsevier; 1999. 16 . mosti g, mattaliano v, polignano r, masina m. la terapia compressiva nel trattamento delle ulcere cutanee. linee guida. acta vulnologica 2009;7:113-35.[article in italian]. 17. canonico s, gallo c, paolisso g, et al. prevalence of varicose veins in an italian elderly population. angiology 1998;49: 129-35. 18. callam mj, harper dr, dale jj, ruckley cv. chronic leg ulceration: socio-economic aspects. scott med j 1988;33:358-60. 19. campitiello f, lauriello c, eds. percorsi diagnostico-terapeutici ospedale-territorio per la gestione delle ulcere cutanee. torino: aiuc associazione italiana ulcere cutanee; 2012 [in italian]. available from: http://www.aiuc.it/upload/ documenti/9/86/percorsi_diagnostico-terapeutici.pdf 20. partsch h, clark m, mosti g, et al. classification of compression bandages: practical aspects. dermatol surg 2008;34: 600-9. 21. martinez mj, bonfill x, moreno rm, et al. phlebotonics for venous insufficiency. cochrane database syst rev 2005:cd 003229. 22. bassi g. compendio di terapia flebologica. torino: editore mm; 1985. 23. second european consensus document on chronic critical leg ischemia. eur j vasc surg 1992;6 suppl a:1-32. 24. mosti g, iabichella ml, partsch h. compression therapy in mixed ulcers increases venous output and arterial perfusion. j vasc surg 2012;55:122-8. no nco mm er cia l u se on ly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: combined endovenous laser therapy and pinhole high ligation in the treatment of symptomatic great saphenous varicose veins by zhu h-p, zhou y-l, zhang x, yan j-l, xu z-y, wang h, zhao q-m, jing z-p. ann vasc surg 2013. [epub ahead of print].   stefano ricci abstract recanalization and dvt/pe are two major complications of eltv, to prevent them minimally invasive pinhole high ligation (phl) has been added to evlt for the treatment of saphenous vein reflux in 200 patients (254 limbs) from february 2011 to may 2012. sixty-eight of them had concurrent trivex suction for clusters of varicose veins (vv). after conscious sedation and local anesthesia, venous access puncture was made using a seldinger needle under us guidance. the tip of the sheath was placed approximately 1 cm distal to sfj, and the location was marked on the skin. a 600-mm laser fiber was introduced through the sheath and advanced to the skin mark. local anesthesia was achieved by injecting 1% lidocaine around the proximal gsv under us guidance with laser beam marking of the skin. two 2-mm pinholes 1 cm distal to sfj using an ophthalmic scalpel, approximately 5 mm from the laser fiber on each side were performed. a cutting needle with a 2-0 silk suture was passed through the pinholes underneath the gsv, but superficial to the femoral vein, which was confirmed by us. the needle and suture were then passed backward through the original two needle holes, but stayed in the subcutaneous space between the gsv and the skin.. a single knot was made first. reinsertion of the laser fiber was gently attempted, and resistance indicated that ligation of the gsv was satisfactory. us was performed to confirm femoral vein patency, and then two more knots were tied down and buried in the subcutaneous space. if us showed that the femoral vein was captured, the needle and suture were removed and direct pressure was applied for 5 minutes to prevent bleeding. then high ligation of gsv was performed again. evlt was started immediately distal to the pinhole ligation, which was approximately 1 cm distal to the sfj. an 810nm diode laser system was used. in the 68 patients with venous clusters, transilluminated powered phlebectomy (tipp) was performed using a trivex system. after the procedures, compression pads were applied over the treated gsv and venous cluster areas. elastic bandages were placed starting from the foot to the upper thigh. the technical success rate was 100%. total occlusion of gsv was achieved in all treated limbs. there was no gsv recanalization during the 3 20 months of follow-up. no reintervention was needed for any patient. there were no cases of dvt. use of phl avoids the complications after open high ligation, and can be performed within 5-10 min in >90% of patients. comment by stefano ricci this interesting paper appears, curiously, at the same time (the first one just a bit later) to: less invasive ultrasonography-guided high ligation of great saphenous vein in endovenous laser ablation, by okazaki y, orihashi k. ann vasc dis 2013;6:221-5 (already commented in bybliolab 2013) , as in a kind of competition. both try to suggest a method of eliminating dvt and recanalisation, even if, accordingly, these events are relatively rare by evlt. okazaki’s technique, using descamps needle by ultrasound assistance seems sufficiently safe for avoiding additional complications, while hui-peng zhu’s method, using a cutting needle passed blindly around the gsv but superficial to the femoral vein is much more worrying. the same author, in fact, describes the possibility of capturing the femoral vein with the need of removing the suture, but don’t report the number of these inconveniences. it would also be interesting to know how many gsvs were unintentionally transfixed and, consequently, only partially ligated and why 10 % of the patients could not enjoy the method. in any case, the possibility to interrupt the gsv in a simple and fast way may be interesting in many other phlebological situations that could be worthwhile investigating. [top] hrev_master veins and lymphatics 2013; volume 2:e18 [veins and lymphatics 2013; 2:e18] [page 63] the valves and tributary veins of the saphenofemoral junction: ultrasound findings in normal limbs riordon dickson, geraldine hill, ian a. thomson, andre m. van rij department of surgical sciences, dunedin school of medicine, university of otago, dunedin, new zealand abstract in the past the saphenofemoral junction (sfj) for the surgeon was regarded as a simple conduit to be obliterated. with modern ultrasound we can distinguish the components of this complex structure and examine their haemodynamic function and suggest more haemodynamically-focused interventions. despite this, there are no ultrasound studies describing the components of the normal sfj and their haemodynamic significance. patients attending our vascular laboratory with suspected deep vein thrombosis were screened and the sfj in 75 limbs with no physiological or haemodynamic abnormalities were examined. the terminal (tv) and preterminal (ptv) valve morphology and the distance from the sfj were assessed. the number of tributaries and their position relative to these valves was also examined. tv and ptvs were identified on ultrasound in all 75 limbs. tvs were found at a mean distance of 0.4 cm (range 0–1.2 cm) from the sfj. nearly a third of all limbs had at least one tributary vein identified superior to the tv. the greater the distance to the tv, the greater the number of tributary veins one should expect to find superior to the tv. ptv location was more variable. ptvs were identified at a mean distance of 3.1 cm (range 0.4–8.7 cm), giving rise to a large number of configurations of tributary veins in the intervalve space. this study characterizes the ultrasound appearances of the normal sfj and compares these with reported anatomical studies. valves can be consistently identified whereas the number and location of the tributaries are very variable. this should inform planning of haemodynamically-focused treatment at the sfj. introduction the saphenofemoral junction (sfj) has at times been regarded as a relatively simple conduit and treated as such in traditional ablative interventions. with the increased resolution of modern ultrasound, it has become possible to view, in real time, the valves, tributaries and the associated structures of the sfj and assess their function. this has resulted in a new way of understanding its function. in contrast to traditional thinking, it may be more appropriate to consider the sfj as a sophisticated multi-part structure comprised of the arch of the great saphenous vein (gsv), terminal and preterminal valves (tv and ptv), plus a number of tributary veins.1 a normal sfj relies on the integrated functioning of each of the component parts. consequently, the tv and ptv has become the subject of increasing interest as their integrity may ultimately determine the function of the entire gsv. loss of function at these valves has been associated with retrograde flow and according to the long held descending theory of valve failure, led to the development of varicose veins.2 other evidence would suggest antegrade progression of valve incompetence is more likely with eventual failure of the tv and ptv.3 the nomenclature of the valves of the sfj has not been without difficulty. an awareness of the importance of the most proximal and second most proximal valves of the gsv has been seen in the literature since pichot et al.4 the terms subterminal valve4,5 and preterminal valve6,7 have been used interchangeably to describe the second most proximal gsv valve. there are further variations in the use of this terminology. a report by muhlberger6 was criticized by caggiati8 for reporting the absence of tvs in circumstances where the tv was located distal to one or more gsv superficial tributary veins and also other inaccuracies when the ptv is located proximal to other superficial tributaries. given the highly variable nature of the sfj and its tributary veins, it is no wonder there is confusion as to the use of this nomenclature. more relevant is the relative hemodynamic significance of these variations. the implications of the haemodynamic impact of each component of the sfj has lead to alternative treatments for varicose veins, which are focused on treating the dysfunctional components and sparing those that are not.9 it has called into question the traditional understanding and approaches to treatment of sfj reflux. total obliteration of the sfj, as the previous gold standard, has been challenged. limited interventions that preserve normal venous drainage from superficial tributary veins such as the superior epigastric or pudendal veins may help reduce the high rates of recurrence associated with traditional vein stripping.9 much of the evidence regarding the architecture of the sfj comes from studies of the abnormal sfj before and after treatment, and evidence is sparse regarding studies in the normal subject. anatomical cadaver studies of normal limbs have been carried out, but the authors of such studies6 note a need for ultrasound investigations of the sfj in normal limbs to inform the debate. our study aims to characterize the functional anatomy and relationship of the valves and major superficial tributaries of the sfj in normal limbs in the absence of reflux. materials and methods subjects for a five-month period all subjects attending our vascular diagnostics clinical laboratory for venous assessment for suspected deep vein thrombosis (dvt) were screened to select limbs with normal venous system including a normal (non-refluxing) sfj, superficial and deep systems, and clinical absence of venous disease. subjects were excluded from further study also for technical reasons such as body habitus, lack of mobility, inability to be tilted or to complete an adequate valsalva maneuver. ultrasound imaging detailed duplex ultrasound examination correspondence: andre van rij, department of surgical sciences, dunedin school of medicine, po box 56, dunedin 9054, new zealand. tel. +64 3 474 0999 extension 8834 fax: +64 3 474 6722. e-mail: andre.vanrij@otago.ac.nz key words: saphenofemoral, great saphenous vein, terminal valve, preterminal valve. contributions: rd (main author), gh, amvr, study conception, analysis, editing and structuring of the manuscript; iat, vascular consultant involved in the care of the participants. conflicts of interest: there are no conflicts of interest for any of the authors involved. acknowledgments: the authors would like to acknowledge the artwork contribution of mr. robbie mcphee, mr. matthew smart for his assistance in editing the figures, miss kimberley johnston’s help with the ultrasound images and associate professor greg jones’ advice regarding statistics. received for publication: 23 may 2013. revision received: not required. accepted for publication: 9 july 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright et al., 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e18 doi:10.4081/vl.2013.e18 no nco mm er cia l u se on ly article [page 64] [veins and lymphatics 2013; 2:e18] was carried out to evaluate the morphology and distance of the terminal and preterminal valves from the sfj, and the number and relationship of tributary vessels to these valves. all measurements were taken from the sfj to the attachment site of the respective valve. the tv was defined as the most proximal valve of the gsv. the ptv was defined as the second most proximal valve of the gsv. patients were scanned with either an atl 5000 scanner (phillips medical systems, eindhoven, netherlands) or at later dates with a toshiba aplio xg scanner (toshiba medical systems, tokyo, japan). a 12–12.5 mhz linear array probe with colour and spectral doppler modalities was used to visualize the sfj in long section and trans-section in the 35° reverse trendelenburg position. colour and spectral doppler imaging was used to demonstrate reflux in limbs that were excluded, while bmode imaging only was used when imaging structures of interest to maximize the spatial and contrast resolution when dealing with these small structures. during the valsalva maneuver, the subject was asked to blow into their cheeks and tense their abdominal muscles until spectral analysis at the common femoral vein (cfv) showed abolishment of the normal phasic antegrade flow. the prevailing international standards of retrograde flow duration <1 s at the cfv and <0.5 s elsewhere in the limb were considered normal.10 the patient was asked to practice this maneuver until the sonographer was certain that they understood it fully and could reproduce it correctly when asked. analysis all statistical analysis was carried out using statview version 5.0.1 (sas institute inc., cary, nc, usa). significance was p<0.05, continuous variables were analyzed by calculating the mean, range and using a box plots. the nominal variables were assessed using kruskalwallis analysis. results a total of 221 limbs were screened, of whom 75 were eligible. the remaining 146 limbs were excluded due to: incompetent sfj and/or gsv (54); unfavorable habitus (18); dvt and/or superficial thrombophlebitis (17); technical difficulties (28); absent sfj and/or gsv (17); deep system reflux (2); other (10). there were 30 males and 45 females with a mean age of 59. terminal and preterminal valves were identified in all 75 included limbs (figures 1 and 2). seven limbs initially appeared to have monocuspid terminal valves (figure 3) and were reassessed on a subsequent occasion. of these, five were found to be bicuspid. in these limbs the leaflet attached to the anterior vein wall was difficult to visualize due to artifactual echo signals generated by the venous wall being erroneously represented in the anechoic lumen and also the echogenicity of slow moving erythrocytes at the margin of the lumen. the other two limbs had one dominant valve leaflet and one degraded valve leaflet (figure 3). despite this, they did not demonstrate significant reflux at the cfv or the gsv. the tvs were identified at a mean distance of 0.41 cm from the sfj (range of 0 cm to 1.24 cm). in 20 out of the 75 limbs (27%) the tv was recorded less than 0.1 cm from the sfj, with 18 of these having the tv exactly where the gsv connects with the cfv. the mean distance to the ptvs was 3.06 cm (range 0.43 cm to 8.71 cm). very few ptvs were identified closer than 1.3 cm to the sfj. all but 7 (9%) were identified at distances greater than this. the mean distance between terminal and ptv was 2.6±1.3 cm. the identity and sources of tributaries and their confluences about the normal sfj were often difficult to follow because of low volume of flow and smaller size compared to that seen in incompetent systems. consequently naming each tributary was inconsistent and therefore was not included in this study. in 22 out of 75 limbs (29%), one or more tributary vessels were observed between the sfj and the tv (figure 4). twenty-one of these limbs possessed one tributary, while one limb had two tributaries identified. most limbs (74, 99%) had at least one tributary vessel identified between the terminal and preterminal valve. the maximum total number of tributaries identified was four, which was demonstrated in only three limbs (4%). in one limb no tributaries were identified (1%). the greater the distance to the tv the greater the number of tributary veins found superior to the tv. a similar relationship appeared to exist for the length of the intervalve segment (figure 5) but the significance of this was not confirmed following kruskal wallis analysis, (p=0.57). figure 1. brightness mode (b mode) ultrasound image of the saphenofemoral junction. measurements were made from the deep valve leaflet attachment site, to the point where the great saphenous vein (gsv) joined the common femoral vein (cfv) and from the terminal valve to the preterminal valve. (a) the point where the gsv tributaries with the cfv where all measurements were taken from. (b) bicuspid terminal valve (tv) leaflets. (c) bicuspid preterminal valve leaflets (ptv). figure 2. distance (cm) from the saphenofemoral junction (sfj) to the terminal and preterminal valves. plot showing lower quartile, median and upper quartile (n=75). no nco mm er cia l u se on ly article [veins and lymphatics 2013; 2:e18] [page 65] discussion and conclusions the debate about the significance of the valves located in the saphenous arch of the gsv remains relevant today. while mühlberger6 described the relationships of these valves in normal cadavers and cappelli1 did so with ultrasound in limbs with venous disease, both these authors point out the need for studies in normal ambulant limbs. we agree that this is required to make any inferences regarding the importance of these valves in the development of venous disease and its treatment. this study has described the ultrasound features of these valves and their relationship to tributaries in the normal great saphenous arch in 75 normal legs. the valves of the sfj are small very fine structures that require high frequency ultrasound to visualize them accurately enough to determine valve morphology. with the trade off between ultrasound penetration and resolution, there were a significant number of subjects who were unsuitable for the study because of habitus and related technical reasons. a large number of subjects (146) were excluded from this study, leaving a smaller but sizeable population in which imaging was technically excellent. while it is unlikely that the excluded limbs would be drastically different this cannot be discounted and this may limit the application of this data to similar subjects. while this cohort was selected from those attending a vascular laboratory service, the limbs studied were functionally and physiologically normal and we believe they are representative of the normal situation. even in these selected limbs, it was still at times difficult to image the terminal valves, more specifically the superficial leaflet of the tv. this lead to some repeated examinations to confirm figure 4. the relationship between intervalve distance (cm) and the number of tributary veins identified entering the intervalve segment. error bars indicate the standard error of the mean. a higher number of tributary veins entering the intervalve segment did not associate with longer intervalve distances. kruskal-wallis analysis (p=0.57). error bars indicate the standard error of the mean. figure 5. the structure of the great saphenous vein and its tributary veins in relation to the terminal (tv) and preterminal valves (ptv). the location of the tributaries relative to the valves may have differing haemodynamic implications corresponding to the ascending or descending etiologies of reflux development. figure 3. images of competent monocuspid terminal valve. (a) the single terminal valve leaflet protruding across the lumen and on valsalva appearing to close against the opposite side of the vein wall. (b) repeat b-mode ultrasound image, still without significant reflux to valsalva or distal augmentation, which revealed a previously unseen short irregular valve leaflet on the superficial wall of the great saphenous vein. no nco mm er cia l u se on ly article [page 66] [veins and lymphatics 2013; 2:e18] valve morphology. this difficulty may have implications in more detailed study of early mechanisms of valve dysfunction in at risk groups such as the obese subject. the suitability of this assessment for the more minimalist interventions may also be affected and perhaps intraoperative or intravenous ultrasound may give the best definition for indeterminate conventional ultrasound findings. to minimize ambiguity, the nomenclature of terminal and preterminal valves (as defined by caggiati et al.) was used.8 the tv, the most proximal, is the first valve of the hydrostatic column of the gsv and was seen in our study in every normally functioning limb and found consistently to lie within 1.3 cm of the sfj. this is similar to that reported by muhlberger6 in a cadaver study at a range of 0 cm to 1.4 cm from the sfj. it would be tempting to categorize the valves located at 0 cm in our study as ostial valves and not as terminal valves. however, franklin states a valve which is not inserted into the circumference of the actual entry is not an ostial, but a parietal valve, no matter how near it is to the entry.11 we do not believe that ultrasound, even in our idealized population, would be definitive enough to make this distinction. interestingly, a recent report by tasch and brenner12 documented a 21% incidence of ostial gsv valves, which is highly congruent with our reported 24% incidence (18/75). the definitive identification of ostial valves in the gsv may always remain dissection-based, but the long-term haemodyamic implications of having a functional bicuspid ostial valve as opposed to a terminal valve, at some distance from the orifice of the gsv, would certainly warrant further investigation. the ptv is much more variably placed in the normal limb, as far as 8.3 cm from the sfj. this is similar to that reported in the cadaver study in normals (1.4 cm to 8.7 cm)6 and ultrasound imaging of patients with non varicose legs (3 cm to 5 cm).8 the significance of this greater variability is not clear but it does give rise to considerable scope for variation to the number and identity of which tributaries enter the gsv in the segment between the tv and ptv. this may have significant implications for development of reflux and for treatment. for example, despite the very short distance from the sfj to the tv, 29% (22/75) of limbs had at least one tributary vessel superior to the tv (labeled tributary a in the schematic representation of the sfj (figure 5). the greater the distance to the tv, the more tributaries above it (figure 6). if these tributaries were to become incompetent, reflux may be observed at the sfj despite intact terminal and preterminal valves and no reflux in the gsv. this phenomena may apply not only to more proximal vessels draining the perineum and from above the inguinal ligament but also to the accessory gsv vessels in particular the anterior accessory saphenous vein (aasv) which muhlberger6 reported was often one of the most proximal tributaries identified. it is our observation that this reflux into the aasv does occur in association with clinically evident varicosities. under such circumstances traditional ablative intervention may entail obliterating the sfj and a non-refluxing gsv below. more minimalist intervention may simply ligate the aasv and leave the gsv intact. the relative placement of the valves and tributaries may lead to other important variations in reflux patterns and treatments. if the descending theory applies and the tv becomes incompetent but there is an intact ptv, then reflux may similarly occur down any of the tributaries, most frequently the aasv. this pattern of incompetence was shown to occur in approximately 6% of patients presenting with varicosities.13 if conversely the ascending theory of incompetence is in play with an incompetent ptv but an intact tv, then reflux demonstrated following valsalva is not from the cfv but from the tributaries refluxing into the gsv. the absence of one or both of these valves will have different haemodynamic implications relative to which theory of reflux development that each surgeon prescribes to. the number of tributary veins joining the gsv was extremely variable. the classic idealized saphenous star comprised of the gsv and its five independent major superficial tributaries was not seen in this study. in some limbs, only one or two tributaries were seen. the discrepancy between our findings and the idealized saphenous star reported by mühlberger6 was not unexpected due to differences in methodology. the two limbs in the present study with ptvs identified at 7 cm and 8.28 cm from sfj had the highest number of tributary vessels. given the highly conjoined nature of the tributary vessels of the sfj, it is probable that all 5 major tributary vessels were present in these limbs but were not identified using ultrasound. the reduced size of normal superficial veins and their associated tributary vessels, coupled with the lowered volume of flow in the normal sfj, compounds the difficulties posed by their variable course and made ultrasound identification tributary vessels more problematic in the normal sfj compared to in an incompetent sfj. mühlberger reported that in only 68% of limbs did the posterior accessory saphenous vein (pasv) drain directly into the gsv and that in many cases tributary veins merged into conjoined vessels before draining into the gsv or elsewhere. muhlberger,6 in their very large cadaver study reported 69 possible configurations of superficial tributary veins comprising the saphenous star. this offers a plausible explanation why five tributary vessels were not identified entering the gsv in any limbs in our study. it appears from our study and of others that the greater the distance to the tv, the greater the number of tributary veins one should expect to find superior to the tv. a similar relationship may exist for the length of the intervalve segment and the number of tributary veins but this could not be substantiated. a larger sample size may help elucidate whether this relationship holds. these findings may have implications in surgical planning and may influence the technical success of varicose vein surgeries. in procedures such as endovenous laser therapy, closure of the gsv is limited to within 2-3 cm distal to the sfj in order to spare the cfv from treatment effects and leaves a residual untreated proximal gsv stump.14 initially, this stump was thought to allow normal drainage of sfj tributaries and prevent recurrence associated with these vessels as seen after venous surgery with the traditional ligation and crossectomy.15 the variability of the distances of these tributaries from the sfj and their variable level of conjoining with each other before entering the gsv may result in a variably draining stump. the most proximal of the tributaries would be expected to have preserved drainage but less so for the more distal, namely the pasv. little attention has been given to the impact of therapies on the state of the valves within the residual stump. this is not surprising when it comes to sfj high ligation and associated variations in which the whole sfj complex is destroyed. with minimal surgery preserving the sfj complex, the intent is to preserve the valves. the effect of endovenous therapies on these valves is less clear. the proximity of devices to the valves will vary with the location of the delicate valves. figure 6. the relationship between the terminal valve (tv) distance (cm) from the saphenofemoral junction and the number of tributary veins identified superior to the tv *(0 vs 1 p<0.01). shorter terminal valve distances correlated strongly with no tributaries being identified above the tv. due to n=1 we were unable to compare the 2 tributary population against the other sub groups. error bars indicate the standard error of the mean. no nco mm er cia l u se on ly article [veins and lymphatics 2013; 2:e18] [page 67] whether the valves remain functional may influence outcomes including stump thrombosis and patterns of recurrence. this deserves further investigation. limitations to the ultrasound description of normal anatomical detail include the technical issues of the depth of tissue and available imaging windows. following tributaries is not straightforward. in cadaveric studies, it is easier to examine all these small tributaries with micro-dissection. despite this, the number of tributaries assessed as individual vessels draining into the gsv by ultrasound was similar to the description by muhlberger.6 it is our impression from examining patients with reflux disease that these tributaries are larger with greater flow with venous remodeling and hence easier to identify and track. ultimately, it is the function of these vessels rather than their identity that determines their relevance to intervention. while it would be desirable to recommend detailed examination of the sfj valves and tributaries for understanding of sfj incompetence and for treatment planning purposes, it may not be possible in all patients and may not be required for traditional interventions. eighteen subjects, out of a total of 221 subjects screened, were excluded from the current study due to unfavorable habitus. repeated imaging was required in seven limbs when the initial examination suggested monocuspid terminal valves. subsequently these were found to be either bicuspid (the anterior wall valve leaflet not being seen at the initial investigation) or only possessing one leaflet with degradation of the other. further research will be required to determine the utility of the parameters examined in this study in regular practice. the increasing sensitivity of ultrasound equipment enables a more detailed examination of the sfj and facilitates at least further research into these anatomical features and their influence on treatment outcome. references 1. cappelli m, molino lova r, ermini s, zamboni p. hemodynamics of the sapheno-femoral junction. patterns of reflux and their clinical implications. int angiol 2004;23:25-8. 2. moore hd. deep venous valves in the aetiology of varicose veins. lancet 1951;2:7-10. 3. bernardini e, de rango p, piccioli r, et al. development of primary superficial venous insufficiency: the ascending theory. observational and hemodynamic data from a 9-year experience. ann vasc surg 2010;24:709-20. 4. pichot o, sessa c, chandler jg, et al. role of duplex imaging in endovenous obliteration for primary venous insufficiency. j endovasc ther 2000;7:451-9. 5. pichot o, sessa c, bosson jl. duplex imaging analysis of the long saphenous vein reflux: basis for strategy of endovenous obliteration treatment. int angiol 2002;21:333-6. 6. mühlberger d, morandini l, brenner e. venous valves and major superficial tributary veins near the saphenofemoral junction. j vasc surg 2009;49:1562-9. 7. caggiati a, bergan jj, gloviczki p, et al. nomenclature of the veins of the lower limb: extensions, refinements, and clinical application. j vasc surg 2005;41:719-24. 8. caggiati a. regarding "venous valves and major superficial tributary veins near the saphenofemoral junction". j vasc surg 2009;50:1547. 9. carandina s, mari c, de palma m, et al. varicose vein stripping vs haemodynamic correction (chiva): a long term randomised trial. eur j vasc endovasc surg 2008;35:230-7. 10. labropoulos n, gasparis ap, tassiopoulos ak. prospective evaluation of the clinical deterioration in post-thrombotic limbs. j vasc surg 2009;50:826-30. 11. franklin kj. valves in veins: an historical survey. proc r soc med 1927;21:1-33. 12. tasch c, brenner e. the ostial valve of the great saphenous vein. phlebology 2012;27:179-83. 13. pittaluga p, chastane s, rea b, barbe r. classification of saphenous refluxes: implications for treatment. phlebology 2008;23:2-9. 14. pleister i, evans j, vaccaro ps, satiani b. natural history of the great saphenous vein stump following endovenous laser therapy. vasc endovascular surg 2008;42:348-51. 15. van rij am, jones gt, hill bg, et al. mechanical inhibition of angiogenesis at the saphenofemoral junction in the surgical treatment of varicose veins: early results of a blinded randomized controlled trial. circulation 2008;118:66-74. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2014; volume 3:1863 [veins and lymphatics 2014; 3:1863] [page 1] on the consistency of flow rate color doppler assessment for the internal jugular vein francesco sisini,1 sergio gianesini,2 erica menegatti,2 angelo taibi,1 mirko tessari,2 giovanni di domenico,1 anna maria malagoni,2 mauro gambaccini1 1department of physics and earth sciences, university of ferrara; 2vascular diseases center, university of ferrara, cona (fe), italy abstract color doppler methodology to assess the vessel blood flow rate is based on the time averaged velocity of the blood measured in the longitudinal plane and the cross sectional area measurement taken either in the longitudinal plane, by assuming circular cross sectional area, or in the transversal plane. the measurement option in longitudinal plane is based on the assumption of circular cross sectional area, while the transversal one needs to evaluate both time-averaged velocity and cross sectional area in the same vessel point. a precise and validated assessment methodology is still lacking. four healthy volunteers underwent internal jugular vein colour doppler scanning. the cross sectional area was assessed by means of b-mode imaging in the transversal plane all along the vessel cervical course. during this assessment, cross sectional area, major and minor axis of the vessel were measured and recorded. the distance between the internal jugular vein wall and the skin surface were measured together with the intra-luminal diameter and statistically correlated with the cross sectional area data. the internal jugular vein cross sectional area measured on the transversal plane were significantly different from the cross sectional area calculated using the assumption of circular shape. the intra-luminal distance showed high correlation with the measured cross sectional area. the proper anatomical point in the cross sectional area transversal measurement can be identified by using the internal jugular vein intra-luminal distance as landmark. introduction venous flow rate is a main measure scientifically recognized for the clinical practice.1-7 it is a derived value coming from the product of time-averaged velocity (tav) and the cross sectional area (csa), thus measurable by color doppler (cd). nowadays, the available cd software can calculate the flow value only along longitudinal (l) plane. such value is obtained by contouring the doppler spectrum wave and by calculating the csa, which is in turn obtained by the measurement of the vessel intra-luminal diameter. the assumption for the flow rate assessment is that the point where such diameter is measured has to be precisely positioned in the same anatomical site of the tav sample volume. moreover, a circular vessel shape must be assumed for this kind of csa calculation. this last assumption guarantees that the above-described method can be considered reliable for the arterial evaluation thanks to the circular shape. on the contrary, both venous diameter and shape undergo extreme variations linked to trans-mural pressure and compliance features, together with surrounding muscles extrinsic compressions,8,9 and thus suggesting the need for a more reliable methodology for the venous flow assessment. nevertheless, many scientific investigations concerning venous flow rate still refer to a csa that is obtained by assuming that the vein is a perfect cylinder. such inaccuracy can determine a considerable loss in the significance of venous flow assessment. nowadays, the only available methodology to overcome this issue is to assess the tav along the l plane, while measuring the csa along the transverse plane (t).1-4,6,10 of course this method includes a high risk of reliability loss since the tav and csa assessment sites could not remain the same when moving from l to t scanning plane. aim of the present study is to evaluate different ways of csa measurement and to identify a consistent methodology to assess the flow rate, so as to avoid the significance loss risk when moving from l to t scanning. materials and methods the internal jugular vein geometry model we designed a geometry model of the internal jugular vein (ijv), so as to identify anatomical landmarks aimed to find corresponding sites between t and l evaluations. ijv anatomic feature can be schematized by considering the ellipse minor (b) and major (a) axis for its shape and the distance from the skin for its location. in l ultrasound images the ijv walls are both visible. we named lh the distance between the vessel inner linings and ld the distance between the skin and the superior wall inner lining (figure 1). in t images, the whole csa contour is easily traceable. if we consider the ultrasound path crossing the vein center, td is the distance from the skin to the vein wall and th is the distance between the vessel walls (figure 2). in this way ld, lh, td and th constitute the anatomical landmarks of the investigated vessel. patient population four consecutive healthy volunteers (age ranging from 23 to 25 years old, male:female ratio 1:1), were enrolled in this study. all the study participants underwent cd investigation (esaote my-lab 70, genoa, italy) with the same condition of room temperature (23°c). measurements were all performed in the morning hours following the recommendation to drink 500 ml after waking up, for comparable hydration conditions.11 color doppler study of the internal jugular veins first subject the first subject underwent a recorded ijv correspondence: francesco sisini, department of physics and earth sciences, university of ferrara, via saragat 1, 44122 ferrara, italy. e-mail: ssf@unife.it key words: echo-color-doppler, ultrasound, flow rate, internal jugular vein. contributions: fs developed the geometrical model and the equations, collected and analysed the raw data, performed the statistical analysis and wrote the paper. em performed the colordoppler scannings and collected the data. sg, gd and at wrote the paper and revised it critically. amm, mt contributed to collect and analyse the data. mg provided scientific supervision and founded the study. all authors participated in the design study, read and approved the final manuscript. conflict of interests: the authors declare no potential conflict of interests. funding: this study was partially supported by the italian ministry of education, university and research (miur programme prin 2010-2011), grant no. 2010xe5l2r. received for publication: 5 august 2013. revision received: 22 november 2013 accepted for publication: 23 dcember 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright f. sisini et al., 2014 licensee pagepress, italy veins and lymphatics 2014; 3:1863 doi:10.4081/vl.2014.1863 no nco mm er cia l u se on ly article [page 2] [veins and lymphatics 2014; 3:1863] transverse scanning from j1 to j3:11 the assessment was performed at a constant velocity, for a total length of 12 cm, and lasted 5 seconds. the total number of analyzed frames was 38. the analysis of each frame image included a, b, th, td and csa measurements. the csa was measured by manually tracking the boundaries of the lumen. in the following we call this measure contoured csa (concsa). for reliability purposes, the operator repeated the same scanning 5 times. the reliability of the constant velocity assumption was previously tested in the laboratory by asking the operator to scan a phantom having a thickness linearly related to the displacement (pmma step wedge). after the operator training, the chi square test showed a p>0.9 indicating a uniform motion of the probe. by dividing the 12 cm total length (l) by the number (n) of acquired images, we calculated the sampling distance and we named this value as unit length (ul). then we multiplied the image number (in) by ul to obtain the exact observation site along the ijv (y). y = in ¥ ul (1) besides, we obtained the manually traced concsa, the vessel circular csa (circsa) and the elliptical csa (ellcsa) by using the measured th, a and b values. the circular area can be calculated using the radius r=b/2 as follows: circsa = π �× r2 (2) while the elliptical one can be calculated using maximum (r=a/2) and minimum (r) radii: ellcsa = π �× r×� r (3) we measured the mean concsa from all the acquired frames. the pearson’s r coefficient was calculated to determine the linear correlation between the concsa and the td and th parameters. three control subjects the subjects were placed in supine position and underwent ijv transverse scanning at level of j1, j2 and j3. each assessment (total of 9) was performed by keeping the probe in a fixed position among j1, j2 and j3. the acquired image sequences were processed by considering a number of frames within at least one cardiac cycle. for each analyzed frame we measured the major and minor axis (a and b), while the concsa was obtained by manually tracking the boundaries of the lumen. total of 370 data record (corresponding to about 40 records for each ijv segment) was collected, and the analyses were performed either separately for each subject or as a whole. statistical analysis the statistical difference among the concsa, the ellcsa and the circsa was tested by using appropriately homoscedastic and heteroscedastic student’s t test; p value<0.05 was considered significant. homoscedasticity and heteroscedastic hypothesis of the variances has been tested by f test. the pearson’s r coefficient was calculated to measure the linear correlation between the concsa and the td and th parameters. the reported uncertainties refer to one standard deviation. table 1. p-value of t-test for elliptical and circular cross sectional area hypothesis. p-value subject no. concsa vs ellcsa concsa vs circsa 1 0.95 <0.001 2 0.35 <0.001 3 0.09 <0.001 4 0.11 <0.001 concsa, contoured cross sectional area; ellcsa, elliptical csa; circcsa, circular csa. figure 1. schematic representation of an ultrasound probe insonating an internal jugular vein (ijv) in the l plane. the ijv’s walls are represented. the distance ld between the ijv and the skin and the wall distance lh of the ijv are shown. figure 2. schematic representation of ultrasound probe insonating an internal jugular vein (ijv) in the t plane. the ijv is represented as an ellipse of major and minor axis a and b respectively. the distance td between the ijv and the skin and the depth th of the ijv are shown. no nco mm er cia l u se on ly article [veins and lymphatics 2014; 3:1863] [page 3] results first subject the measured concsa data range from a maximum of 0.82 cm2 in j1 to a minimum of 0.14 cm2 in j3 with a mean value of 0.36±0.17 cm2 (figure 3). the mean circsa was 0.22±0.16 cm2, while the mean ellcsa was 0.36±0.16 cm2. in figure 4 elliptical and circular ijv csa are plotted as a function of the contoured csa. it shows a significant lack of overlapping between concsa and circsa while there is a good agreement between ellcsa and concsa. this also results in a significant statistical difference between these quantities (see the p value in table 1). the correlation coefficient r between td and concsa resulted 0.5 while it resulted 0.95 between th and concsa. three control subjects in figure 5, elliptical and circular ijv csa are plotted as function of the contoured csa. again, the plot shows a significant lack of overlapping between concsa and circsa while there is a good agreement between ellcsa and concsa. p values are reported separately for each subject in table 1. this finding is very interesting because it shows that the elliptical shape assumption remains valid also in the vein pulsation phase, and thus suggesting that the use of the th and lh landmarks is reliable. discussion the main outcome of a circsa lower than the concsa, in the observed t scanning, demonstrates the risk of a flow rate underestimation, under the assumption of a cylindrical venous shape (figures 4 and 5). moreover, the significant concsa variability along the vein tract points out the consistency loss when the us probe is positioned in a different anatomical site between t and l scannings. the present study offers an assessment methodology, endowed with anatomical landmarks (ld, lh, td and th) that can become extremely useful for a correct sample volume positioning, in particular thanks to the high th correlation coefficient. conversely, the lack of correlation between td and concsa indicates that this parameter is unsuitable for our purpose. it is worth noting that although this method helps to identify the same anatomical site in both l and t planes, the actual csa of the vein depends on the probe compression applied by the operator. anyway, this does not affect the flow calculation because also the blood velocity is affected by the csa change hence, if the velocity and the csa are measured by using the same pressure, the resulting calculated flow is virtually invariant (high compression can alter the haemodynamics and the flow). since there are no warranties that the operator applies the same pressure on both the t and l plane, there is no certainty that the csa assumes the same value when measured in the t and l plane hence, there is the risk to use the landmarks in a misleading way. for this reason we are investigating the use of a correction factor that allows to calculate the elliptical csa based on the lh parameter that has to be measured on the same plane where the tav is also measured. the true reliability of the novel measuring method has not been assessed in this paper since no direct flow measurement is done. actual flow measurement is not possible on human subjects with figure 3. the measured cross sectional area is plotted as function of the position along the internal jugular vein (ijv) from j1 to j3. figure 4. elliptical and circular internal jugular vein (ijv) cross sectional area (csa) of one subject are plotted as function of the measured csa. different measured csa correspond to different assessment along the ijv length. no nco mm er cia l u se on ly article [page 4] [veins and lymphatics 2014; 3:1863] non-invasive methods. for this reason we are planning to verify this methodology by laboratory in vitro investigation. finally, if a quantitative flow calculation of the ijv is requested for a clinical reason, we believe that its calculation based on the vein diameter acquired in the l plane is not correct. conclusions the flow value assessment is often based on the assumption of constant csa, which can generate a possible significant inaccuracy. we have demonstrated that, thanks to validated longitudinal and transversal landmarks, the tav can be measured in the l plane in a point where the lh is equal to th. references 1. valdueza jm, von münster t, hoffman o, et al. postural dependency of the cerebral venous outflow. lancet 2000;355:200-1. 2. schreiber sj, lurtzing f, gotze r, et al. extrajugular pathways of human cerebral venous blood drainage assessed by duplex ultrasound. j appl physiol 2003;94:1802-5. 3. gisolf j, van lieshout jj, van heusden k, et al. human cerebral venous outflow pathway depends on posture and central venous pressure. j physiol 2004;560:317-27. 4. doepp f, schreiber sj, von münster t, et al. how does the blood leave the brain? a systematic ultrasound analysis of cerebral venous drainage patterns. neuroradiology 2004;46:565-70. 5. zamboni p, menegatti e, pomidori l, et al. does thoracic pump influence the cerebral venous return? j appl physiol 2012;112: 904-10. 6. yamaki t, nozaki m, fujiwara o, yoshida e. comparative evaluation of duplex-derived parameters in patients with chronic venous insufficiency: correlation with clinical manifestations. j am coll surg 2002;195:822-30. 7. griffin m, nicolaides an, bond d, geroulakos g, kalodiki e. the efficacy of a new stimulation technology to increase venous flow and prevent venous stasis. eur j vasc endovasc surg 2010;40:766-71. 8. fung yc. biomechanics circulation. 2nd ed. berlin: springer; 1997. 9. attinger eo. wall properties of veins. biomedical engineering. ieee trans 1969; 16:253-61. 10. zamboni p, sisini f, menegatti e, et al. an ultrasound model to calculate the brain blood outflow through collateral vessels: a pilot study. bmc neurol 2013;13:81. 11. zamboni p, morovic s, menegatti e, et al. the intersociety faculty: screening for chronic cerebrospinal venous insufficiency (ccsvi) using ultrasound. recommen dation for a protocol. int angiol 2011; 30:571-97. figure 5. manually contoured, elliptical and circular internal jugular vein (ijv) cross sectional area (csa) of three subject are plotted as function of the contoured csa. different measured csa correspond to different assessment along the ijv length and to a different assessment during the cardiac cycle. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2017; volume 6:6855 [page 82] [veins and lymphatics 2017; 6:6855] stenting for obstructive iliac vein lesions arjun jayaraj, seshadri raju the rane center for venous & lymphatic diseases, st. dominic hospital, jackson, ms, usa abstract endovenous stenting has supplanted open surgery as the treatment of choice for iliocaval obstruction. this review provides a brief overview of such obstructive pathology and an in-depth assessment of femoroilio-caval stenting. introduction obstructive iliac vein lesions can result from primary or non-thrombotic and secondary or post-thrombotic pathology. the latter is responsible for a majority of all obstructive iliac vein lesions because of post thrombotic syndrome (pts) development in 20 to 50% of patients who present with lower extremity deep venous thrombosis (dvt).1 among non-thrombotic iliac vein lesions (nivl), may-thurner syndrome (mts)/iliac vein compression syndrome (ivcs) is the most frequent etiology.2,3 while obstruction is seen primarily of the left common iliac vein, the right common iliac or either external iliac vein can also be involved in mts/ivcs. other less common causes of nivl nclude retroperitoneal fibrosis; iatrogenic, blunt and penetrating trauma; congenital venous anomalies or benign/malignant tumors. endovenous interventions have supplanted open surgery as the treatment of choice in patients with non-malignant obstructive iliac vein lesions. for patients with malignancy, venous stenting is used only when excision of the tumor/open reconstructive surgery is not possible and the goal of therapy is palliation. adjunctive procedures such as femoral vein endophlebectomy/creation of arteriovenous fistula are added to venous stenting to provide improved inflow. diagnosis clinical manifestations of chronic venous insufficiency arising from obstructive lesions of the femoro-ilio-caval tract include swelling; varicosity; hyperpigmentation; venous claudication (pelvic, thigh or hip pain that develops after exercise); skin and subcutaneous inflammatory changes (eczema, lipodermatosclerosis, induration and venous ulcerations) of the affected limb. of these, swelling has been noted to be the most common symptom followed by venous claudication in one review.4 in this study the incidence of active ulcers was approximately 19%. diagnostic testing is focused on confirming the presence of an obstructive femoro-ilio-caval lesion and determining etiology. additionally, inflow and outflow patterns should be ascertained. such testing includes venous duplex scanning, which should be used as a screening tool and performed in all patients with clinical presentation suggestive of obstructive venous pathology. duplex scanning helps define location, etiology (obstructive vs obstructive with concomitant valvular incompetence), and severity of the underlying problem. air plethysmography can help evaluate global leg hemodynamics by measuring obstruction, reflux and calf pump function. cross-sectional imaging including magnetic resonance (mr) venography and computed tomographic (ct) venography will identify obstructive pathology and provide sufficient information in most patients with regard to venous anatomy, collateral circulation and occlusion/stenosis. ascending venography helps defines the site(s) of obstruction, collateral venous circulation and patterns of preferential flow. this is done by cannulation of the dorsal vein of the foot to assess the veins of the leg and through separate access of the common femoral vein to assess the ilio-caval system. ambulatory venous pressure measurement by venous cannulation in the foot helps quantify venous hypertension. intravascular ultrasound (ivus) is used to assess degree of iliac vein stenosis before stenting; to assess apposition of stent to vein wall post-stenting and to evaluate stent/flow status during follow-up of patients with recurrent symptoms. ivus is generally considered the gold standard from a diagnostic and therapeutic standpoint. treatment conservative management initial management of femoro-iliocaval obstruction is usually conservative, including frequent leg elevation, use of graduated compression stockings (30 to 40 mm hg), and local wound care. compression garments require strict compliance, which can be an issue due to a variety of reasons, including warm weather and a sense of tightness of the limb. benefits attributed to graduated compression stockings arise from their ability to impact venous hemodynamics, skin circulation, and calf muscle pump function. patients with persistent disabling symptoms not responding to conservative measures should be considered for endovascular intervention. endovascular treatment femoro-ilio-caval stenting has become the primary treatment for obstructive venous pathology. open approach is reserved for patients who are not candidates for or who have failed an endovascular approach. endovascular intervention is usually performed under general anesthesia (some interventionalists prefer moderate intravenous sedation) given the frequent severe intraoperative pain/discomfort associated with balloon angioplasty. access to the mid-thigh femoral vein is obtained under ultrasound guidance. this allows angioplasty/stenting of the common femoral vein if needed, without being impeded by the sheath. a 0.035 glide wire (terumo medical corp, somerset, nj) is passed into the inferior vena cava and a short (10 cm) 11 fr sheath is placed. an ascending venogram of the ilio-femoral segments and inferior vena cava is performed. in patients with renal dysfunction, the venogram is skipped. intravascular ultrasound [volcano, san diego, ca] is then performed using the 0.035” catheter and planimetric measurements of the luminal areas of the common femoral vein (cfv), external iliac vein (eiv) and common iliac vein (civ) are made. 125 mm2, 150 mm2 and 200 mm2 are used as normal luminal area cutoffs in the cfv, eiv and civ respectively. any decrease in luminal correspondence: arjun jayaraj, the rane center, 971 lakeland drive, suite #401, jackson, ms 39216, usa. tel.: +1.601.939.4230. e-mail: arjunjayaraj2015@gmail.com key words: iliac vein stenting; venous stents; obstructive iliac vein lesions; may thurner syndrome; iliac vein compression syndrome. received for publication: 18 june 2017. revision received: 14 august 2017. accepted for publication: 14 august 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright a. jayaraj and s. raju, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6855 doi:10.4081/vl.2017.6855 review areas below the reference values shown in table 1 in a symptomatic patient is considered abnormal, meriting angioplasty and stenting.5 it is important avoid using any particular threshold value of stenosis for treatment because unlike the arterial system, elevated peripheral venous pressure is the driving force behind clinical symptoms/signs. in this regard, even a minor stenosis of around 30% or so can significantly elevate venous pressure in postthrombotic limbs. the basis of cvi is venous hypertension and the aim of stenting is to relieve the same. predilation of the stenosis is performed using an 18×60 mm atlas angioplasty balloon (bard peripheral vascular, tempe, az). stenting is then carried out using 1820 mm wallstents (boston scientific, marlborough, ma) with landing zones determined by ivus defined bony landmarks. the proximal landing zone is typically 1-2 cm above the iliac confluence that can be related to the corresponding vertebral body (upper, middle or lower border). the distal landing zone is an area of adequate inflow in the cfv and can be related to a body landmark of the pubic ramus, femoral head or lesser trochanter. attention must be paid to the vein at the level of the inguinal ligament since this is often an area of compression. stenting across the inguinal ligament must be performed in these cases and can be done with good results (figure 1).6 given the relatively low radial strength of the wallstent, a gianturco z stent (cook medical, bloomington, indiana) is used to provide additional strength across the confluence with an extension of the gianturco stent beyond the wallstent proximally into the ivc. the gianturco z stent should be oversized relative to the wallstent with an overlap of the lower half of the z stent within the wallstent to prevent stent embolization. an overlap of 3 cm or so between each wallstent in the stack is required to compensate for foreshortening during post-dilation. post-dilation is performed using the 18×60 mm angioplasty balloon. completion ivus is performed to ensure adequacy of the luminal area. any residual narrowing on ivus interrogation is overcome by repeat dilation using sustained inflation or, if necessary, a larger caliber angioplasty balloon (20 mm). completion venogram is then performed. the 11fr sheath is subsequently withdrawn to just outside the vein and a surgicel fibrillar patch (ethicon, somerville, nj) is introduced via the sheath to aid in local hemostasis. manual pressure is maintained to complement the hemostatic effect. a retrograde access through the right internal jugular vein is also used if the obstruction cannot be crossed from the femoral access. kurlinsky at al. reported their experience with stenting 91 post-thrombotic iliac or iliofemoral veins. primary, primary assisted and secondary patencies at 3 years were 71%, 90% and 95%, respectively.7 in the largest single institutional study, 6-year follow-up data of 982 stents placed for chronic nonmalignant obstructive lesions of the femoro-ilio-caval vein demonstrated primary, primary assisted and secondary patency rates of 79%, 100%, and 100% in nonthrombotic disease and 57%, 80%, and 86% in post-thrombotic disease, respectively.8 chronic total occlusion recanalization of chronic total occlusion (cto) is most commonly done through the use of an 0.035” glidecath (terumo medical corp, somerset, nj) and 0.035” glidewire. a mid-thigh femoral vein approach is satisfactory in most instances with a short entry to lesion length, allowing greater pushability of instruments. access of the profunda femoris vein or the popliteal vein may sometimes be required depending on inflow. the internal jugular vein approach is sometimes necessary when the antegrade approach fails. a body floss techtable 1. luminal area values. vein luminal area diameter (mm2) (mm) cfv 125 12 eiv 150 14 civ 200 16 cfv, common femoral vein; eiv, external iliac vein; civ, common figure 1. stenting across the inguinal ligament using gianturco z stent/wallstent combination. stenting can be carried out safely across the inguinal ligament without compromising stent outcomes. figure 2. trabeculae in chronically thrombosed vein segment. successful recanalization requires localization and subsequent threading of guidewire through such trabeculae. [veins and lymphatics 2017; 6:6855] [page 83] nique may be necessary occasionally as described by kolbel and colleagues.9 less commonly, other devices may be needed for recanalization of cto lesions including quick-cross support catheter (spectranetics corp, colorado springs, co) and the triforce peripheral crossing set (cook medical, bloomington, in). the key is to gain entry into a trabecular channel, which then leads one all the way into a patent segment (figure 2). there is no role for subintimal entry/angioplasty as is utilized to perform recanalization of arterial segment ctos. once wire recanalization is attained, angioplasty is performed as previously outlined. sometimes, angioplasty with sequentially larger balloons may have to be employed due to inadequate purchase of the initial large caliber balloon. rupture/hemorrhage from this maneuver is extremely rare. angioplasty is carried out caudal to cranial (femoral access) or cranial to caudal (jugular access) as this facilitates easier retrieval of the angioplasty balloon should it disrupt. the likelihood of the latter happening is higher in cto than in stenotic lesions. use of stents, post-dilation, ivus interrogation and venogram are all performed as previously described. fatima et al reported 90% two-year patency rate and 80% symptomfree survival in a series of 28 patients undergoing inferior vena cava (ivc) stenting for occlusion (16)/high grade stenosis.12 freedom from reintervention in this group, which included 13 patients with ivc filters at the 2-year mark, was 84%.10 raju et al described their experience in 120 patients with chronic obstruction of the ivc and reported cumulative stent patency of 82% at 2 years.11 relief of pain and swelling of 74% and 51% respectively was noted at 42 months follow-up. the cumulative rate of complete ulcer healing in this group at 2 years was 63%.11 more recently murphy et al published outcomes following endovascular management of cto of the inferior vena cava/iliac veins and noted primary, primary assisted, and secondary patency rates at 60 months of 52%, 85%, and 93%, respectively. the authors reported complete cumulative relief of pain and swelling in 66% and 41% respectively, with the venous clinical severity score improving from 8.4±5.1 (range, 4-27) prior to intervention to 3.9±3.2 (range, 0-14) post-intervention (p<0.001).12 stenting across inferior vena cava filters inferior vena cava filters can over time serve as a nidus for a fibrotic reaction that leads to ivc stenosis/occlusion. trapped emboli may start the process in some instances. the occluded filter and ivc segment must be recanalized to provide adequate outflow. this can be accomplished by removal of the filter if possible, or crushing the filter and stenting across it. 24 mm wallstents are typically used in the ivc/across ivc filters and have had good results (figure 3a-f). patients need to be counseled about loss of filter protection for pulmonary embolism consequent to such procedures. in a review of 121 limbs that underwent stenting for postthrombotic ilio-caval occlusions, limbs stented for recanalized occlusions with (n=23) and without ivc filters (n=92) showed no difference in patency rates. cumulative primary and secondary patency rates were 30% and 35% (p=0.97) and 71% and 73% (p=0.93) respectively. the authors conclude that the primary factor affecting stent patency in such patients was severity of postthrombotic disease and not presence of a filter.13 bilateral iliocaval stenting there is a limited role for simultaneous bilateral femoro-ilio-caval stenting, except for bilateral recanalization procedures. typically, the more affected leg is stented, giving adequate time for the less affected leg to improve from off-loading of cross collaterals. in patients with persistent symptoms in the contralateral lower extremity, contralateral stenting can be pursued. in the presence of a prior gianturco z stent, the flowering technique is used wherein the cranial nylon suture of the new gianturco z stent is cut so as to allow the struts to flower out and allow it to mesh with the older contralateral gianturco z stent (figure 4). if the contralateral stent is a wallstent then a fenestrum needs to be created by wire access across the wall stent interstice and dilation of same using an 18x60 mm angioplasty balloon. stenting across this fenestrum is accomplished using a combination of wallstent and gianturco ‘crown’ as previously described. the wide struts of the gianturco z stent lining the fenestrum allow free flow in the contralateral stent across the fenestrum (figure 5). the authors’ preference is to use a bilateral wallstent/gianturco z stent combination for management of the iliac confluence as opposed to the apposition, double barrel or fenestrum techniques. raju et al reported 2-year cumulative primary and secondary patency of 69% and 93% respectively in 273 limbs intervened on by using the z stent technique.14 hybrid treatment venous stents are combined with femoral vein endophlebectomy/patch angioplasty or arteriovenous fistula (avf) creation or both to improve inflow into the stents. the stent is typically placed proximal to the patch or can be extended into the patch. the common femoral or superficial femoral artery can be used for inflow to create the fistula, which is typically fashioned using a 4 to 6 mm externally supported ptfe graft. acceptable outcomes following endophlebectomy and avf creation have been reported.15-18 anticoagulation for perioperative thromboprophylaxis, the authors use enoxaparin 40 mg given subcutaneously preoperatively, in addition to bivalrudin 75 mg given intravenously in the operating room prior to the start of the procedure. the authors use this combination of direct and indirect thrombin inhibitors to reduce early stent complications including thrombosis. following iliocaval stenting, in patients with thrombophilia/post-thrombotic syndrome therapeutic anticoagulation is continued. those in whom thrombophilia workup is negative and who have non-thrombotic femoro-iliocaval lesion, aspirin 81 mg with cilastazol 50 mg twice daily is typically used unless contraindicated. the latter is used for its suppressive effect on neointimal hyperplasia. presence of significant in-stent restenosis, but with no symptom recurrence is an indication to switch to apixaban 2.5 mg on a twice-daily basis. recurrence of symptoms is an indication for repeat ivus interrogation and possible angioplasty. follow-up venous duplex ultrasound is performed on post-operative day one to obtain baseline post-procedure metrics, including stent patency, and to assess stent compression and/or in-stent restenosis. these parameters are again evaluated by repeat duplex ultrasound in addition to assessing symptom relief at clinic visits 2 weeks and 4 weeks post-procedure. three to six monthly follow-up is required subsequently, which is gradually reduced to annual follow up depending on symptoms and status of stents. more frequent follow-up is typically required for pts and recanalization patients. review [page 84] [veins and lymphatics 2017; 6:6855] review figure 3. a-g) recanalization iliocaval occlusion with ivc filter (a and b: right and left venogram demonstrating bilateral cto with occluded ivc filter; c and d: ivc filter crush with 24 mm angioplasty balloon and subsequent stenting across filter; e: stenting up to hepatic vein confluence to provide good outflow using gianturco z stent across renal veins; f: iliocaval confluence stenting using gianturco z stent/wall stent technique; g: completion venogram). [veins and lymphatics 2017; 6:6855] [page 85] complications of iliac stenting and their management femoro-ilio-caval stenting can be performed with minimal mortality and low morbidity. reintervention is required at times. raju et al. noted a reintervention rate of 13% following femoro-ilio-caval stenting in 1085 limbs. median time to reintervention after the initial procedure was 15 months. post-reintervention the group reported cumulative improvement in pain and swelling of 67% and 72%, respectively, at 18 months follow-up. complete cumulative healing of venous dermatitis/ulcer at 12 months’ post-reintervention was 90%.19 some of the potential complications that can be encountered are considered in the following paragraphs. access site-related such complications can be reduced by use of ultrasound guidance for access. clinically significant hematoma/arterial injury/pseudoaneurysm/nerve injury is extremely rare (<0.1%). in most cases access site hematomas can be effectively managed with compression and delayed start of anticoagulation. pseudoaneurysm, when indicated, is best managed by ultrasound-guided thrombin injection. patients who sustain nerve injuries attain symptom relief over time. however, counseling and setting realistic expectations are key. vein injury/rupture frank rupture of the intervened vein is uncommon due to relatively low pressure and significant periadventitial fibrosis around the vein. when rupture occurs use of a stent graft can help exclude the site of extravasation.20 in-stent restenosis in-stent restenosis (isr) arises from either thrombus buildup or neointimal hyperplasia within the stent. the authors note an incidence of up to 25% in their experience. patients presenting with recurrence of symptoms require reintervention with angioplasty. this often involves use of an angioplasty balloon larger than the rated size of the stent used (e.g., for a 20 mm stent we can use a 22 mm angioplasty balloon). this is termed hyperdilation as opposed to isodilation, which is dilation with use of an angioplasty balloon of the same rated diameter as the stent. therapeutic anticoagulation and use of cilastazol immediately after index stent procedure may help reduce occurrence. stent compression stent compression occurs due to extrinsic compression of the stent due to fibrotic tissue build up. this is a phenomenon unique to the venous system. incidence is significantly lower than isr, with treatment being hyperdilation in symptomatic patients. larger caliber balloons may have to be used to overcome the stent compression (22-24 mm) than in isr. stent thrombosis layering of thrombus within the stent occurs can occur due to poor inflow, poor outflow or mechanical effects of an inadequate stent stack with potential for stent thrombosis. the overall incidence of stent thrombosis is approximately 3.5% in the authors experience, with chronic thrombosis more common than acute.21 contributing factors to an inadequate stent stack include use of undersized stent and understenting (not covering all areas of disease). lack of perioperative use of anticoagulation/ antiplatelet agent(s) can also contribute to stent thrombosis. restenting after fracturing the previously placed undersized stents with large caliber angioplasty balloons or extension of stent stack proximally or distally as the case may be is required for undersized stent and under stenting, respectively. for acute/subacute occlusions treatment is with pharmacomechanical thrombectomy +/– balloon maceration (no pulmonary embolisms in the authors experience). for more chronic occlusions (cto), recanalization can be pursued as described earlier. acceptable results have been noted in both situations. laser recanalization or radiofrequency wire recanalization has also been used as a last resort in occluded stents with modest success. review figure 4. bilateral stenting with use of gianturco z stents overcomes challenges arising from double barrel and fenestral techniques. figure 5. bilateral stenting using fenestrum creation through contralateral stent. used when contralateral stent extends to ipsilateral caval wall and "standard" gianturco z stent/wallstent combination is not an option. [page 86] [veins and lymphatics 2017; 6:6855] review [veins and lymphatics 2017; 6:6855] [page 87] contralateral iliac vein thrombosis this is a rare event occurring from jailing of contralateral common iliac vein by ipsilateral stent. it can be overcome by use of wallstent-gianturco z stent (boston scientific, marlborough, macook medical, bloomington, in) combination and limiting extension into ivc. the latter technique reduces the risk of contralateral thrombosis by up to 85%.22 stent migration occurs due to the choke point effect of the iliac confluence. it is imperative to extend the stent stack proximal to the confluence to overcome this effect. furthermore, use of the gianturco z stent (cook medical, bloomington, in) helps provide additional radial force and checks migration. mortality worldwide experience has proven venous stenting to be a low-risk procedure with negligible morbidity and mortality.23 references 1. kahn sr, comerota aj, cushman m, et al. the postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the american heart association. circulation 2014;130: 1636-61. 2. raju s, neglen p. high prevalence of nonthrombotic iliac vein lesions in chronic venous disease: a permissive role in pathogenicity. j vasc surg 2006;44:136-43; discussion 44. 3. titus jm, moise ma, bena j, et al. iliofemoral stenting for venous occlusive disease. j vasc surg 2011;53:70612. 4. garg n, gloviczki p, karimi km, et al. factors affecting outcome of open and hybrid reconstructions for nonmalignant obstruction of iliofemoral veins and inferior vena cava. j vasc surg 2011;53:383-93. 5. raju s bw, crim w, jayaraj a. optimal sizing of iliac vein stents. phlebol venous forum r soc med 2017 [in press]. 6. neglen p, tackett tp, jr., raju s. venous stenting across the inguinal ligament. j vasc surg 2008;48:1255-61. 7. kurklinsky ak, bjarnason h, friese jl, et al. outcomes of venoplasty with stent placement for chronic thrombosis of the iliac and femoral veins: single-center experience. j vasc interv radiol 2012;23:1009-15. 8. neglen p, hollis kc, olivier j, raju s. stenting of the venous outflow in chronic venous disease: long-term stent-related outcome, clinical, and hemodynamic result. j vasc surg 2007;46:979-90. 9. kolbel t, lindh m, akesson m, et al. chronic iliac vein occlusion: midterm results of endovascular recanalization. j endovasc ther 2009;16:483-91. 10. fatima j, algaby a, bena j, et al. technical considerations, outcomes, and durability of inferior vena cava stenting. j vasc surg 2015;3:380-8. 11. raju s, hollis k, neglen p. obstructive lesions of the inferior vena cava: clinical features and endovenous treatment. j vasc surg 2006;44:820-7. 12. murphy eh, johns b, varney e, raju s. endovascular management of chronic total occlusions of the inferior vena cava and iliac veins. j vasc surg venous lymph disord 2017;5:47-59. 13. neglen p, oglesbee m, olivier j, raju s. stenting of chronically obstructed inferior vena cava filters. j vasc surg 2011;54:153-61. 14. raju s, ward m, jr., kirk o. a modification of iliac vein stent technique. ann vasc surg 2014;28:1485-92. 15. de wolf ma, jalaie h, van laanen jh, et al. endophlebectomy of the common femoral vein and arteriovenous fistula creation as adjuncts to venous stenting for post-thrombotic syndrome. br j surg 2017;104:718-25. 16. de wolf ma, arnoldussen cw, wittens ch. indications for endophlebectomy and/or arteriovenous fistula after stenting. phlebol venous forum r soc med 2013;28 suppl 1:123-8. 17. comerota aj. venous thrombectomy and arteriovenous fistula versus anticoagulation in the treatment of iliofemoral venous thrombosis. j vasc surg 1992;15:887-9. 18. comerota aj, grewal nk, thakur s, assi z. endovenectomy of the common femoral vein and intraoperative iliac vein recanalization for chronic iliofemoral venous occlusion. j vasc surg 2010;52:243-7. 19. raju s, tackett p, jr., neglen p. reinterventions for nonocclusive iliofemoral venous stent malfunctions. j vasc surg 2009;49:511-8. 20. adams mk, anaya-ayala je, davies mg, bismuth j, peden ek. endovascular management of iliac vein rupture during percutaneous interventions for occlusive lesions. ann vasc surg 2012;26:575e5-9. 21. jayaraj acw, murphy eh, raju s. occlusion following iliocaval stentingcharacteristics and outcomes. j vasc surg 2016;63:53s-4s. 22. murphy eh, johns b, varney e, et al. deep venous thrombosis associated with caval extension of iliac stents. j vasc surg venous lymph disord 2017;5:8-17. 23. raju s. best management options for chronic iliac vein stenosis and occlusion. j vasc surg 2013;57:1163-9. franz schelling letter to the editor corner how to prevent further chronic cerebrospinal venous insufficiency in multiple sclerosis misadventures? franz schelling, md gaissau, austria dr.franz.schelling@gmail.com hector ferral, md northshore university healthsystem, department of radiology, section of interventional radiology, chicago, usa hectorferral@gmail.com sir, reading of the editorial published on neurology by bourdette and cohen, who claimed for ending a therapeutic ccsvi in ms misadventure, we would briefly discuss on how to prevent it.1 envisaging brain and cord changes that relate to the more central venous changes of ccsvi is the first step. the diagnosis of ccsvi is based upon venous flow reversals, narrowings, and direct or position-dependent signs of venous stasis. the related flow reversals deep in the brain find little attention.2,3 bedside diagnoses of ms have no concrete identifying features. they rely on cryptogenic neurodysfunctions perchance fitting in with pragmatically convened on patterns of a progression in time. writing statistics on the co-occurrence of ccsvi with cerebrospinal dysfunctions defined but by numbers and times cannot but breed further misadventures.3 a recent re-evaluation of ccsvi criterion two, the expiratory cerebral venous flow reversal stresses its topical relevance.2 corresponding pressure surges arise during compressions of extracranial veins in dependence of some hindrance to the venting of pressurized venous blood in direction of the heart and an insufficient venting via collaterals. ccsvi criterion two directly explains the emergence of the vein-specific brain pathology peculiar to ms.4,5 focusing on the vein-specific ms symptom relationship and further research on the topic will prevent us from ruining the prospects of ccsvi-ms patients desperate for a cure. references bourdette dn, cohen ja. venous angioplasty for "ccsvi" in multiple sclerosis: ending a therapeutic misadventure. neurology 2014 2014;83:388-9. [crossref] [pubmed] tromba l, blasi s, vestri a, et al. prevalence of chronic cerebrospinal venous insufficiency in multiple sclerosis: a blinded sonographic evaluation. phlebology 2013 nov 15. [epub ahead of print]. [full text] [pubmed] zamboni p, menegatti e, occhionorelli s, salvi f. the controversy on chronic cerebrospinal venous insufficiency. veins and lymphatics 2013;2:e14. [crossref] ms-info.net; epub 2002. available from: http://www.ms-info.net/evo/msmanu/1021.html schelling f. chronic cerebrospinal venous insufficiency in multiple sclerosis: weighing the findings. sang thrombose vaisseaux 2012;24:394-404. [abstract] [top] hrev_master veins and lymphatics 2018; volume 7:7199 [page 8] [veins and lymphatics 2018; 7:7199] who knows the rationale of the refilling time measured by plethysmography? claude franceschi centre de soins marie thérèse, paris, france abstract this mini-review analyzes the pathophysiology significance of the refilling time (rt) assessed in limbs after exercise by the means of plethysmographic techniques. based on such a rationale the author offers an interpretation of rt following suppression of reflux points respectively achieved by chiva or by ablative techniques, showing the pathophysiologic differences between two different and controversial strategies of managing chronic venous insufficiency. pathophysiology significance of the refilling time let’s analyze the rationale of the refilling time (rt) in order to understand the related hemodynamics basis, as well as field and borders of interest in the venous insufficiency assessment. normally, the leg elevation as well as the calf pumping exhausts the calf blood volume accumulated by the standing or sitting still posture. reclining down the leg or pumping stop reverses the pressure gradient but not the flow because it closes the valves. the valves open again when the refilling of the venous bed is achieved. the normal plethysmographic rt by calf pumping measured at the end of several free foot flexions and dorsi-flexions ranges between 18 and >20 seconds. the venous bed is quicker refilled and consequently the rt time is shortened by the reflux due to the deep and/or superficial valve incompetence (figure 1). furthermore, rt is also proportional to the volume reduction achieved by the previous calf pumping or leg elevation. this reduction is obtained at maximum during the elevation while it depends on the pump efficiency during the calf activation. so, due to the difference of volume reduction, the expected rt will be longer after elevation than after calf activation. the calf pump efficiency can be impaired by several reasons, as valve incompetence, venous obstacles, and defect of muscle volume, strength or mobility. according to cestmir recek’s the strain gauge measurements improved the plethysmographic parameters as follows: after great saphenous vein (gsv) crossectomy, the mean of 30 measurements was: refill time t-90 by 24.5 s; t-50 by 10.6 s; refill volume by 0.94 ml/100 ml (a mean of 30 measurements).1 after crossectomy and stripping, the mean of 18 measurements was: refill time t90 by 26.2 s; t-50 by 10.8 s; refill volume by 1.1 ml/100 ml.² the recek’s conclusion was: the differences were minimal and the postoperative results both after high ligation and after high ligation plus stripping were well in the range of normal values. the hemodynamic analysis of these results shows limitations and sometimes misinterpretations of the data. indeed, though very minimal in terms of figures, the rt difference after crossectomy alone and crossectomy + stripping is very relevant in terms of pathophysiology and paradoxically not in favor of the supposed best result, i.e after stripping. in fact, the improved rt reflects not only the overloading reflux volume abolition, but it also inevitably reflects the impairment of the physiologic superficial flow caused by stripping or any endovenous destructive procedure. in case of sapheno-femoral junction (sfj) and gsv total incompetence, the refilling time is shortened by the huge spill from the femoral vein (n1 network) into n1 again but below the knee via the gsv (n2 network) then. this represents a typical closed shunts (n1>n2>n1). the gsv closed shunt disconnection at the sfj eliminates n1 flow, and leaves behind n2 flow only, which achieves a normal range rt1 despite a still reversed gsv flow. as a matter of fact, the physiological drainage hierarchy is restored (n2>n1 instead of n1>n2>n1). yet, the rt normalization does not take account of a still too high foot-groin hydrostatic pressure though shorter than the previous foot-heart height. stripping or saphenous endovenous ablation not only suppress the foot-groin column but increases rt even more because the whole gsv physiological flow is also ablated. this explains the slightly longer refilling time after stripping2 i.e after ablation of most of the n2 volume flow. this last plethysmographic improvement reflects in fact superficial drainage impairment. as a matter of fact, stripping or any other endo venous superficial ablative techniques impair the skin drainage, which is responsible for reactive neo-angiogenesis, matting, telangiectasias and varicose recurrence. that is why rt interpretation following surgery does not take into account all the aspects of the venous insufficiency, particularly the hydrostatic pressure and the drainage impairment. that is why in case of sfj and total gsv trunk incompetence (n2) the column should be segmented twice, at the groin and below the knee (flush below a leg re-entry perforator). most of the time, the gsv trunk is incompetent at the thigh but competent below the knee and the reflux reaches the ankle or the foot through an incompetent tributary (n3). in that case, if there is an interposed re-entry perforator on the gsv trunk, the second hydrostatic column segmentation is performed flush the n2>n3 escape point, and stops at the same time the shunt ii overload n2>n3. in shunt iii, there is no available interposed re-entry on the n2 trunk. then, the n2>n3 flush ligation is a first step of the chiva 2 steps strategy. the one step strategy is possible. it consists of both n1>n2 and n2>n3 flush ligation combined with a n2 devalvulation down to a re-entry perforator. this chiva strategy segments the superficial network in two distinct drained territories (thigh and leg). consequently, rt at the leg is improved, even if not as much after stripping but for a better functional result and less recurrence.3-9 so the refilling time is fortunately increased up to the normal range but less than after stripping or endo-venous ablative procedures. furthermore, the concept of reflux should be revisited. indeed, the normal refilling time restore after crossectomy or chiva crossotomy despite a still reversed flow (reflux) demonstrates that the reflux after chiva is not pathogenic flow because it is no more overloaded and drains the tissues according to the physiological hierarchy n3>n2>n1 or n3>n1. finally, as reported in one of the first prospective randomised study10 comparing chiva with compression in the treatment correspondence: claude franceschi, centre de soins marie thérèse, paris, france. e-mail: claude.franceschi@gmail.com key words: plethysmography; venous pathophysiology; chronic venous insufficiency; chiva; saphenous ablation; lower limb drainage. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright c. franceschi, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7199 doi:10.4081/vl.2018.7199 no nco mm er cia l u se on ly brief report [veins and lymphatics 2018; 7:7199] [page 9] of venous ulceration, the surgical group showed a sifnificant improvement of all plethysmographic parameters except of ejection fraction, at 6 months. however, the reverse direction of the flow is not responsible for inflammation but just its amount.11,12 references 1. recek c, karisch e, gruber j. veränderungen der perforansvenen und tiefen unterschenkelvenen nach beseitigung des saphena-refluxes. phlebologie 2000;29:37-40. 2. recek c. saphena-reflux als ursache der venösen zirkulationsstörung bei primärer varikose mit chronischer veneninsuffizienz. acta chir austriaca 1998. 3. franceschi c, cappelli m, ermini s, et al. chiva: hemodynamic concept, strategy and results. int angiol 2016;35:8-30. 4. pares jo, juan j, tellez r, et al. varicose vein surgery: stripping versus the chiva method: a randomized controlled trial. ann surg 2010;251:62431. 5. carandina s, mari c, de palma m, et al. varicose vein stripping vs haemody namic correction (chiva): a long term randomised trial. eur j vasc endovasc surg 2008;35:230-7. 6. bellmunt-montoya s, escribano jm, dilme j, martinez-zapata mj. chiva methodfor the treatment of chronic venous insufficiency. cochrane database syst rev 2013;7:cd009648. 7. chan c-y, chen t-c, hsieh y-k, huang j-h. retrospective comparison of clinical outcomes between endovenous laser and saphenous vein-sparing surgery for treatment of varicose veins. world j surg 2011;35:1679-86. 8. wang h, chen q, fei z, et al. hemodynamic classification and chiva treatment of varicose veins in lower extremities (vvle). int j clin exp med 2016;9:2465-71. 9. mendoza e. primum non nocere. veins and lymphatics 2017;6:6646. 10. zamboni p, cisno c, marchetti f, et al. minimally invasive surgical management of primary venous ulcers vs. compression treatment: a randomized clinical trial. eur j vasc endovasc surg 2003;25:313-8. erratum in: eur j vasc endovasc surg 2003;26:337-8. 11. tisato v, zauli g, gianesini s, et al. modulation of circulating cytokinechemokine profile in patients affected by chronic venous insufficiency undergoing surgical hemodynamic correction. j immunol res 2014;2014: 473765. 12. zamboni p, spath p, tisato v, et al. oscillatory flow suppression improves inflammation in chronic venous disease. j surg res 2016;205:238-45. figure 1. in case of venous incompetence, the diastolic refilling time will be quicker, less than 20 seconds, fed by the venous reflux, in proportion to the valve incompetence rate. a: emptying volume and time. b: refilling volume and time in case of venous incompetence: capillary ouflow + relux flow. c: refilling volume and time normal venous competence: capillary ouflow. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2015; volume 4:4570 [page 24] [veins and lymphatics 2015; 4:4570] analysis of patients with chronic cerebro-spinal venous insufficiency and multiple sclerosis: identification of parameters of clinical severity sandro mandolesi,1 aldo d’alessandro,2 marco matteo ciccone,3 annapaola zito,3 ettore manconi,4 tarcisio niglio,5 augusto orsini,6 dimitri mandolesi,7 alessandro d’alessandro,8 francesco fedele1 1department of cardio-vascular and respiratory sciences, la sapienza university, roma; 2department of neuroscience, imaging and clinical sciences, chieti-pescara university; 3cardiovascular diseases section, department of emergency and organ transplantation (deto), university of bari; 4department of cardiovascular and neurological sciences, university of cagliari; 5italian national health institute, roma, italy; 6department of vascular surgery, gioia hospital, sora (fr); 7medicina del lavoro, la sapienza university, roma, italy; 8faculty of medicine, foggia, italy abstract the aims of this study were: i) analysis of clinical severity evolution in multiple sclerosis patients; ii) identification of temporal indicators for clinical worsening. we investigated by echo-color-doppler (ecd) 789 patients (490 female plus 299 male), aged 45.4 years, with chronic cerebro-spinal venous insufficiency (ccsvi) and multiple sclerosis (ms). all patients tested positive for ccsvi by ecd assessment were divided into three groups, namely: type 1 ccsvi (371) presenting an endo-vascular obstacle to the venous drainage; type 2 ccsvi (40) presenting an extra-vascular obstacle to the venous drainage, for external compression of the vessel; type 3 ccsvi (315) presenting both venous endo-vascular and extra-vascular obstructed drains. we analyzed the morphological and hemodynamic data recorded on computerized map (mem-net). all data were collected by respecting the italian privacy laws and they are available on the national epidemiological observatory on ccsvi website (www.osservatorioccsvi.org). we focused in the three main parameters in all studied patients. first parameter was expanded disability status scale (edss) score; second parameter was illness duration; third parameter was ccsvi type. the ms duration values stratified by edss grouped values in ccsvitype-1 and ccsvi-type-3 patients shows that the differences were statistical significant by kruskal-wallis test: h=44.2829; degree of freedom=1 for ccsvi-type-1 (p<0.001); and h=37.3036; degree of freedom=1 for ccsvitype-3 (p<0.001). the present study confirmed and completed scientific literature about relation between ccsvi and ms. on the same time, we found a strong correlation between ms illness duration and severity of edss score. in fact there is a clinical severity worsening after 11 years of illness in ms patients with ccsvi type-1 or type-3 (p<0.001). these data may suggest the influence of chronic vascular disease on ms. further searches need in order to learn more about this new aspect in ms etiology. introduction multiple sclerosis (ms) is an inflammatory demyelinating disease with autoimmune pathogenesis that affects the central and peripheral nervous system, causing a variety of clinical signs and symptoms;1 these are mainly due to scar formation (better known as plaques or lesions) that form in the white matter of the spinal cord and brain.2,3 it is estimated that this disease has a prevalence that ranges between 2 and 150 cases per 100,000 individuals.4 it is believed that multiple sclerosis is an immune-mediated disease caused by a complex interaction between genetic subset of the individual and not yet identified environmental factors.5 in 2008, paolo zamboni noted that multiple sclerosis is related to altered vasculature where the cervical and thoracic veins are not able to efficiently remove blood from the central nervous system presumably because of stenosis and malformations of jugular veins and azygos.6-8 therefore, he identified it as chronic cerebro-spinal venous insufficiency (ccsvi) and diagnosed it on the basis of hemodynamic alterations in relation to postural changes of the extra-and intracranial veins studied by doppler sonography.9 according to zamboni, ccsvi itself would facilitate ferrous cerebral accumulation, to which the body would respond with an immune reaction.10 zamboni discovered this condition in most of people affected with multiple sclerosis, and after performing a surgical procedure to correct the problem stated that 73% of patients had achieved improvements.7 the aim of this study was to analyze the evolution of the profiles of clinical severity in a sample of patients with multiple sclerosis and ccsvi with the intent to identify any temporal indicators of clinical worsening. materials and methods we assessed by echo-color-doppler method (ecd) 789 patients with multiple sclerosis, their diagnosis was made in compliance with mcdonald’s revised criteria.11,12 all patients were assessed in the department of cardiovascular, respiratory, geriatric and morphologic sciences of polyclinic umberto i of rome. among the patients, 490 were female, 299 were male, with an overall mean age of 45.4 years. a total of 728 patients tested positive for ccsvi, while 61 were negative. in addition the morphological and hemodynamic ecd data were analyzed using a computerized map. this is a hemodynamic and morphological map named mem-net, adopted after the consensus conference of the national scientific societies of vascular area to share the symbols and terminology to use for writing mem-net mapping for a shared and standardized database. this allows us to stratify the data in the different degrees of venous disease, providing answers on the likely impact of ccsvi in ms and the various treatment options. all data were collected by respecting the italian privacy laws and available on the national epidemiological observatory on ccsvi website (www.mem-net.it). all patients tested positive for ccsvi by ecd assessment were divided into three groups, namely: i) patients affected by type 1 ccsvi (371) presenting an endo-vascular obstacle to the venous drainage, with congenital or acquired abnormalities that restrict and block the drainage of the investigated veins; ii) patients affected by type 2 ccsvi (40) presenting an extra-vascular obstacle to the venous drainage, for external compression of the vessel; iii) patients affected by type 3 ccsvi (315) presenting both venous endo-vascular and extra-vascular obstructed drains. in order to simplify this classification, we correspondence: sandro mandolesi, via san montebello 17, 00185, roma, italy. tel.: +39.335.6512303 fax: +39.06.4873984. e-mail: s.mandolesi@email.it key words: multiple sclerosis, chronic cerebrospinal venous insufficiency, echo-color-doppler. received for publication: 12 july 2014. revision received: 4 march 2015. accepted for publication: 5 march 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s. mandolesi et al., 2015 licensee pagepress, italy veins and lymphatics 2015; 4:4570 doi:10.4081/vl.2015.4570 no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:4570] [page 25] can say that there is a hydraulic ccsvi (type 1), a mechanical ccsvi (type 2) and a mixed ccsvi of the previous two types (type 3). the method used to diagnose the presence of an obstacle due to external compression of the vessel (ccsvi type 2) and not by narrowing the inside of the same (ccsvi type 1) was a simple intuition: through the valsalva maneuver and appropriate rotation of the head by the examined subject, it was possible to note a significant change in the crossing section area and the reappearance of the flow within the studied vessel. we have presented in 2011 at the national congress of the italian society of cardiology the division into 3 types of ccsvi.13,14 we focused three main parameters to stratify all studied patients for parametric and nonparametric statistical tests. first parameter was ccsvi-type; second parameter was ill duration; third parameter was expanded disability status scale (edss) total score. in our sample the ccsvi-type-2 patients were few in number for statistical tests; so we analyzed only ccsvi-type-1 and ccsvi-type-3 patients. after the analysis of variance (anova), we divided all ill duration into two groups (before and after the median value): less than 12 years (1-11 years of illness) and more than 11 years (12 or more). edss total scores were analyzed as natural values (see kurtzke,15 for details) or as grouped values. we stratified edss total scores into three categories: 123 or mild impairment (edss total score: 1 or 2 or 3); 456 or medium impairment (edss total score: 4 or 5 or 6); 789 or severe impairment (edss total score: 7 or 8 or 9). in our tests, we considered only mild (123) and severe (789) grouped edss values. medium status of illness (456 grouped edss values) was not considered to increase strength in differences between initial and final ms period. diagnosis of chronic cerebro-spinal venous insufficiency by echo-colordoppler in order to make a diagnosis of ccsvi, according to zamboni’s protocol, it is necessary that the patient has at least 2 of the following 5 parameters: i) reflux in internal jugular veins and/or vertebral veins in the supine and sitting position; reflux disease is defined as a reverse flow that lasts more than 0.88 seconds;16 ii) reflux in intracranial veins (internal cerebral vein, basal vein of rosenthal, and great cerebral vein of galen); iii) presence of stenosis in the internal jugular vein using bmode high-resolution echography; in this regard it is possible to identify hemodynamically (intraluminal defects such as fixed valves and/or malformed valves, spider webs, septa) or hemodynamically presence of stenosis in the internal jugular vein b-mode high-resolution in this regard it is possible to identify stenosis hemodynamically (intraluminal defects such as fixed valves and/or malformed, spider webs, septa) or nothemodynamically significant stenosis;17 iv) no detectable flow using doppler in the internal jugular veins and/or vertebral veins; v) reverse postural control of the main cerebral venous outflow pathways by evaluating the d cross sectional area (dcsa) in the internal jugular vein, that is the difference between the circumference of the internal jugular vein in the supine and sitting position, measured at its midpoint,18-22 the finding of a negative csa indicates a loss of postural control of the predominant way of venous drainage in the supine position. during the ecd assessment before the patient is positioned in the supine position and then in a sitting position; the examination is conducted with both quiet breathing (without moving shoulders, to activate the respiratory pump and check if there is an induction of cerebro-spinal drainage) and deep breathing (to induce the maximum flow in the vessels which must be examined and for assessing the correct drainage and valvular functioning). in all our ecd assessments we performed the following ecd dynamic tests: neck movements, on right, on left rotation and anterior/posterior intrusion of the neck; valsalva’s maneuver, performed by moderately forceful attempted exhalation against a closed airway, usually done by closing one’s mouth and pinching one’s nose shut. the protocol requires the use of two probes: a 6.6-10 mhz linear probe, which is necessary for scanning the veins of the neck and a transcranial probe from 2.0 to 3.3 mhz for the study of the intracranial circulation. it can optionally be used a micro-convex probe from 5.0 to 8.0 mhz that allows to make a more accurate assessment of the lower part of the neck vessels, i.e. jugular-subclavian ostium and intrarachidian veins.7 statistical analysis all data were analyzed by spss software to perform a stratified data description for numeric parametric variables. statistical significance between and within groups was calculated on continuous variables by anova to test the equality of means. the chi-square (c²) yates corrected test was used for non-continuous variables by statcalc and analysis programs from epi-info (2008, nih & cdc atlanta, ga, usa; italian version 3.5.1). a p value less than 0.05 was considered significant, and 95% confidence intervals were also calculated. the collected data of this study were assessed by the kruskal-wallis statistical test that is the non-parametric equivalent test of the analysis of variance in which the data are replaced by their rank; it was used because the studied population did not follow a normal gaussian distribution. this non-parametric method has the purpose of comparing the equality of medians in the different groups. results in table 1 we show the cross tabulation between edss grouped values vs ms duration (less or more than 11 years) in ccsvi-type-1 and ccsvi-type-3 patients. the differences were statistical significant (p<0.001). in table 2 we show the anova of edss values stratified by ms duration in ccsvi-type-1 and ccsvi-type-3 patients. the differences were statistical significant by kruskal-wallis test: h=8.0345; degree of freedom=1 for ccsvi-type-1 (p<0.01); and h=8.4757; degree of freedom=1 for ccsvi-type-3 (p<0.01). in table 3 we show the anova of ms duration values stratified by edss grouped values in ccsvi-type-1 and ccsvi-type-3 patients. the differences were statistical significant by kruskal-wallis test: h=44.2829; degree of freedom=1 for ccsvi-type-1 (p<0.001); and h=37.3036; degree of freedom=1 for ccsvitype-3 (p<0.001). in table 4 we show the anova of edss values stratified by ccsvi-type-1 or ccsvi-type-3 patients in ms duration values (less or more than 11 years). the differences relived were not statistical significant. if we consider instead the edss profiles of three clinical types we find that the relapsingremitting (rr) patients are more present in the period before 11 years, the secondary progressive (sp) are more frequent after 11 years and the primary progressive (pp) uniformly distributed in the pre-and post-11 years. discussion the present study confirmed the data on the prevalence of ccsvi in ms patients, already mentioned in previous papers. in a large study, which involved 6 centers, bastianello et al. analyzed the clinical data of 710 ms patients who underwent venous echo-color-doppler. significant associations were found between ccsvi and clinical data.23 similar results were quite recently described by an active multicenter epidemiological registry.24 therefore, our results replicate those coming from developed international scientific literature about this topic, as well as from several confirming metaanalysis.25 recently it was also shown that diagnostic procedure by ecd is reproducible between different operators from the technical perspective.26 in recent years several studies have dealt with the association between ccsvi no n c om me rci al us e o nly article [page 26] [veins and lymphatics 2015; 4:4570] table 1. cutoff in chronic cerebro-spinal venous insufficiency-type-1 and -type-3 patients. edss ms duration (years) total type-1 type-3 type-1 type-3 grouped values <12 >11 <12 >11 123 73 22 40 28 95 68 row % 76.8 23.2 58.8 41.2 100.0 100.0 % column 82.0 34.9 75.5 32.6 62.5 48.9 789 16 41 13 58 57 71 row % 28.1 71.9 18.3 81.7 100.0 100.0 % column 18.0 65.1 24.5 67.4 37.5 51.1 total 89 63 53 86 152 139 row % 58.6 41.4 38.1 61.9 100.0 100.0 % column 100.0 100.0 100.0 100.0 100.0 100.0 p<0.001 p<0.001 edss, expanded disability status scale; ms, multiple sclerosis. table 2. expanded disability status scale values in cerebro-spinal venous insufficiency-type-1 and -type-3 patients. ms duration obs σ mean variance std.dev. (years) type-1* type-3° type-1* type-3° type-1* type-3° type-1* type-3° type-1* type-3° <12 16 15 630.000 735.000 39.375 49.000 62.625 64.000 25.025 25.298 >11 26 25 1600.000 1705.000 61.538 68.200 43.954 24.767 20.965 15.737 minimum 25% median 75% maximum mode type-1* type-3° type-1* type-3° type-1* type-3° type-1* type-3° type-1* type-3° type-1* type-3° <12 15.000 15.000 15.000 25.000 25.000 65.000 65.000 65.000 75.000 85.000 15.000 65.000 >11 15.000 15.000 65.000 65.000 65.000 75.000 75.000 75.000 85.000 85.000 65.000 75.000 ms, multiple sclerosis; obs, number of observations; σ, total sum; std.dev., standard deviation. *stratification by ms duration. kruskal-wallis: h=8.0345; degree of freedom (df)=1; p<0.01; °stratification by ms duration. kruskal-wallis: h=8.4757; df=1; p<0.01. table 3. multiple sclerosis duration values in cerebro-spinal venous insufficiency-type-1 and -type-3 patients. edss grouped obs σ mean variance std.dev. values type-1* type-3° type-1* type-3° type-1* type-3° type-1* type-3° type-1* type-3° 123 95 68 742.0000 733.0000 7.8105 10.7794 44.0701 58.2640 6.6385 7.6331 789 57 71 990.0000 1480.0000 17.3684 20.8451 84.1654 87.8471 9.1742 9.3727 minimum 25% median 75% maximum mode type-1* type-3° type-1* type-3° type-1* type-3° type-1* type-3° type-1*type-3° type-1* type-3° 123 0.0000 0.0000 2.0000 4.5000 6.0000 9.0000 11.0000 16.0000 27.0000 36.0000 2.0000 2.0000 789 3.0000 5.0000 11.0000 14.0000 16.0000 21.0000 22.0000 28.0000 46.0000 50.0000 11.0000 31.0000 edss, expanded disability status scale; obs, number of observations; σ, total sum; std.dev., standard deviation. *stratification by edss grouped values. kruskal-wallis: h=44.2829; degree of freedom (df)=1; p<0.001; °stratification by edss grouped values. kruskal-wallis: h=37.3036; df=1; p<0.001. table 4. expanded disability status scale values in patients with multiple sclerosis duration <12 and >11 years. ccsvi type obs σ mean variance std.dev. <12 years* >11 years° <12 years* >11 years° <12 years* >11 years° <12 years* >11 years° <12 years* >11 years° 1 16 26 63.0000 160.0000 3.9375 6.1538 6.2625 4.3954 2.5025 2.0965 3 15 25 73.5000 170.5000 4.9000 6.8200 6.4000 2.4767 2.5298 1.5737 minimum 25% median 75% maximum mode <12 years*>11 years° <12 years* >11 years° <12 years* >11 years° <12 years*>11 years° <12 years* >11 years° <12 years* >11 years° 1 1.5000 1.5000 1.5000 6.5000 2.5000 6.5000 6.5000 7.5000 7.5000 8.5000 1.5000 6.5000 3 1.5000 1.5000 2.5000 6.5000 6.5000 7.5000 6.5000 7.5000 8.5000 8.5000 6.5000 7.5000 ccsvi, chronic cerebro-spinal venous insufficiency; obs, number of observations; σ, total sum; std.dev., standard deviation. *stratification by ccsvi-type. kruskal-wallis: h=1.2725; degree of freedom (df)=1; not significant; °stratification by ccsvi-type. kruskal-wallis: h=2.5481; df=1; not significant. no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:4570] [page 27] and ms. among these, very interesting is the work conducted by zivadinov and co-workers, who described the effective association between the neurodegenerative disease (ms) and this functional-hemodynamic finding which affects the vessels draining the cerebral blood. furthermore they have shown that the higher disability the higher the prevalence of ccsvi is in ms patients. in particular, it emerged that the prevalence of ccsvi was higher in patients with progressive ms than in those with non-progressive ms. therefore the authors concluded with the assumption that a high probability of disease progression which was associated with a high level of clinical disability was induced by morphological and hemodynamic alterations of cerebral veins.27 in our previous study we have also found that patients aged more than 30 years showed a statistically significant higher presence of disabilities (mean edss score equal to 5) compared to younger patients (mean edss score equal to 3).28 the same considerations may be made in present study, in which we highlighted that ms clinical severity worsening in ccsvi patients after 11 years of disease duration (p<0.001). on 2009 zamboni suggested that the rr and sp clinical courses are associated with significantly different ccsvi patterns compared to those with pp form.7 in the same paper, zamboni suggest that location of venous obstructions could play a key role in determining the clinical course of the disease. yamout et al., however, have subsequently stated that the extra-cranial venous stenosis are unlikely the cause of ms, since in their study they were not present in most patients in the early stages of the disease and rarely involved more than one extra-cranial vein. they supposed, therefore, that ccsvi was a late secondary phenomenon.29 several authors have contrasted the initial hypothesis of zamboni, for example baracchini et al., in their work, have shown that ccsvi is not a late secondary phenomenon of ms and is not associated with the worsening of disability.30 baracchini himself, in 2011, did not support a cause-effect relationship between ccsvi and ms onset.31 centonze et al. in their work also found no statistically significant differences in the frequency of ccsvi in ms patients and controls.32 in addition, they have found no difference between patients ccsvi-positive and ccsvi-negative in terms of relevant clinical changes, such as the disease duration, the time that elapses between the onset and the first exacerbation, remitting or gradual course of disease and the risk of secondary progressive course. another datum emerged from this study: there were no statistically significant differences between ccsvi-positive and ccsvi-negative ms patients in mean edss, mean index of progression and mean score of severity of ms. no significant correlation was found between the severity of the disability and the number of positive criteria for ccsvi. their results therefore indicated that ccsvi has no role in either the risk or severity of ms. in present work, we do not found statistical significant differences between the different types of ccsvi and the edss score in patients with the same ms duration. patients with progressive ms had higher probability of having also ccsvi than those with rr ms. these findings suggested that the presence of ccsvi may favor a late development of ms in patients with a lower susceptibility to autoimmune diseases and may increase its severity. already, other studies have found scores of clinical severity generally higher in ccsvi-positive patients.33 recently, some papers stated that ccsvi has no effect on neurological function and on the progression of disability in patients with ms.34 other casecontrol clinical works35 showed that ccsvi was more frequent among ms patients with an ill duration more than 144 months. the same clinical aspects were found in sp ms and pp ms versus rr ms patients. a stronger association was found considering the forms sp and pp of ms. the authors therefore showed a higher frequency of ccsvi in ms patients, more evident in patients with advanced disease, suggesting that ccsvi may be related to disability in ms. still about the study of the association between ccsvi and clinical disability in ms, leone et al.36 evaluated the association of ccsvi with ms in a cross-sectional blinded study and sought some association of ccsvi with the prevalence of ms. the prevalence of ccsvi was related to age in ms patients but not in controls. ccsvi-positive and ccsvi-negative patients were similar in clinical type, age at onset of illness, disability and fatigue. the disease duration was greater in ccsvi-positive patients than in negative ones. the authors concluded that ccsvi was not associated with ms, nor its severity. in addition, they could not affirm that ccsvi is a consequence of ms or aging. from this examination of the literature we understand how there are different and conflicting opinions about the correlation between ccsvi and ms, especially with regard to its relationship with the age from first clinical evidence, the degree of ill progression and patient capabilities deterioration. conclusions present study confirmed and complete previous papers about relation between ccsvi and ms. on the same time, we found a strong correlation between ms illness duration and severity of edss score. in fact there is a clinical severity cut-off after 11 years of illness in ms patients with ccsvi-type-1 or ccsvi-type3. on the contrary, we did not found statistical significant differences comparing ms patients with ccsvi-type-1 versus ms patients with ccsvi-type-3. if we consider instead the edss profiles of three clinical types we find that the rr patients are more present in the period before 11 years, the sp are more frequent after 11 years and the pp uniformly distributed in the pre-and post-11 years. these data may suggest chronic vascular disease influence on ms. further searches need in order to learn more about this new aspect in ms etiology. references 1. compston a, coles a. multiple sclerosis. lancet 2008;372:1502-17. 2. clanet m. jean-martin charcot. 1825 to 1893. int ms j 2008;15:59-61. 3. charcot j. histologie de la sclerose en plaques. gazette des hopitaux, paris 1868;41:554-5. 4. rosati g. the prevalence of multiple sclerosis in the world: an update. neurol sci 2001;22:117-39. 5. compston a, coles a. multiple sclerosis. lancet 2002;359:1221-31. 6. zamboni p, galeotti r. the chronic cerebrospinal venous insufficiency syndrome. phlebology 2010;25:269-79. 7. zamboni p, galeotti r, menegatti e, et al. chronic cerebro-spinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80: 392-9. 8. radak d, kolar j, tanaskovic s, et al. morphological and haemodynamic abnormalities in the jugular veins of patients with multiple sclerosis. phlebology 2012; 27:168-72. 9. zamboni p, morovic s, menegatti e, et al. screening for chronic cerebrospinal venous insufficiency (ccsvi) using ultrasound recommendations for a protocol. int j angiol 2011;30:571-97. 10. singh av, zamboni p. anomalous venous blood flow and iron deposition in multiple sclerosis. j cereb blood flow metab 2009;29:1867-78. 11. polman ch, reingold sc, edan g, et al. diagnostic criteria for multiple sclerosis: 2005 revisions to the "mcdonald criteria". ann neurol 2005;58:840-6. 12. mcdonald wi, compston a, edan g, et al. recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. ann neurol 2001;50: 121-7. 13. mandolesi s, ciciarello f, marceca a, et al. no n c om me rci al us e o nly article [page 28] [veins and lymphatics 2015; 4:4570] data analysis of the chronic cerebro-spinal venous insufficiency in patients with multiple sclerosis: new disease classification. 72° congresso nazionale della società italiana di cardiologia, 10-12 dicembre 2011, roma, italy. 14. mandolesi s, manconi e, niglio t, et al. incidence of anatomical compressions of the internal jugular veins with full block of their flow in patients with chronic cerebro-spinal venous insufficiency and multiple sclerosis. in: allegra c, antignani pl, eds. proc. 21st eurochap-iua european chapter congress of the international union of angiology. sept 28-oct 1, 2013, rome, italy. turin: ed. minerva medica; 2013. pp 12-17. 15. kurtzke jf. rating neurologic impairment in multiple sclerosis: an expanded disability status scale (edss) neurology 1983;33:1444-52. 16. valdueza jm, schmierer k, mehraein s, einhaupl km. assessment of normal flow velocity in basal cerebral veins. a transcranial doppler ultrasound study. stroke 1996;27:1221-5. 17. lepori d, capasso p, fournier d, et al. high-resolution ultrasound evaluation of internal jugular venous valves. eur radiol 1999;9:1222-6. 18. schaller b. physiology of cerebral venous blood flow: from experimental data in animals to normal function in humans. brain res rev 2004;46:243-60. 19. valdueza, jm, von munster t, hoffman o, et al. postural dependency of the cerebral venous outflow. lancet 2000;355:200-1. 20. gisolf, j, van lieshout jj, van heusden k, et al. human cerebral venous outflow pathway depends on posture and central venous pressure. j physiol 2004;560:317-27. 21. schreiber sj, lurtzing f, gotze r, et al. extrajugular pathways of human cerebral venous blood drainage assessed by duplex ultrasound. j appl physiol 2003;94:1802-5. 22. menegatti e, zamboni p. doppler haemodynamics of cerebral venous return. curr neurovasc res 2008;5:260-5. 23. bastianello s, romani a, viselner g, et al. chroniccerebrospinalvenousinsufficiency in multiple sclerosis: clinicalcorrelates from a multicentrestudy. bmc neurol 2011;11:132. 24. mandolesi s, d’alessandro a, ciccone mm, et al. italian chronic cerebrospinal venous insufficiency national epidemio logical observatory methodology and preliminary data. veins and lympha tics 2014;3:4707. 25. zamboni p, menegatti e, occhionorelli s, salvi f. the controversy on chronic cerebrospinal venous insufficiency. veins and lymphatics 2013;2:e14. 26. ciccone mm, galeandro ai, scicchitano p, et al. multigate quality doppler profiles and morphological/hemodynamic alterations in multiple sclerosis patients. curr neurovasc res 2012;9:120-7. 27. zivadinov r, marr k, cutter g, et al. prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in ms. neurology 2011;77:138-44. 28. ciciarello f, mandolesi s, galeandro ai, et al. age-related vascular differences among patients suffering from multiple sclerosis. curr neurovasc res 2014;11:23-30. 29. yamout b, herlopian a, issa z, et al. extracranial venous stenosis is an unlikely cause of multiple sclerosis. mult scler 2010;16:1341-8. 30. baracchini c, perini p, causin f, et al. progressive multiple sclerosis is not associated with chronic cerebrospinal venous insufficiency. neurology 2011;77:844-50. 31. baracchini c, perini p, calabrese m, et al. no evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset. ann neurol 2011;69:90-9. 32. centonze d, floris r, stefanini m, et al. proposed chronic cerebrospinal venous insufficiency criteria do not predict multiple sclerosis risk or severity. ann neurol 2011;70:51-8. 33. weinstock-guttman b, cutter g, marr k, et al. clinical correlates of chronic cerebrospinal venous insufficiency in multiple sclerosis. multiple sclerosis 2010;16:s224. 34. garaci fg, marziali s, meschini a, et al. brain hemodynamic changes associated with chronic cerebrospinal venous insufficiency are not specific to multiple sclerosis and do not increase its severity. radiology 2012;265:233-9. 35. patti f, nicoletti a, leone c, et al. multiple sclerosis and ccsvi: a population-based case control study. plos one 2012;7: e41227. 36. leone ma, raymkulova o, nald pi, et al. chronic cerebrospinal venous insufficiency is not associated with multiple sclerosis and its severity: a blind-verified study. plos one 2013;8:e56031. no n c om me rci al us e o nly 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2012; volume 1:e2 [page 2] [veins and lymphatics 2012; 1:e2] retinal abnormalities in multiple sclerosis patients with associated chronic cerebrospinal venous insufficiency aneta adamczyk-ludyga,1 justyna wróbeł,1 marian simka,2 tomasz ludyga,2 paweł� latacz,2 marek kazibudzki2 1euromedic specialist clinics, department of ophthalmology, katowice, poland; 2euromedic specialist clinics, department of vascular & endovascular surgery, katowice, poland abstract optical coherence tomography (oct) is a non-invasive method for the assessment of optic nerve fibers and retinal ganglion cells. this study was aimed at the assessment of retinal abnormalities in multiple sclerosis patients in the context of chronic cerebrospinal venous insufficiency using oct of the retina and the optic nerve. we examined 239 multiple sclerosis (ms) patients, including 220 patients with associated chronic cerebrospinal venous insufficiency and 19 ms patients without venous pathology. the following oct parameters were assessed: average ganglion cell complex thickness, global loss volume, focal loss volume and average retinal nerve fibre layer thickness. abnormalities in the azygous and internal jugular veins were evaluated using catheter venography. we found a higher prevalence of abnormal oct parameters in the patients with previous history of optic neuritis, not only on the side of inflammatory event, but also in the contralateral eye, which is in line with already existing body of evidence. the new and intriguing discovery is that we found statistically significant higher prevalence of abnormal oct values in multiple sclerosis patients with unilateral stenosis of internal jugular vein. patients who were not found venous abnormalities, as well as those presenting with pathologic azygous or bilateral internal jugular venous outflows, did not demonstrate a changed frequency of abnormal oct parameters. potential association between venous malformations and eye manifestations of multiple sclerosis, as has been demonstrated in this report, justifies further studies on this topic. introduction optical coherence tomography (oct) uses light interference patterns to make a cross-section image of the layers of retina and intraocular portion of the optic nerve. in this way oct is capable of assessment of the retinal ganglion cells and their unmyelinated axons as they converge on the optic disc. this diagnostic tool provides precise and reproducible information on these structures in different pathologies affecting the anterior visual pathway, including also multiple sclerosis (ms).1-3 axonal loss within the anterior optic pathway in ms patients can be detected not only after an episode of optic neuritis (on), one of the most common manifestations of ms, but also in the patients without a history of on, thus reflecting a disperse ms-associated neurodegeneration.4-7 it has recently been described that majority of ms patients present with the so-called chronic cerebrospinal venous insufficiency (ccsvi), vascular pathology comprising venous malformations in the main veins draining the central nervous system.8,9 it this paper we present the results of study that evaluated relations between oct findings and venous outflow abnormalities in ms patients. we found that unilateral stenosis of the internal jugular vein (ijv), a subtype of ccsvi, was associated with an increased prevalence of abnormal oct values. materials and methods this ophthalmological study was a part of clinical trial on endovascular treatments for ccsvi in ms patients. the entire study was designed to assess safety and efficacy of endovascular procedures performed to alleviate venous outflow blockages in the main veins draining the central nervous system in these patients. the study was approved by the bioethical committee of the regional silesian board of physicians in katowice, poland (approval no: 7/2010) and was registered at clinicaltrials.gov; identifier: nct01264848. all patients provided their written consent to undergo the procedures and diagnostic tests. oct of the eyes was one of pre-procedural non-invasive tests. primary aim of this examination was to evaluate ms-related damage to the retina and optic nerves, and also to assess these abnormalities at follow-ups after endovascular treatments for ccsvi. in this paper we present oct findings before endovascular treatment. there were assessed 239 patients (476 eyes examined) with clinically defined ms, 168 women and 71 men. the patients were aged 17-69 years, with a median age of 43 years. they suffered from ms for 0.5 to 40 years, with a median duration of the disease of 10 years. reliable data on history of on were available in 180 patients: 103 patients presented with positive history of on, 57 on one side (23 of right optic nerve and 34 on the left side) and 46 bilaterally. oct examination was performed on rt100-2 oct scanner (optoview inc., fremont, ca, usa). the following oct parameters were assessed: i. average ganglion cell complex thickness (agcc) in the macula; ii. global loss volume (glv) of ganglion cell complex; iii. focal loss volume (flv) of ganglion cell complex; iv. average retinal nerve fibre layer thickness (arnfl). the findings were interpreted as: normal, borderline or pathological, according to the built-in software, which compared value of each oct parameter to the database coming correspondence: marian simka, ul. jednosci 20, 43-245 studzionka, poland. tel. +48.322.120.498. e-mail: mariansimka@poczta.onet.pl key words: multiple sclerosis, optic nerve, optical coherence tomography, retina, venous insufficiency. contributions: aa-l, jw, ms, tl, pl, mk, conception and design, article revising and final approval; aa-l, jw, interpretation of data, ophthalmological part of the study; ms, collection and interpretation of data, statistical analysis; tl, pl, mk, endovascular part of the study. conflict of interests: all authors are employed in the hospital, where the treatments for ccsvi are patient-paid; aa-l her family member is the coowner of hospital where the treatments for ccsvi are patient-paid; ms received publication fees from servier international and speaker fees from american access care; received congress costs reimbursement from esaote international; tl is the owner of patent on stent design that potentially could be used for the treatment of venous lesions (the stent is not yet available in the market); his family member is the co-owner of hospital where the treatments for ccsvi are patient-paid. acknowledgements: the paper has been presented at 2nd annual meeting of international society of neurovascular disease, orlando, usa, 18-22nd february 2012 and at 14th annual meeting of australasian college of phlebology, melbourne, australia, 30th march-3rd april 2011. received for publication: 14 march 2012. revision received: 21 may 2012. accepted for publication: 31 may 2012. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright a. adamczyk-ludyga et al., 2012 licensee pagepress, italy veins and lymphatics 2012; 1:e2 doi:10.4081/vl.2012.e2 no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e2] [page 3] from healthy population, after adjusting for the age, sex and ethnicity. hemodynamic and/or structural abnormalities in the ijvs, brachiocephalic and azygous veins were evaluated using catheter venography. in this study we did not include the patients with rather infrequently seen outflow blockages in the brachiocephalic veins, since these lesions actually represent tandem stenoses (together with coexisting lesions in the ijvs), making difficult an unequivocal interpretation of the results. the details of the venographic protocol for the assessment of examined veins can be found in our previous paper.10 the following venographic flow patterns were regarded abnormal and were categorised into four grades: i. grade 1: venous outflow slowed down, no reflux detected; ii. grade 2: venous outflow slowed down, mild reflux and/or pre-stenotic dilation of the vein; iii. grade 3: venous outflow slowed down, with reflux and outflow through collaterals; iv. grade 4: no outflow through the vein, huge outflow through collaterals. statistical analysis the χ2 test was used to test the null hypothesis that the frequencies of particular oct parameter were equal, regardless of the distribution of venous lesions, against the alternative hypothesis that these frequencies differed significantly between patients’ subgroups. the samples were compared to average oct results in ccsvi-positive patients. analysis was performed using past data analysis package (version 2.09; university of oslo, norway). significance of p values was set at p<0.05. results pathological optical coherence tomography parameters abnormal agcc values were found in 46.2% and borderline values in 12.4% of ms patients; glv values in 57.6% and 9.9%; flv values in 52.6% and 7.2%; arnfl values in 43.7% and 18.2%, respectively. pathological venographic findings venous outflow abnormalities in at least one vein draining the central nervous system (left or right ijv, or the azygous vein) were found in 220 cases (92.1% of the patients). lesions in one vein were found in 78 patients (32.6%), in two veins: 131 patients (54.8%) and in three veins: 11 patients (4.6%). most of the lesions were found in the ijvs, only two patients presented with isolated stenoses of the azygous vein. outflow abnormalities of the azygous vein, isolated or in combination with ijv lesions, were found in 17 patients (7.1%). figure 1. optical coherence tomography (oct) findings and venous abnormalities: average ganglion cell complex thickness: a, average findings [chronic cerebrospinal venous insufficiency (ccsvi) patients]; b, no ccsvi detected; c, one pathological vein (*p=0.04); d, two pathological veins; e, three pathological veins; f, pathological azygous vein; g, the only affected vein: ccsvi score=1; h, the only affected vein: ccsvi score=2; i, the only affected vein: ccsvi score=3 (**p=0.01); j, the only affected vein: ccsvi score=4 (***p=0.046); k, unilateral stenosis of internal jugular vein (ijv) (grade 3 or 4) ipsilateral eye (****p=0.03); l, unilateral stenosis of ijv (grade 3 or 4) contralateral eye (p=0.055). figure 2. optical coherence tomography (oct) findings and venous abnormalities: global loss volume of ganglion cell complex: a, average findings [chronic cerebrospinal venous insufficiency (ccsvi) patients]; b, no ccsvi detected; c, one pathological vein; d, two pathological veins; e, three pathological veins; f, pathological azygous vein; g, the most affected vein: ccsvi score=1; h, the most affected vein: ccsvi score=2; i, the most affected vein: ccsvi score=3; j, the most affected vein: ccsvi score=4; k, the only affected vein: ccsvi score=1; l, the only affected vein: ccsvi score=2; m, the only affected vein: ccsvi score=3 (*p=0.01); n, the only affected vein: ccsvi score=4 (p=0.06); o, unilateral stenosis of internal jugular vein (ijv) (grade 3 or 4) ipsilateral eye; p, unilateral stenosis of ijv (grade 3 or 4) contralateral eye. no nco mm er cia l u se on ly article [page 4] [veins and lymphatics 2012; 1:e2] correlations between optical coherence tomography findings and optic neuritis history we found a much higher prevalence of abnormal oct parameters in the patients with previous history of on, not only on the side of such an inflammatory event, but also in the contralateral eye. these differences were statistically significant if compared to the frequency of this ocular pathology in the patients with negative on history (details not shown). correlations between optical coherence tomography findings and venographic patterns of chronic cerebrospinal venous insufficiency we found a higher, statistically significant prevalence of abnormal oct parameters: agcc, flv and arnfl in the patients with unilateral stenosis of ijv, and also a trend towards such an increased frequency of pathologic glv values. looking into details, it could be seen that especially severe (grade 3 and 4) unilateral lesions were associated with increased prevalence of pathological oct values, while the patients with mild-degree lesions exhibited less frequent ocular abnormalities. although abnormal oct parameters were primarily found in the eyes ipsilaterally to high grade stenoses of the ijv, they were also seen even if this tendency was less pronounced in the eyes contralaterally to such a stenosis. ccsvi-negative patients, as well as those presenting with bilateral ijv stenoses, or azygous vein pathology, demonstrated a similar prevalence of abnormal oct results. only in the case of the flv, ccsvi-negative patients exhibited a trend towards less frequent oct abnormalities. the details of oct findings are presented in figures 1-4. discussion many authors, using oct techniques, have already described the signs of loss of retinal ganglion cells in ms patients. damage to these neurons was traditionally thought to be a result of on. indeed, frequency of retinal pathology measured with oct technology is more common in the cases with previous on and our findings are in line with these studies.6,7 still, we also revealed that abnormal oct values were more common in ms patients with unilateral blockage of the ijv. still, we were unable to demonstrate significantly changed prevalence of abnormal oct values in ms patients presenting with other anatomical variants of ccsvi (bilateral stenoses of the ijvs, lesions in the azygous vein) or in the patients with no venous pathology detected. figure 3. optical coherence tomography (oct) findings and venous abnormalities: focal loss volume of ganglion cell complex: a, average findings [chronic cerebrospinal venous insufficiency (ccsvi) patients]; b, no ccsvi detected; c, one pathological vein (*p=0.005); d, two pathological veins; e, three pathological veins; f, pathological azygous vein; g, the only affected vein: ccsvi score=1; h, the only affected vein: ccsvi score=2 (**p=0.04 ocular abnormalities less frequent); i, the only affected vein: ccsvi score=3 (***p=0.006); j, the only affected vein: ccsvi score=4 (****p=0.02); k, unilateral stenosis of internal jugular vein (ijv) (grade 3 or 4) ipsilateral eye (******p=0.001); l, unilateral stenosis of ijv (grade 3 or 4) contralateral eye. figure 4. optical coherence tomography (oct) findings and venous abnormalities: average retinal nerve fiber layer thickness: a, average findings [chronic cerebrospinal venous insufficiency (ccsvi) patients]; b, no ccsvi detected; c, one pathological vein (*p=0.03); d, two pathological veins; e, three pathological veins; f, pathological azygous vein; g, the only affected vein: ccsvi score=1; h, the only affected vein: ccsvi score=2; i, the only affected vein: ccsvi score=3 (**p=0.001); j, the only affected vein: ccsvi score=4; k, unilateral stenosis of internal jugular vein (ijv) (grade 3 or 4) ipsilateral eye (***p=0.03); l, unilateral stenosis of ijv (grade 3 or 4) contralateral eye. no nco mm er cia l u se on ly article [veins and lymphatics 2012; 1:e2] [page 5] these findings suggest that extracranial venous abnormality can contribute to neurological pathology in the settings of ms. at the moment it is difficult to explain our findings unequivocally. to the best of our knowledge it is the first study looking at potential impact of venous lesions on retinal abnormalities in ms. in order to reveal a potential link between ccsvi and ms, we looked at correlations between two different objective tests: oct of the retina and catheter venography of the azygous and ijvs. although both tests have established roles in current medical diagnostics and are considered reliable, there are also several limitations that could challenge final conclusions coming from our study. oct has been shown to be a reproducible imaging technique, still a number of procedural and biological factors might influence the results. these include: operator-related artifacts (e.g., defocusing and depolarisation errors), poor patients cooperation, concomitant eye pathologies (e.g., cataract, retinal drusen), age and ethnicity of the patients. most likely, we were unable to avoid at least some of these errors. moreover, which of the oct parameters should be used for the assessment of ms-related damage of the anterior visual pathway is still the matter of debate. therefore, our results, even statistically significant, should be interpreted with caution. catheter venography is regarded as a gold standard for the assessment of pathologies of large veins. it is far more reliable and much less operator-dependent than other tests evaluating venous flow and anatomy. still, the use of catheter venography in this study is somewhat weakened by the fact that assessment of the flow in azygous and jugular veins is new field of expertise. consequently, diagnostic accuracy of this test was probably far from perfect. in addition, our scale of ccsvi grading10 is not yet widely accepted. although most of the current scientific research on ms is focused on immune processes, a potential link between ms and the veins has been well known for decades. for example, in 1935 putnam demonstrated mslike cerebral plaques in the dogs with artificially obstructed cerebral venous outflow,11 while retinal periphlebitis, common eye manifestation of ms, was described for the first time in 1947.12 theoretically, ophthalmic veins can be vulnerable in the case of disturbed blood flow, since they connect the intraand extracranial venous networks and can be overloaded if extracranial portion of the ijv vein becomes obstructed. disturbed blood-brain barrier (bbb) can be the other source of injury to the retina and optic nerves in the settings of disturbed venous outflow. disintegration of bbb is a hallmark of ms. such a dysfunctional bbb is not necessarily an effect of inflammation, but may also be triggered by pathologic venous circulation.13 interestingly, it is known that even at physiologic settings microvessels of the prelaminar optic nerve head lack the bbb characteristics.14 we found an increased prevalence of oct abnormalities in ms patients with severe unilateral obstruction of the ijv, while the patients with bilateral blockages presented with a less frequent eye pathology. although one might expected a higher rate of retinal pathology in the patients with more numerous venous lesions, actually from anatomical and physiological point of view unilateral occlusion of the ijv can be more deleterious for the eye. in such a case venous outflow from the brain can be preferentially shifted via ophthalmic veins towards external jugular vein system, resulting in the overload of veins draining the eye and optic nerves. indeed, in some ms patients we have observed this outflow pattern during venography. on the other hand, an obstructed azygous vein is unlikely to impair ocular circulation. thus, an unchanged prevalence of retinal pathology in ms patients with azygous vein involvement is in line with these theoretical conjectures. interestingly, in one study ms patients with benign clinical course of the disease were found more pronounced retinal nerve fibre layer thinning.15 although at the moment no strong evidence exists for a correlation between the severity of venous blockages and more aggressive course of ms, some preliminary observations indicate that such a relationship may exist.16 consequently, the patients with unilateral ijv stenosis seem to be more likely to exhibit a benign clinical course of ms. interestingly, in our patient series an unilateral on was seen more often on the left side. a similar slightly higher frequency of on on the left side has already been reported.17,18 this unequal distribution of on seems to mirror distribution of venous abnormalities in ms patients, since the stenoses are primarily found in the left ijv.19,20 discovery of venous pathologies accompanying ms a risk factor for injury to the retinal ganglion cells may solve some puzzles related to this disease. ms patients very often exhibit ocular pathology, even with no previous history of on. therefore, it could be suspected that ms-related neurodegeneration, and not on, is primarily responsible for this injury. however, longitudinal studies of the retinal nerve fibre layer did not reveal a progression of retinal abnormalities in ms patients.21,22 also, histological evaluation of the eyes from autopsied patients demonstrated only an insignificant trend towards association of retinal atrophy with the duration of ms.23 the only reasonable explanation of this puzzle may be that: either only the first, even subclinical, attack of on results in retinal ganglion cell loss (which seems not very credible), or that retinal abnormalities develop well before clinically overt symptoms of ms. currently ccsvi is thought to be a congenital pathology.24,25 thus, if these eye pathologies were related to a congenital venous malformation, one should expect that injury to the retina develops much earlier, even in the childhood, which would explain the inconsistencies coming from the above-citied studies. conclusions a potential association between ccsvi and ms, including eye manifestations of ms, as has been demonstrated in this report, justifies further studies on this topic. such a research can bring to light pathomechanisms responsible for retinal damage related to ms and perhaps also other diseases of the eye. references 1. noval s, contreras i, muñoz s, et al. optical coherence tomography in multiple sclerosis and neuromyelitis optica: an update. mult scler int 2011;2011:472790. 2. zaveri ms, conger a, salter a, et al. retinal imaging by laser polarimetry and optical coherence tomography evidence of axonal degeneration in multiple sclerosis. arch neurol 2008;6:924-8. 3. cettomai d, pulicken m, gordon-lipkin e, et al. reproducibility of optical coherence tomography in multiple sclerosis. arch neurol 2008;65:1218-22. 4. henderson apd, trip sa, schlottmann pg, et al. an investigation of the retinal nerve fibre layer in progressive multiple sclerosis using optical coherence tomography. brain 2008;131:277-87. 5. jeanjean l, castelnovo g, carlander b, et al. retinal atrophy using optical coherence tomography (oct) in 15 patients with multiple sclerosis and comparison with healthy subjects. rev neurol (paris) 2008; 164:927-34. 6. davies ec, galetta km, sackel dj, et al. retinal ganglion cell layer volumetric assessment by spectral-domain optical coherence tomography in multiple sclerosis: application of a high-precision manual estimation technique. j neuroophthalmol 2011;31:260-4. 7. bock m, brandt au, dörr j, et al. patterns of retinal nerve fiber layer loss in multiple sclerosis patients with or without optic neuritis and glaucoma patients. clin neurol neurosurg 2010;112:647-52. 8. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:392-9. 9. zamboni p, consorti g, galeotti r, et al. no nco mm er cia l u se on ly article [page 6] [veins and lymphatics 2012; 1:e2] venous collateral circulation of the extracranial cerebrospinal outflow routes. curr neurovasc res 2009;6:204-2. 10. ludyga t, kazibudzki m, simka m, et al. endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? phlebology 2010;25:286-95. 11. putnam t. studies in multiple sclerosis: encephalitis and sclerotic plaques produced by venular obstruction. arch neurol psychiatry 1935;33:929-40. 12. rucker cw. retinopathy of multiple sclerosis. trans am ophthalmol soc 1947;45: 564-70. 13. simka m. blood brain barrier compromise with endothelial inflammation may lead to autoimmune loss of myelin during multiple sclerosis. curr neurovasc res 2009; 6:132-9. 14. hofman p, hoyng p, van der werf f, et al. lack of blood-brain barrier properties in microvessels of the prelaminar optic nerve head. invest ophthalmol vis sci 2001;42: 895-901. 15. galetta km, talman ls, lile dj, et al. visual pathway axonal loss in benign multiple sclerosis [abstract]. mult scler 2010: 16 suppl 10:s23-4. 16. zamboni p, menegatti e, weinstockguttman b, et al. hypoperfusion of brain parenchyma is associated with the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a cross-sectional preliminary report. bmc med 2011;9:22. 17. bradley wg, whitty cw. acute optic neuritis: its clinical features and their relation to prognosis for recovery of vision. j neurol neurosurg psychiatry 1967;30:5318. 18. bradley wg, whitty cw. acute optic neuritis: prognosis for development of multiple sclerosis. j neurol neurosurg psychiatry 1968;31:10-8. 19. simka m, latacz p, ludyga t, et al. prevalence of extracranial venous abnormalities: results from a sample of 586 multiple sclerosis patients. funct neurol 2011; 26:197-203. 20. petrov i, grozdinski l, kaninski g, et al. safety profile of endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j endovasc ther 2011;18:314-23. 21. serbecic n, aboul-enein f, beutelspacher sc, et al. high resolution spectral domain optical coherence tomography (sd-oct) in multiple sclerosis: the first follow up study over two years. plos one 2011; 6:e19843. 22. henderson ap, trip sa, schlottmann pg, et al. a preliminary longitudinal study of the retinal nerve fiber layer in progressive multiple sclerosis. j neurol 2010;257:1083-91. 23. green aj, mcquaid s, hauser sl, et al. ocular pathology in multiple sclerosis: retinal atrophy and inflammation irrespective of disease duration. brain 2010;133: 1591-601. 24. lee bb, bergan j, gloviczki p, et al. diagnosis and treatment of venous malformations. consensus document of the international union of phlebology (iup)2009. int angiol 2009;28:434-51. 25. lee bb, laredo j, neville r. embryological background of truncular venous malformation in the extracranial venous pathways as the cause of chronic cerebrospinal venous insufficiency. int angiol 2010;29:95-108. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2014; volume 3:4485 [veins and lymphatics 2014; 3:4485] [page 41] john j. bergan, 1927-2014 john bergan was born on august 4, 1927 and graduated in medicine at the university of indiana in 1954. he spent the residency in surgery at the chicago wesley memorial hospital and in 1960 was certified in the american board of surgery. the body of his academic career took place at the north western university in chicago, where he devoted himself to vascular surgery and also to its applications in transplantation surgery. scrolling through the records of the north-western registry, it turns out that john performed his first kidney transplant as the first operator in 1964, and was director of the program till 1976. however, for the european phlebologist john was the ambassador of phlébologie in the united states of america. two were his key meetings in the field. the first was with geza de takats, a forerunner of the modern phlebology, who operated for long time in chicago. john was in strong contact with this mentor, to the point that he wrote the obituary on surgery in 1986, when he died. the second was the stellar conjunction with james s. t. yao at the northwestern university. together they released the first complete text-book of phlebology in the united states, venous problems, at the end of the 70’s. in the 80’s, he was one of the founding fathers of the american venus forum, at the famous first meeting at the hotel of coronado, and, subsequently, president. but he also served as president the american college of phlebology. this because was an eclectic and multi-core phlebologist, equally interested and curious about the new features in outpatient practice, as well as in cutting-edge research applied to the venous system. the last years of his academic career were actively spent in a climate much more favourable compared to illinois, at the university of california san diego, in la jolla, where he continued to work and publish on veins. few years ago claude franceschi and me taught venous haemodynamics, at a course organised in arizona by our common friend nick morrison. i will never forget that he sat smiling and enthusiastic between the desks of the trainees. he was a giant in phlebology, but always curious about new things, and was not afraid to get into the game. john was a true gentleman, with whom it was nice to have a discussion or even dispute a controversy, thanks to his unforgettable elegance. paolo zamboni university of ferrara, italy no nco mm er cia l u se on ly 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2014; volume 3:3275 [page 36] [veins and lymphatics 2014; 3:3275] timing and modality of the sclerosing agents binding to the human proteins: laboratory analysis and clinical evidences lorenzo tessari,1 marcello izzo,2 attilio cavezzi,3 francesco zini,4 mirko tessari,5 mario ambrosino,6 roberto fanelli7 1glauco bassi foundation, trieste; 2math. tech. med., university of ferrara; 3eurocenter venalinfa, san benedetto del tronto (ap); 4casa di cura città di parma, parma; 5vascular diseases center, university of ferrara; 6centro duomo analisi, nola (na); 7istituto farmacologico mario negri, milano, italy abstract sclerosing agents (sa) are blood inactivated. nevertheless, investigations concerning the interaction among sa and blood components have never been deeply investigated. aim of the study is to precisely identify sa blood ligands, to determine their binding time and to highlight the clinical consequences. thirty-one blood samples were collected from chronic venous disease patients and tested by capillary and agarose gel (age) electrophoresis before and after adding polidocanol (pol) and sodiumtetradecylsulphate (sts). the two different types of electrophoresis allowed an evaluation of the blood proteins binding with the sclerosing agents, with a reaction time lower than 8 seconds for the age. subsequently six patients underwent foam sclerotherapy and then were subdivided in group a (4 patients) and b (2 patients). in group a blood sample was obtained from the ipsilateral brachial vein immediately before (t0) and repeated 1, 3, 5, and 10 minutes after injection of sts 3% injection into the gsv. in group b, the same procedure was performed with the same timing from the ipsilateral femoral vein. free sts (fsts) and total proteinbound sts (bsts) were measured. pol mainly binds to b-globulins (11%), while sts to albumin and a-globulins (62.6% and 30.7%) on the protidogram, respectively. both in the brachial and in the femoral vein, the average fsts was always 0. sts binds to albumin (62.6%) and aglobulins (30.7%), while pol is bound mainly by the b-globulins (11%). the present paper demonstrates how the vast majority of the sclerosing agent is bound to the blood proteins, suggesting the need to look for possible sclerotherapy complications factors also in the used gas and/or in the subsequent cathabolites release. introduction foam sclerotherapy (fs) has become an important tool in chronic venous disease (cvd) treatment.1 worldwide, the two most commonly used sclerosing agents (sa) in foam production are sodium tetradecyl sulphate (sts) and polidocanol (pol). a few very interesting papers evaluated the sa in vitro effects on coagulation,2,3 together with the same sa inactivation by plasma protein.4 the sts deactivation by the blood was precisely assessed in vitro, demonstrating how small blood volumes can totally inactivate the sclerosing drug. nevertheless, this fundamental investigation was performed only on bovine samples.5 in everyday clinical practice, fs has been demonstrated to be a safe and effective therapeutic option6,7 that has been made even safer by the recent use of carbon dioxide-oxygen in place of atmospheric air.8-10 nevertheless, up to now, investigations concerning the precise interaction between the sa and the human blood components, once the drug reaches the vascular bed, are still lacking. moreover, the pathogenetic mechanisms underlying the origin of fs-induced complications remain unclear.11,12 the aim of this study is to precisely identify sa blood ligands, to determine their binding time and to highlight the associated clinical consequences. materials and methods two parallel investigations were performed. in the first one, 31 blood samples were collected following 12 h or fasting in cvd patients (c1-6 ep as pr) and tested both by capillary (ce) and agarose gel (age) electrophoresis, in order to obtain a normal control curve, to be subsequently compared after addition of sclerosing agents. the assessment was performed at 5, 8, 12, 14 and 16 min by ce evaluation and at 8 s by age. subsequently, the same 31 patients blood samples were evaluated in new ce and age runs adding both 3% sts and 3% pol (200 ml of sa+400 ml of blood). in ce the proteins fractions separations occurred in a fused silica capillary, which was previously filled with a buffer solution. the main components of the system are a vial with the sample, a source and a destination recipient, electrodes, a high voltage henerator, a shallow capillary (in silica), a recorder, a data collector and the support. the migration of the particle is created by the high voltage that was applied to the same solution, thus reducing the migration time to 5 min. the proteins were then assessed and quantified by direct measurement of their 214 nm wave length absorbance.13-20 in age, proteins fractions separation is based on the competition between he applied electric field and the specific protein affinity to the media. in age, an agarose gel matrix is used to deposit the particles. then the proteins separate because of their different charge. the band quantification, together with the standard diagram production, occurs by swartz starch or other substances coloration. subsequently, a cleaning and media diaphanization are performed. at the end of the processing, the colored bands film is created. a densitometer is used for the assessment. the particles separation is obtained following their different electrophoretic mobility.13-20 the study population mean age was 54±8 years, with a female/male ratio of 5/1. no significant co-morbidities were present. the binding time evaluation was also performed for the sa and the plasma proteins. in the second investigation, six patients among the 31 who previously underwent the blood collection, were treated by injection of 3% (1 cc) sts fs in the gsv trunk, and then divided into group a (4 patients) and b (2 patients). in group a, a blood sample was obtained from the ipsilateral brachial vein, before an correspondence: lorenzo tessari, via giovanni falcone 24/b, 37019 peschiera del garda (vr), italy. tel.: +39.045.6401681 fax: +39.045.6409147. e-mail: mirko@tessaristudi.it key words: sclerosing agents, blood proteins, sclerotherapy, safety. contributions: lt, study design, data collection, data analysis, critical review, final approval; mi, data analysis, critical review, final approval; ac, data collection, data analysis, writing, critical review, final approval; fz, data collection, data analysis, final approval; mt, data collection, final approval; ma, data analysis, critical review, writing, final approval; rf, data analysis, critical review, writing, final approval. conflict of interests: the authors declare no potential conflict of interests. received for publication: 23 march 2014. revision received: 14 june 2014. accepted for publication: 18 june 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright l. tessari et al., 2014 licensee pagepress, italy veins and lymphatics 2014; 3:3275 doi:10.4081/vl.2014.3275 no nco mm er cia l u se on ly article [veins and lymphatics 2014; 3:3275] [page 37] sts 3% injection into the gsv (t0). the sampling was repeated 1, 3, 5, 10 min later. in group b (2 patients), the same procedure was performed with the same timing on the ipsilateral femoral vein. free sts (fsts) and total protein-bound sts (bsts) were measured in both groups. the foam was produced according to the tessari technique, thus mixing 1 cc of 3% sts with 4 cc of gas.21 the blood samples were immediately spindried and the plasma was stored in another vial. everything was frozen at �26° and subsequently sent to the laboratory. fsts and total protein-bsts were measured. in group b (2 patients, 1 male and 1 female), the same procedure was performed with the same timing on the ipsilateral femoral vein. an informed consent was obtained from all the patients, both for the clinical and the laboratory procedures. results all the set-up tests were correctly performed and reproduced reliable outcomes. all the proteins fractions absolute values were physiological (figure 1). in the first set of investigations, the human plasma proteins displayed a weak bond with pol, mainly in the b1 an b2 range (only about 11% of the plasma proteins pool) (figure 2a).conversely, the sts-human plasma protein interaction was especially represented in the albumin (62.6%), a1 (10,7%) and a2 (20.0%) fractions (figure 2b). in the binding time analysis, the ce evaluation at 5, 8, 12, 14 and 16 min highlighted a total overlap of sts 3%-plasma proteins (1:2 ratio respectively) with the basal plasma proteins electrophoretic run (figure 3). the age evaluation demonstrated an 8-s drug-protein binding peak, that was equally maintained at the 12 and 60 s evaluation (figure 4). the second investigation, concerning fsts amount, demonstrated that in the brachial vein, the average bsts concentration in mg/ml was 0, 0.568, 5.98, 6.91 and 7.2, respectively at t0, 1, 3, 5, 10 min. in the femoral vein, bsts average concentration in �g/ml was 0, 1.62, 13, 24.6 and 8.67, respectively at t0, 1, 3, 5, 10 min. figure 1. normal electrophoretic run with proteins percentages. figure 2. electrophoretic runs of human blood with: a) polidocanol (pol) 3%; and b) sodiumtetradecylsulphate (sts) 3%. no nco mm er cia l u se on ly article [page 38] [veins and lymphatics 2014; 3:3275] both in the brachial and in the femoral vein fsts was always 0 (figure 5). discussion nowadays, fs is one of the most popular cvd therapeutic tools worldwide.1 some articles have reported possible threatening side-effects.11 nevertheless, recent reviews have demonstrated that fs complications and side effects remain uncommon, thus confirming fs efficacy and safety.12 on the other hand , the pathogenesis of fs-induced side effects still needs deeper investigation. according to recent papers, the gas used to produce foam can be important in modification of the incidence of side effects, with a better safety profile for carbon dioxide-oxygen foam.8,9 but the side effects incidence isn’t related only to the chosen gas.11,12 a deeper analysis of the biochemical interaction between the sclerosing agents and the blood components is mandatory to find out the possible new pathogenetic mechanisms of complications during sclerotherapy. the present paper evaluates the sclerosing drug interaction with the human blood proteins, suggesting clinical consequences that improve the fs safety profile. the first issue in the drug-protein binding assessment is identifying the exact timing in which it occurs. a bias in the drug-protein ce assessed binding is the possible interaction between the two substances inside the test tube, during the same ce required processing time. therefore two different kind of electrophoresis have been used: ce and age. ce is a more sophisticated analysis, designed to separate species and, based on their size, to charge ratio in the interior of a small capillary that is filled with an electrolyte. this characteristic brings a higher sensitivity, but requires some minutes to have the automatized process started. to the contrary, age is a totally manual procedure, bringing less precise measurement, but providing the test result in a few seconds.13-20 the overlapping drug-protein peaks of ce and age demonstrated how the bond, and thus the inactivation, occurs after just a few seconds by the sa contact with the human blood. consequently, all the sclerosing drug circulation within the lungs is bounded to the proteins, and thus inactive. moreover, the fs safety profile is confirmed by the lack of detectible free sclerosing drug not only in the upper limb venous circulation, but also in the ipsilateral femoral vein. further considerations regarding coagulation modification were reported by parsi last year,3 demonstrating how low concentration sclerosants inhibit platelet aggregation because of gpiib/iiia activation. the present study suggests that proteins like antiplasmin could be also involved. this is a a2 globulin which when bound to sts the lock on the plasmin is removed, thus enhancing fibrinolysis this may represent a possible rationale for fewer post-sclerotherapic deep venous thromboses with the sts use. it has recently been suggested that fs complications and side effects may be related to new pathogenetic mechanisms, based on figure 3. sodiumtetradecylsulphate (sts) 3% and blood electrophoretic run along the observation time at a) 5 and b) 16 min. figure 4. sodiumtetradecylsulphate 3% cellulose acetate electrophoretic run. no nco mm er cia l u se on ly article [veins and lymphatics 2014; 3:3275] [page 39] endothelial release of vasoactive molecules, such as endothelin-1, histamine or serotonin.22-28 further analysis should be aimed to elucidate both the post-sclerotherapic endothelial catabolite identification and deeper insight into the drug-protein kinetic. conclusions foam sclerotherapy safety remains a hot topic in the phlebology community, despite everyday clinical use which demonstrates an extremely low complication and side effect rate. no data are available concerning the in vivo binding and neutralization of the sa whenever inside the blood stream. the present paper offers two investigations demonstrating the sa binding features when in contact with human blood and the consequent kinetics within the venous network. the results demonstrate in vivo the rapid inactivation of the sa in circulating blood, thus their high safety profile. references 1. murad mh, coto-yglesias f, zumaetagarcia m, et al. a systemic review and meta-analysis of the treatments of varicose veins. j vasc surg 2011;53:49s-65s. 2. parsi k, exner t, connor de, et al. in vitro effects of detergent sclerosants on coagulation, platelets and microparticles. sur j vasc endovasc surg 2007;34:731-40. 3. parsi k, connor de, pilotelle a, et al. low concentration detergent sclerosants induce platelet activation but inhibit aggregation due to suppression of gpiib/iiia activation in vitro. thromb res 2012;130:472-8. 4. parsi k, exner t, connor de, et al. the lytic effects of detergent scerosants on erythrocytes, platelets, endothelial cells and microparticles are attenuated by albumin and other plasma components in vitro. eur j vasc endovasc surg 2008;36:216-23. 5. watkins mr. deactivation of sodium tetradecyl sulphate injection by blood proteins. eur j vasc endovasc surg 2011; 41:521-5. 6. rathbun s, norris a, stoner j. efficacy and safety of endovenous foam sclerotherapy: metan-analysis for treatment of venous disorders. phlebology 2012;27:105-17. 7. coleridge-smith p. sclerotherapy and foam sclerotherapy for varicose veins. phlebology 2009;24:260-9. 8. morrison n, neuhardt dl, rogers cr, et al. incidence of side effects using carbon dioxide-oxygen foam for chemical ablation of superficial veins of the lower extremity. eur j vasc endovasc surg 2010;40:407-13. 9. morrison n, neuhardt dl, rogers cr et al. comparisons of side effects using air and carbon dioxide foam for endovenous chemical ablation. j vasc surg 2008;47: 830-6. 10. beckitt t, elstone a, ashley s. air versus physiological gas for ultrasound guided foam sclerotherapy treatment of varicose veins. eur j vasc endovasc surg 2011; 42:115. 11. guex jj. complications and side-effects of foam sclerotherapy. phlebology 2009;24: 270-4. 12. guex jj. complications of sclerotherapy: an update. dermatol surg 2010;36:1056-63. 13. merlini g, marciano s, gasparro c, et al. the pavia approach to clinical protein analysis. clin chem lab med 2001;39: 1025-8. 14. gay-bellile c, bengoufa d, houze p, et al. automated multicapillary electrophoresis for analysis of human serum proteins. clin chem 2003;49:1909-15. 15. petersen jr, okorodudu ao, mohammed a, et al. capillary electrophoresis and its application in the clinical laboratory. clin chim acta 2003;330:1-30. 16. bossuyt x. advances in serum protein electrophoresis. adv clin chem 2006;42:43-80. 17. segura carretero a, cruces-blanco c, cortacero ramírez s, et al. application of micellar electrokinetic capillary chromatography to the analysis of uncharged pesticides of environmental impact. j agric food chem 2004;52:5791-5. 18. cavazza a, corradini c, lauria a, et al. rapid analysis of essential and branchedchain amino acids in nutraceutical products by micellar electrokinetic capillary chromatography. j agric food chem 2000; 48:3324-9. 19. dorsey jg, foley jp, cooper wt, barford ra, barth hg. liquid chromatography: theory and methodology. anal chem 1990; 62:324-56. 20. rodrigues mr, caramão eb, arce l, et al. determination of monoterpene hydrocarbons and alcohols in majorana hortensis moench by micellar electrokinetic capillary chromatographic. j agric food chem 2002;50:4215-20. 21. tessari l. nouvelle technique d’obtention de la sclero-mousse. phlebologie 1997; 53:129. 22. dohonal j, garvin j. the interaction of dodecyl and tetradecyl sulfate with profigure 5. assessment of free and bound sodiumtetradecylsulphate (sts) in the brachial and in the femoral vein. no nco mm er cia l u se on ly article [page 40] [veins and lymphatics 2014; 3:3275] teins during polyacrylamide gel electrophoresis. biochim biophys acta 1979; 576 393-403. 23. frullini a, felice f, burchielli s, et al. high production of endothelin after foam sclerotherapy: a new pathogenetic hypothesis for neurological and visual disturbances after sclerotherapy. phlebology 2011;26:203-8. 24. holm p. endothelin in the pulmonary circulation with special reference to hypoxic pulmonary vasoconstriction. scand cardiovasc j suppl 1997;46:1-40. 25. lusher tf. endothelin and endothelin antagonists: pharmacology and clinical implications. agents actions suppl 1995; 45:237-53. 26. ferrara f, allaert fa, ferrara g. les médiateurs chimiques dans certaines complications de la sclérothérapie. phlébologie 2012;65:27-31. 27. hu ww. role of histamine and its receptors in cerebral ischemia. acs chem neurosci 2012;3:238-47. 28. frullini a, barsotti mc, santoni t, et al. significant endothelin release in patients treated with foam sclerotherapy. dermatol surg 2012;38:74-7. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2017; volume 6:6652 anti-infective effects of sugar-vaseline mixture on leg ulcers claude franceschi,1,2 massimo bricchi,2 roberto delfrate2 1centre marie thérèse, hopital saint joseph, paris, france; 2casa di cura figlie di san camillo, cremona, italy abstract fifty patients affected of resistant leg ulcers where treated exclusively with a vaseline-glucose mixture in combination with an etiologic treatment. neither additional topical, systemic anti-infective drugs nor surgical debridement were applied. the dressing turnover rate was 6-7 days. a first bacteriological sampling was followed by a second one (40 days mean), which showed 100% sterilized ulcers. a complete scaring was achieved in 46 (92%) on average of 109 days of apply. this efficient, low cost, painless and quick treatment could proposed as a first line option. introduction leg ulcers are chronic wounds due to various causes (trauma, ischemia, venous hypertension, etc.) that do not heal within a normal period. their healing depends not only on the etiological but also anti-infective treatment because they are usually worsened and prolonged by superinfections. for that reason, in the presence of fungal or bacterial infections, an appropriate anti-infective therapy is recommended. it consists of systemic and/or topical antiinfective therapies combined with or without surgical debridement. the anti-infective efficiency of the sugar is known.1-6 the antiinfective effect and scaring acceleration achieved by a specific mixture of glucose and vaseline without any additional antiinfective drugs or surgical debridement was studied in resistant leg ulcers. materials and methods patients mono centric open-label trial including 50 patients, female (n=32), male (n=18) mean age=65 years presenting leg ulcers not healed since more than 180 days of treatment in other care units. these patients were affected of various pathologies as traumatic, cardiac failure, venous insufficiency, lymph edema, id and no id diabetes and treated with insulin, oral hypoglycemic, anticoagulants, antiplatelet drugs. they all were assessed with arterial, venous and lymphatic duplex ultrasounds in order to diagnose the vascular etiology of their ulcers then treat it specifically. in all patients a first swab bacteriological assessment at bottom line, then a second one within 30 to 60 days (mean=40 days) were performed (table 1). treatment the treatment was applied in an ambulatory care unit and at home. a soft cleaning of the wound and necrotic debris was performed with neutral detergent as tap water. no surgical debridement was carried out.7 the dressing was applied over all the area of the ulcer. it was made of mixture of glucose 60% and vaseline 40% supported by pads (figure 1). vaseline was in 40% proportion in order to hold in place the glucose powder on the wound thanks to an adequate consistency of the mixture as well as providing a high concentration of glucose. neither topical nor systemic antibiotics whatever the antibiogram result were applied.8 neither foam nor any autolytic debriding materials were used whatever the moisture of the wound.9 the bandaging tightness was performed according to the etiology. the dressing turnover was once every 6-7 days. results in table 1 the bacteria assessed by pretreatment swab assessment are given. all the ulcers were germ free at second sampling culture: 50/50 (100%). no pain, no side effects nor complication was noticed except some irritation of the surrounding skin. surprisingly, no more bad smell was noticed when removing the dressing. the completely rate of healed ulcers was n=46 (92%). the healing time mean was 109 days (range: 36-182 days). not healed but improved ulcers were n=4 (8%). details are given in table 2. discussion the results regarding the anti-infective effect of sugar on wounds confirms many previous studies.1-5 a study has shown that sugar gave less good results than natural brown sugar.11 nevertheless, the glucose was 60% in the mix while it is quite absent in refined and natural brown sugar made respectively of 99.8 and 95% of sucrose. correspondence: claude franceschi, 21 quai alphonse le gallo 92100, boulogne, france. e-mail: claude.franceschi@gmail.com key words: ulcer; sugar; honey; anti-infective; debridment. conflict of interest: the authors declare no potential conflict of interest. received for publication: 17 february 2017. revision received: 17 march 2017. accepted for publication: 19 march 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright c. franceschi et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6652 doi:10.4081/vl.2017.6652 table 2. not healed ulcers rate. not healed but improved ulcers at 182 days 4 (8%) ulcer associated with osteomyelitis 1 deep traumatic wound 1 ulcer associated with diabetes and neuropathy 1 arterio-venous mixed ulcer 1 table 1. germs identified at the first sampling. bottom line culture no. proteus mirabilis 2 staphylococcus aureus 14 escherichia coli 9 citrobacter freundii 3 staphylococcus epidermidis 11 candida albicans 3 streptococcus faecalis 7 pseudomonas aeruginosa 1 [page 36] [veins and lymphatics 2017; 6:6652] no n c om me rci al us e o nly article [veins and lymphatics 2017; 6:6652] [page 37] the honey also is different from the vaseline-glucose mix because it contains fructose: 38.2%, glucose: 31.3%, maltose: 7.1%, sucrose: 1.3%.11 the healing time of the ulcers is more difficult to relate to the mixture alone because it depends also on the etiological treatment efficiency. so, the inefficiency of the previous treatments (ulcers lasting for more than 6 months) was not necessarily due to the superinfection but maybe to an inadequate etiological treatment. the venous ulcers were treated with compression and/or deep chiva,12 superficial chiva,13 according to their hemodynamic configuration. nevertheless, this study provides some news. the first one is the anti-infective efficiency of the vaselineglucose mixture alone without antiseptics or antibiotics (topical or systemic). the second one is the efficiency of a single dressing whatever the moisture content. the third one is that contrary to the honey, the vaseline-glucose mix is not allergenic and its consistency, composition and glucose percentage are constant. the fourth one is the absence of debridement, which not only permits a painless change of dressing but also leaves in place the new cells and preserves their growth. the fifth is the low cost due to the cheap material and the only oneweek frequency of the dressing change. conclusions the vaseline-glucose paste alone sterilizes the ulcers and promotes the healing when combined with the etiological treatment. its low cost, efficiency, easy application could represent a first intention treatment. further studies should be done in order to confirm these results but also to identify any other effect than anti-infective in the process of ulcer healing and scaring. references 1. franceschi c, passariello f. low cost medications for venous ulcer. sugarhoney: an on line vasculab survey. acta phlebol 2009;10:41-4. 2. topham j. sugar paste and povidoneiodine in the treatment of wounds. j wound care 1996;5:364-5. 3. topham j. sugar for wounds. j tissue viab 2000;10:86-9. 4. de feo m, gregorio r, renzulli a, et al. treatment of recurrent postoperative mediastinitis with granulated sugar. j cardiovasc surg (torino) 2000;41:7159. 5. tanner ag, owen ertc, seal dv. successful treatment of chronically infected wounds with sugar paste. eur j clin microbiol infect dis 1988;7:524-5. 6. archer hg, barnett s, irving s, et al. a controlled model of moist wound healing: comparison between semi-permeable film, antiseptics and sugar paste. j exp pathol (oxford) 1990;71:155-70. 7. gethin g, cowman s, kolbach dn. debridement for venous leg ulcers. cochrane database syst rev 2015; 14:9. 8. o’meara s, al-kurdi d, ologun y, et al. antibiotics and antiseptics for venous leg ulcers. cochrane database syst rev 2014;10:1. 9. o’meara s, martyn-st james m. foam dressings for venous leg ulcers. cochrane database syst rev 2013; 31:5. 10. léger l, marchal j, delaitre b, et al. local treatment of wounds using bagasse. phlebologie 1974;27(2):123-8. 11. white jw jr, doner lw. honey composition and properties beekeeping in the united states agriculture handbook number 335; revised octaober 1980, pp 82-91. available from: http://beesource.com/ resources/ usda/honey-composition-and-properties/ accessed: 6 february 2011. 12. zamboni p, gianesini s. surgical technique for deep venous reflux suppression in femoral vein duplication. ejves short rep 2016;30:10-2. 13. franceschi c, zamboni p. principles of venous haemodynamics. new york: nova science; 2010. figure 1. gauze compresses with a covering of vaseline-glucose powder mix are applied on the ulcer before bandaging. no n c om me rci al us e o nly hrev_master veins and lymphatics 2014; volume 3:4682 [veins and lymphatics 2014; 3:4682] [page 93] storms, hanged pirates, anemia, exsanguination: the contributions of monro, kellie and abercrombie in understanding intracranial blood circulation pasquale de bonis,1 carmelo anile2 1neurosurgery, s. anna university hospital, cona di ferrara (fe); 2neurosurgery, catholic university school of medicine, rome, italy abstract the so-called monro-kellie doctrine states that with an intact skull, the sum of the volume of the brain plus the cerebrospinal fluid volume plus the intracranial blood volume is constant. therefore an increase in one should cause a reduction in one or both of the remaining two. the researcher who expressed the doctrine in such a way was indeed harvey cushing in 1925, during a lecture in edinburgh. the original monro-kellie doctrine is the result of observations on autopsies and several animal experiments. what the original doctrine states is a dynamic explanation of the intracranial system, aimed at explaining how a pulsatile and continuous perfusion may occur in a closed-non-expandable and fully filled system. during each cardiac cycle the quantity of blood within the head must be the same: during the systole, the brain arteries dilate, and, in the mean time, a quantity of blood, equal to that which is dilating them, is passing out of the head through the veins. during the succeeding diastole, the quantity which dilated the brain arteries passes into the corresponding veins and, at the same time, as much passes from the sinuses out of the head, as enters into the head from the arteries situated between the heart and the head. monro implicitly states that the blood coming out from the cerebral veins into the sinuses must be pulsatile and (almost) synchronous with the arteries. that is deeply different from the concept of a constant content of a rigid case, as expressed by cushing. introduction when we, insiders, think on the so called monro-kellie doctrine, the first notions our minds make us deal with are that, with an intact skull, the sum of the volume of the brain plus the cerebral spinal fluid (csf) volume plus the intracranial blood volume is constant. therefore an increase in one should cause a reduction in one or both of the remaining two. this law is now widely accepted and has been used as a physiological basis in order to explain what occurs in case of increased intracranial pressure (especially due to a foreign body, such as a tumor) or in case of decreased intracranial pressure, as in the case of csf leaks (intracranial hypotension).1 this doctrine is very easy to be understood and has been expressed so as to be scientifically reproducible: a mathematical formula (brain vol + csf vol + blood vol =k). nonetheless, what the researches whose lasting eponymous fame was linked to this law demonstrated in their essays, was not exactly what that formula shows. the researcher who expressed the doctrine in such a precise formula was indeed harvey cushing in 1925, during a lecture in edinburgh.2 one could argue that both monro and kellie ignored the existence of the csf. in fact, from the ancient times, based on hippocrates (460-370 b.c.) and galen (130200 a.d.), it was thought that cerebral ventricles were filled with pneuma psychikon (latin: spiritus animalis), i.e. animal spirit. despite several anatomists had described the presence of a fluid within the ventricles and/or around the spinal canal (niccolò massa in 1536, thomas willis in 1664, marcello malpighi in 1665, antonio valsalva in 1692, antonio pacchioni in 1705, domenico cotugno in 1764), the name cerebrospinal fluid was introduced by françois magendie in the first half of the 19th century.3 both monro and kellie describe the presence of serum fluid within the cranium.4,5 despite this neglected aspect, the difference between the previous formula and the original doctrine is significant. both monro and kellie (together with another scottish doctor: john abercrombie), discuss about the blood circulation within the brain. their conclusions are the logical consequence of observation performed during human autopsies and (in the case of kellie and abercrombie) animal experiments. the doctrine is based on two principles: i) the brain is enclosed in a non-expandable case of bone; ii) the brain completely fills this case and is not compressible. in his article, kellie describes that one of my oldest physiological recollections, indeed, is of this doctrine having been inculcated by my illustrious preceptor in anatomy, the second monro, a doctrine which he used to illustrate by exhibiting a hollow glass ball, filled with water, and desiring his pupils to remark that not a drop of fluid escaped, when inverted with its aperture downwards. abercrombie (kellie expressed this with very similar words) stated that: the cranium is a complete sphere of bone, which is exactly filled by its contents, the brain, and by which the brain is closely shut up from atmospheric pressure, and from all influence from without except what is communicated through the blood vessels which enter it.6 therefore the notion of a rigid case completely filled with the intracranial non-compressible content (the brain alone or brain plus fluids-blood and csfbeing fluid non-compressible too) constituted the doctrine starting point instead of the conclusion. while it is quite simple to demonstrate that the case is non-expandable, on the brain non-compressibility abercrombie stated that: in this investigation it is unnecessary to introduce the question, whether the brain is compressible, because we may safely assert that it is not compressible by any such force as can be conveyed to it from the heart through the carotid and vertebral arteries.6 the intracranial content can therefore be compared with a fluid, which is non-compressible (at least if the only available compressing force comes from the heart). this raises a question: how can cerebral blood circulation occur, since at every heart systole a certain amount of blood enters the brain? the doctrine answers to this fundamental question. alexander monro was the first to provide an explanation to this. nonetheless, we have no demonstrations of how he drew his conclusions. kellie himself writes that: it can scarcely be supposed that this doctrine should have been thus broadly maintained by so practiced an anatomist, so acute an observer, and so excelcorrespondence: pasquale de bonis, neurosurgery, s. anna university hospital, viale a. moro 8, 44121 cona di ferrara, italy. tel +39.0532236292. e-mail: debonisvox@gmail.com. key words: monro-kellie doctrine, intracranial system, cerebral blood flow, cerebral autoregulation, intracranial veins. contributions: pdb, books search, manuscript writing, manuscript reviewing; ca, manuscript reviewing. conflict of interest: the authors declare no potential conflict of interests. received for publication: 30 august 2014. revision received: 16 november 2014. accepted for publication: 16 november 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright p. de bonis and c. anile, 2014 licensee pagepress, italy veins and lymphatics 2014; 3:4682 doi:10.4081/vl.2014.4682 no n c om me rci al us e o nly review [page 94] [veins and lymphatics 2014; 3:4682] lent a pathologist, to be, that, in the course of his very extensive experience, he had observed nothing in the appearances of the vascular system of the brain, under the varied circumstances of health and disease, which seemed to militate against the hypothesis. it is, at least, by such an appeal to nature that the merits of the hypothesis are to be tried. therefore, kellie (and, to a lesser extent, abercrombie) demonstrated monro’s doctrine through autopsy findings and animal experiments. the autopsy findings by kellie the first cases described by kellie concern a man and a woman found dead after lying outside during a storm on november 4th, 1821. kellie and his colleague dr. cheyne (the doctor who described the cheyne-stokes respiration) were asked by the magistrates to ascertain the cause of death. kellie and cheyne concluded that those individuals had died of torpor from cold. in the head, the same bloodless state of the scalp, the same turgidity of the vessels on the surface of the brain, the same congestion of the sinuses, the same soundness of the cerebral texture, […] but here, too, we find but little blood in the arteries, and the less perhaps the more the veins appear congested. it may, therefore, be concluded, that the blood which after death we find congested within one set of vessels in the brain, is just that quantity of blood which was circulated within the head, and at every instant of time distributed, in some proportion or other, between the arteries and veins during life. in these cases the scalp was bloodless; in the intracranial space: the sinuses and the veins were congested while the arteries contained little blood. a different condition was that of two pirates: peter heamen and francois gautiez, who were hanged on january 10th 1821 at leith for piracy and murder (figure 1). dr monro very politely afforded me the opportunity of being present at the examination he was to make of the brain of one of them immediately after execution. i have remarked that one eye only of each subject was much reddened and suffused, and i observed also that the corresponding side of the face of each was evidently more livid than the other, and the truth of this observation was admitted by several of the gentlemen present, to whom i made the remark. the manner in which the instrument of death is adjusted affords, i think, a ready and natural explanation of the fact. as the noose of the cord is adjusted by the executioner on one side of the neck, it becomes, as it were, the point of suspension, so that, by the weight of the victim, it slips upwards from the neck on that side towards the mastoidal process behind the ear; figure 1. original account of the execution of the two pirates. no n c om me rci al us e o nly review [veins and lymphatics 2014; 3:4682] [page 95] and there is, consequently, a space on this side corresponding to the rising of the noose, which is not any, pressure. the mark of the rope, accordingly, did not form a circle round the whole neck, but was observed to rise obliquely upwards, behind the ear, on that side on which the eye was the least suffused, and the countenance the least livid. on dividing the scalp the blood flowed freely, and in such quantity as to afford ample proof of the congestion of the vessels exterior to the cranium. […] all the sinuses contained blood, but in no extraordinary quantity. the larger vessels on the surface, and between the convolutions of the brain, were but moderately filled, and the pia mater was, upon the whole, paler, and less vascular. kellie also performed a literature review and found a description of a similar case by morgagni: cutis cranium tegens interiore facie sanguiferis turgebat vasculis. cerebrum nihil, quantum judicare sensus poterant, ab naturali constitutione discrepebat (the veins within the scalp were engorged. nothing in the brain, so far as we were able to judge, differed from its natural appearance).7 in these cases, the extracranial vessels were very congested; in the intracranial space: sinuses and veins were but moderately filled and the arteries contained little blood. kellie then describes the case of a patient with long-lasting anemia: the body in general was nearly bloodless. on dividing the integuments of the cranium, a reddish serum only flowed out. […] the dura mater was uncommonly pale, bloodless, and transparent, except only in the course of the longitudinal sinus, which was distinguished by a faint pink tint. […] the larger vessels ramifying over the hemispheres, and between the convolutions of the brain, were all conspicuous, from the color given to them by the same pale pink-colored fluid, with which they were filled, though not distended. the vessels of the basis of the brain, cerebellum, and medulla elongata, contained little or no colored fluid. […] the vessels of this brain, however, are far from furnishing an example of unqualified depletion. compared with the rest of the body, i would say that they contained more than the usual relative quantity of fluid which had circulated during life. also in this case, the quantity of intracranial blood was much more usual than the extracranial blood, with veins full of little colored fluid and arteries with little or no fluid inside. in conclusion, the cause of death has no influence on the intracranial quantity of blood, which is distributed between arteries and veins. kellie’s animal experiments in order to determine the effect of exsanguination and posture, kellie performed a series of animal experiments (using sheeps and dogs). a, g, and h, are examples of depletion from simple arterial hemorrhage; b and i, of uncomplicated venous hemorrhage. c and d afford examples of more rapid hemorrhage and death, from the knife of the butcher. in e the carotids were tied, with the view of arresting the expectation of voiding the brain to the greatest possible extent. in f, on the contrary, the jugulars were tied with the view of obstructing the return of blood from the head, while one carotid artery was laid open, and the animal allowed bleeding to death as a comparativefigure 2. original chapter of the circulation of the blood within the head by a. monro.5 no n c om me rci al us e o nly review [page 96] [veins and lymphatics 2014; 4682] experiment. kellie therefore concludes that: in our dissections, we do not meet with very striking varieties in the appearances of those vessels: the sinuses of the dura mater, and the veins in general, are found filled, or congested. even the brains of those who have been largely depleted during life, or who have sunk from inanition, does not appear much voided of their blood. the brains of our apoplectic patients themselves, whom we have, in the course of one or two days, of a few hours perhaps before death, bled to a great extent, with the very purpose of unloading their vessels, are still found congested with blood. in animals bled to death, the brain still retains much of its blood; the vessels on its surface are red, well filled, and sometimes exhibit the appearance even of turgidity and congestion. in conclusion, what monro, kellie and abercrombie demonstrated was perfectly expressed in these sentences by monro, describing what happens during each cardiac cycle: as the substance of the brain, like that of the other solids of our body, is nearly incompressible, the quantity of blood within the head must be the same, or very nearly the same, at all times, whether in health or disease, in life or after death. it does not, however, follow from this, that every individual artery or vein within the head is constantly of the same size, or that, at all times, it contains the same quantity of blood, and, of course, that the arteries within the head are immoveable, like metalline tubes, or want pulsation […]. for, whilst the heart is performing its systole, the arteries here, as elsewhere, may be dilating, and, in the mean time, a quantity of blood, equal to that which is dilating them, is passing out of the head by the veins. during the succeeding period of diastole of the heart and systole of the arteries, the quantity which dilated the arteries of the brain passes into the corresponding veins and sinuses; at the same time, as much passes from the sinuses out of the head, as enters into the head from the contracting trunks of the arteries situated between the heart and the head (figure 2). the original monro-kellie doctrine is therefore a dynamic explanation of the intracranial system, aimed at explaining how a pulsatile and continuous perfusion may occur in a closed and fully filled system. monro implicitly states that the blood coming out from the cerebral veins into the sinuses must be pulsatile and (almost) synchronous with the arteries. that is deeply different from the concept of a constant content of a rigid case, as expressed by cushing. actuality of monro-kellieabercrombie the original monro doctrine has therefore been neglected for centuries. at present, the available models on the intracranial system do not consider that doctrine as is, but as a static, fully filled container. the correct application of the doctrine could revolution the knowledge of the intracranial system and help to understand the pathophysiology of several conditions in which the intracranial system homeostasis is impaired. in the original doctrine, monro, kellie and abercrombie did not consider two fundamental elements. the first is the so called starling resistor, which is located at the level of the bridging veins (starling described it several years later). the second is the little knowledge of the effects of gravitation on the human body: the authors improperly talk about the effects of the atmosphere in their observations. instead, the force determining modifications leading to conditions such as the sinking skin flap syndrome after removal of a portion of skull (the sinking skin flap syndrome resembles the animal experiments of kellie) is gravitation. references 1. macintyre i. a hotbed of medical innovation: george kellie (1770-1829), his colleagues at leith and the monro-kellie doctrine. j med biogr 2013;22:93-100. 2. cushing h. studies in intracranial physiology and surgery: the third circulation, the hypophysics, the gliomas. london: h. milford, oxford university press; 1926. 3. herbowski l. the maze of the cerebrospinal fluid discovery. anat res int 2013;2013:8. 4. kellie g. an account of the appearances observed in the dissection of two of three individuals presumed to have perished in the storm of the 3d, and whose bodies were discovered in the vicinity of leith on the morning of the 4th, november 1821: with some reflections on the pathology of the brain. trans med chir soc edinb 1824;1:84-169. 5. monro a. observations on the structure and functions of the nervous system: illustrated with tables / by alexander monro. edinburgh: printed for, and sold by, william creech and joseph johnson, london; 1783. 6. abercrombie j. pathological and practical researches on diseases of the brain and the spinal cord. edinburg: waugh and innes; 1828. 7. morgagni g, chaussier f, adelon np. de sedibus et causis morborum per anatomen indagatis: libri quinque: in quibus continentur dissectiones et animadversiones propemodum innumerae, medicis, chirurgis, anatomicis profuturae. paris: apud m. c. compère; 1820. no n c om me rci al us e o nly hrev_master veins and lymphatics 2013; volume 2:e1 [veins and lymphatics 2013; 2:e1] [page 1] stiffness of compression devices giovanni mosti angiology department, clinica md barbantini, lucca, italy this issue of veins and lymphatics collects papers coming from the international compression club (icc) meeting on stiffness of compression devices, which took place in vienna on may 2012. several studies have demonstrated that the stiffness of compression products plays a major role for their hemodynamic efficacy. according to the european committee for standardization (cen), stiffness is defined as the pressure increase produced by medical compression hosiery (mch) per 1 cm of increase in leg circumference.1 in other words stiffness could be defined as the ability of the bandage/stockings to oppose the muscle expansion during contraction. measurements of stiffness are performed in textile laboratories using different extensometers. however, up to now pressure ranges are declared only for compression stockings; no pressure ranges can be declared for bandages as the exerted pressure depends on the stretch applied to the bandages, number of layers and leg configuration. information concerning stiffness is not given either for elastic stockings or for bandages. in vivo experiments have offered useful surrogate data. the leg circumference increases when moving from the supine to the standing position and during muscle activities.2-4 to assess stiffness according to cen definition, it would be necessary to measure the increase of compression pressure and of leg circumference simultaneously, requiring a pressure measurement device and a strain gauge plethysmograph. in order to simplify the stiffness calculation it has been proposed to assume that the increase of leg-circumference, moving from lying to standing position, is always 1 cm. in this case the so-called static stiffness index (ssi) could simply be calculated by subtracting the supine from the standing pressure.5 a comparison between the two measuring systems of stiffness (the first including the measurement of the leg circumference increase and the second just calculating ssi) was performed showing the same sensitivity and specificity in distinguishing between elastic and inelastic systems.2 the conclusion of this comparison clarified that ssi is an effective method to calculate stiffness and that more complex measurements do not give more information. nevertheless the assessment of stiffness in vivo, as recommended in a previous consensus meeting of the icc,6 came under some criticism. despite the fact that ssi is basically able to differentiate the elastic properties of mch, a great variability among different patients could be a major issue. this variability depends on the fact that some other variables play a role in ssi calculation in addition to elastic properties of material: the leg position during measurements, the configuration and consistency at the measuring site of the leg, the individual muscle strength, the presence of fat and others.7 a new standardized method to measure the stiffness on a mannequin leg was reported8 which presents the advantages to be simple, highly reproducible, easily available and cheap. if this method will be widely adopted, it would also be possible to avoid that every company producing mch measure stiffness with different systems thereby increasing the confusion. in order to differentiate between measurement in vivo and in laboratory (lab) the so called in vitro measurement, it was proposed to name the in vitro calculation not anymore stiffness in vitro, but resistance.9 regarding the measuring site on the leg, the b1 point described in the icc consensus paper6 was brilliantly confirmed as the most suitable site for stiffness measurement.10 stiffness, together with pressure and hysteresis,11 is an important parameter for effectiveness combined with comfort of mch. neumann’s paper rises two important points.11 one is the relevance of another indicator of stiffness the so-called dynamic stiffness index (dsi) requiring complex measuring systems. nevertheless, an excellent correlation between ssi and dsi could be shown by using this lab equipment12 but also in vivo during muscle exercise.2,13 this supports the idea that in vivo testing is a valuable tool for assessing the elastic properties especially in connection with clinical effectiveness of compression devices. the second point is the importance of the hysteresis of different compression materials. hysteresis can be measured only in the lab and remains something obscure for the clinicians whereas they should receive full information by companies on this parameter. an ideal compression device should exert a low, comfortable pressure during rest, with a strong or very strong pressure14 during standing and working in order to counteract ambulatory venous hypertension (effective). such a device would have a very high ssi but, unfortunately, it doesn’t exist yet. inelastic material presenting high stiffness comes close to an ideal compression device;15 especially when pressure decreases after some hours from application in the supine position, the difference between standing and supine pressure is very high exerting an effective massaging effect on the leg during walking and improving significantly the hemodynamic impairment of chronic venous insufficiency. elastic material, exerting a sustained pressure, not very different between supine and standing position or during muscle exercise, shows a small improvement on the impaired venous hemodynamics which is always significantly smaller than that from inelastic material.16,17 actually stiff materials exerting strong or very strong pressure showed to be clinically effective in ulcer treatment16,18,19 when a significant impact on venous hemodynamics is very important and also in lymphoedema.20 pressure and stiffness can be critically reduced in some areas of the leg with concave rather than convex shape as this is the case in the retro-malleolar space. unfortunately this is a critical area where often venous ulcers occur. it has been shown that in this region the pressure as well as stiffness can be close to zero as the pressure doesn’t increase in standing position or during muscle activity. pressure and stiffness in these areas can be significantly increased by applying local compression straps21 which greatly improve the clinical outcome.22 an increase of pressure and stiffness can be achieved also at thigh level by means of eccentric devices, which are able to compress the thigh veins otherwise difficult to compress.23 in this region higher pressure and stiffness leads to better outcome following surgical or endovascular procedures on the great saphenous vein.24,25 in conclusion it is important to realize that stiffness can be mainly considered as a surrogate indicator of comfort and effectiveness. the higher the stiffness the greater comfort and effectiveness in improving the clinical outcomes. stiffness is very high only with inelascorrespondence: giovanni mosti, angiology department, clinica md barbantini, lucca, italy. e-mail: jmosti@tin.it key words: international compression club, stiffness, compression devices, conference presentation. conference presentation: part of this paper was presented at the international compression club (icc) meeting on stiffness of compression devices, 2012 may 25, vienna, austria (http://www.icc-compressionclub.com/). received for publication: 15 november 2012. revision received: 23 january 2013. accepted for publication: 28 january 2013 this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright g. mosti, 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e1 doi:10.4081/vl.2013.e1 no nco mm er cia l u se on ly editorial [page 2] [veins and lymphatics 2013; 2:e1] tic material, or multilayer systems and can be enhanced by straps applied in a fan distribution or by eccentric compression devices in the leg segment that need to be treated. in vivo measurement techniques must be better defined in order to minimize the variability; a parallel match with the lab assessments is a mandatory target for future researches. only in this way the stiffness effective value will scientifically demonstrate to correspond to the great impact that already empirically presents in our everyday clinical practice. references 1. european committee for standardization (cen). non active medical devices. working group 2 env 12718: european pre-standard ‘medical compression hosiery.’ cen tc 205. brussels: cen; 2001. 2. mosti g, mattaliano v. simultaneous changes of leg circumference and interface pressure under different compression bandages. eur j vasc endovasc surg 2007; 33:476-82. 3. stolk r, wengen van der-franken cpm, neumann ham. a method for measuring the dynamic behaviour of medical compression hosiery during walking. dermatol surg 2004;30:729-36. 4. wienert v, hansen r. anmessen von medizinischen kompressionsstrümpfen am liegenden oder am stehenden patienten? phlebologie 1992;21:236-8. 5. partsch h. the static stiffness index: a simple method to assess the elastic property of compression material in vivo. dermatol surg 2005;31:625-30. 6. partsch h, clark m, bassez s, et al. measurement of lower leg compression in vivo: reccommendations for the performance of measurements of interface pressure and stiffness. dermatol surg 2006;32:224-33. 7. schuren j, bichel j. sub-bandage dynamics: stiffness unraveled. veins and lymphatics 2013;2:e2. 8. hirai m, partsch h. the mannequin-leg: a new instrument to assess stiffness of compression materials. veins and lymphatics 2013;2:e3. 9. cornu-thénard a, benigni j-p, uhl j-f. terminology: resistance or stiffness for medical compression stockings? veins and lymphatics 2013;2:e4. 10. uhl j-f, benigni j-p, cornu-thénard a. where should be stiffness measured in vivo? veins and lymphatics 2013;2:e5. 11. neumann ham. elasticity, hysteresis and stiffness: the magic triangle. veins and lymphatics 2013;2:e6. 12. van der wegen-franken k, tank b, neumann m. correlation between the static and dynamic stiffness indices of medical elastic compression stockings. dermatol surg 2008;34:1477-85. 13. mosti g, mattaliano v, partsch h. inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous reflux. phlebology 2008;23:287-94. 14. partsch h, clark m, mosti g, et al. classification of compression bandages: practical aspects. dermatol surg 2008;34:600-9. 15. andriessen a, abel m. experimental study on efficacy of compression systems with a high static stiffness index for treatment of venous ulcer patients. veins and lymphatics 2013;2:e8. 16. mosti g. relevance of stiffness of compression material on venous hemodynamics and edema. veins and lymphatics 2013;2:e9. 17. bender dj, fronek h, arkans e. quantified hemodynamics of compression garments. veins and lymphatics 2013;2:e10. 18. wong ik, andriessen a, lee dt, et al. randomized controlled trial comparing treatment outcome of two compression bandaging systems and standard care without compression in patients with venous leg ulcers. j vasc surg 2012;55: 1376-85. 19. mosti g, crespi a, mattaliano v. compa rison between a new, two-component compression system with zinc paste bandages for leg ulcer healing: a prospective, multicenter, randomized, controlled trial monitoring sub-bandage pressures. wounds 2011;23:126-34. 20. schingale f-j, partsch h. alginate hydrocolloid impregnated zinc paste bandagesan alternative in the management of lymphoedema? veins and lymphatics 2013;2: e11. 21. hopkins a, worboys f, partsch h. the use of strapping to increase local pressure: reporting of a sub-bandage pressure study. veins and lymphatics 2013;2:e12. 22. hopkins a, worboys f, bull r, farrelly i. compression strapping: the development of a novel compression technique to enhance compression therapy and healing for ‘hard-to-heal’ leg ulcers. int wound j 2011;8:474-83. 23. partsch h, mosti g, mosti f. narrowing of leg veins under compression demonstrated by magnetic resonance imaging (mri). int angiol 2010;29:408-10. 24. mosti g, mattaliano v, arleo s, partsch h. thigh compression after great saphenous surgery is more effective with high pressure. int angiol 2009;28:274-80. 25. lugli m, cogo a, guerzoni s, et al. effects of eccentric compression by a crossed-tape technique after endovenous laser ablation of the great saphenous vein: a randomized study. phlebology 2009;24:151-6.no nco mm er cia l u se on ly hrev_master veins and lymphatics 2018; volume 7:7280 [veins and lymphatics 2018; 7:7280] [page 29] the superficial venous pump konstantin mazayshvili surgical department, surgut state university, russia abstract the present study has revealed the relationship between the cross sectional area of the great saphenous vein and the degree of tension in the superficial fascia of the thigh. we conducted an ultrasound examination with 27 patients (54 lower limbs) in both standing and walking positions. with an increase and decrease in the degree of tension of the superficial fascia, the blood is pushed to the sapheno-femoral junction. nearly 200 mm3 of blood flows in, and is pushed out of, a 100-mm great saphenous vein segment in the thigh, towards the sapheno-femoral junction during a step cycle. as a result, the active function of the fascial compartment of the great saphenous vein has been found. we have called this mechanism the superficial venous pump. introduction the main functions of the venous system are: to return blood to the heart, and to serve as a capacitance in order to maintain the filling of the heart. motive forces in the venous return are common knowledge in medical literature, but are limited to respiration and skeletal muscle contractions of the extremities. miller et al.1 determined that phasic blood flow coincides with breath. the respiratory modulation of venous return from the lower limb is dependent not only on the pressures produced by the respiratory and skeletal muscle pumps, but is also critically dependent upon the capacitance and compliance of the venous vasculature which separates them. the compliance is the ratio of the change in volume resulting from a change in transmural distending pressure. because venous compliance is very high at low pressures, this is one of the main factors of the pumping mechanism itself. the peripheral venous pump is able to perform its main function of moving blood to the heart by the contraction of muscles in the foot, and the compression of the plantar vein when pressure is applied to the foot.2 ricci et al.3 considered the compression of the deep plantar arch, located between the bone arch of the foot and the plantar aponeurosis, as foot systole. elsner et al.4 have contributed data to the research of the venous pump function, namely that the medial outflow tract from the deep plantar venous plexus is fixed by fibrous bands connected to the first metatarsophalangeal joint. in addition, they were able to deduce that passive movements in the joint lead up to a 55 percent increase in blood flow; active movements result in an increase of up to 78 percent. in 1995, staubesand et al. investigated the so-called ankle pump. with the aid of duplex ultrasound they measured the rate of blood flow in the gsv of the lower extremity during a relaxed state, as well as during active and passive movements of the ankle joint. as a result of their observations, they reached the conclusion that movements in the ankle joint significantly increase the rate of blood flow in the gsv.5 during movement the muscles contract, resulting in blood being pushed away from the leg veins to the popliteal vein, which rapidly increases blood flow. as a result of the arising pressure gradient, distal valves in the deep and communicant veins close, thus preventing backflow. when the muscles in the calf are relaxed, the pressure created within the deeper veins is less than that in the superficial venous system, and blood repeatedly accumulates and leaves there through perforating veins and muscular branches.6 the muscles of the venous pump also participate in preventing orthostatic intolerance by enhancing the venous return.7 the muscular venous pump in each of the lower extremity segments ensures significant acceleration of blood flow in the deep veins of the lower extremities. meanwhile, little data is available concerning the relation between the pumping mechanism and the variation of superficial venous outflow in the superficial gsv. the course of the gsv in a fascial canal derived from the deep fascia of the lower extremity is described.8,9 the fascial canal is a sheath surrounding the gsv, and is continuous from the thigh to the leg (figure 1). as described, it supports the vein from the hydrostatic pressure of the blood and prevents its dilation.8 the malfunction of this fascial envelope of the vein, in whole or in part, may be involved in the pathogenesis or complications in the varicosities, of the gsv. ultrasonic examination of the gsv topography demonstrates that the gsv lies between sheets of saphenous fascia that are loosely adherent to its wall (figure 2). figure 2 shows that there is tissue space between the gsv and the sheets of saphenous fascia, and that the fascia rests on a small segment of the venous wall. this study aims at identifying mechanisms of effect of the saphenous fascia on the gsv diameter and, therefore, on expelling blood from the limb. this help understanding of how the venous vessel network can optimize blood flow in response to various mechanical forces. materials and methods our investigation was approved by the local ethics committee the national medical and surgical center, russia. this study was performed in order to determine the role of the saphenous fascial compartment in the venous outflow of the gsv. we used duplex ultrasound to analyze types of gsv location in the thigh (i-type: a single gsv in the saphenous compartment without branching; h-type: gsv in the saphenous compartment with a tributary branching out of the compartment; s-type: gsv is not visible, but there is a tributary vein which is not in the saphenous compartment)10 and the effect of saphenous fascia on the gsv diameter. for this study, linear transducers with a frequency range of 7.5-13.0 mhz, were used. a total of 54 limbs in 27 consecutive patients (3 male and 24 female) were observed. all patients were caucasians, with a mean age of 43.0 (sd 14.8) years. the ceap clinical class for these patients was: с0 in 3 limbs, с1 in 28 limbs, с2 in 16 limbs, с3 in 3 limbs and с4 in 4 limbs. the data was analyzed with statsoft’s statistica 6.0, by using a dependent t-test for physical properties. a p value of less than 0.05 was considered statistically significant for all tests. a reflux in the thigh segment was found in 15 limbs; no reflux was found in 39 limbs. reflux defined as retrograde flow lasting for more than 0.5 s, whereas less than 0.5 s is defined as normal or no correspondence: konstantin mazayshvili, surgical department, surgut state university, russia. e-mail: nmspl322@gmail.com key words: superficial venous pump; great saphenous vein; venous outflow. received for publication: 31 july 2017. revision received: 28 november 2017. accepted for publication: 28 november 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright k. mazayshvili, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7280 doi:10.4081/vl.2018.7280 no nco mm er cia l u se on ly article reflux11. patients who participated in the study were asked to imitate walking movements during their examinations. in the first stage, the gsv diameter was measured in the standing position, with the knee fully extended; this produced the highest degree of tension in the saphenous fascia (figure 3). the second stage of the patient examination was carried out in the standing position, with the knee flexed (imitating walking movement); this produced a relaxation of the fascial compartment (figure 4). in order to replicate a working process, we asked the patients to lift one knee up until calf and thigh forms a right angle. after that, patients lowered that leg and repeated with the other leg. the effect of the saphenous fascia on the gsv diameter was analyzed during two different phases of the step cycle. the gsv diameter was measured at four different levels: at the sapheno-femoral junction (level 1); in the lower third of the thigh (level 2); in the upper third of the calf (level 3); in the lower third of the calf (level 4). the gsv diameter was measured in the vertical position, transversal to vein axis. the vein capacity was calculated with a theoretically selected gsv segment of 100 mm in the middle third of the thigh. to simplify the model, it was assumed that in such a segment of the gsv, differences in blood vessel configurations could be ignored. the selected vein segment for our purposes was considered to be cylindrical. the cross-sectional area of the gsv, and the volume of blood it contained, were calculated at two phases of the step cycle: i) during maximum tension of the saphenous fascia and, consequently, maximum compression of the gsv; ii) during maximum relaxation of the fascial compartment, when the gsv cross section assumed the form of a circle. the tension of the fascia was not measured itself. the assessment point of the sfj was standardized according to coleridge-smith et al.12 the cross-sectional area of the blood vessel was calculated utilizing the basic formula to determine the area of an ellipse: (1) where s is the gsv cross sectional area; а is the minimum gsv diameter; b is the maximum gsv diameter. the blood volume within the selected gsv segment was calculated utilizing the formula for the volume of a cylinder: v = s ⋅ h (2) figure 1. anatomic relationship between the gsv and the fascial compartment. figure 2. ultrasonic image of the gsv and its fascial compartment. figure 3. patient examination in the midstance position of the step cycle. [page 30] [veins and lymphatics 2018; 7:7280] no nco mm er cia l u se on ly article [veins and lymphatics 2018; 7:7280] [page 31] where v is the volume of the selected gsv segment; h is the length of the selected gsv segment; s is the gsv cross sectional area. based on the previous two results, we calculated the blood volume forced out of the selected gsv segment during the step cycle, due to compression of the gsv by the walls of the fascial compartment. the calculations were based on the following formula: dv = v1 – v2 (3) where dv is the blood volume pushed out during the step cycle; v1 is the blood volume in the gsv segment during maximum relaxation of the fascial compartment; v2 is the blood volume in the gsv segment during maximum tension of the fascial compartment. results and discussion the results of this study show that maximum fascial tension is reached during the midstance position of the step cycle, which results in gsv compression. this occurs because when tense, the sheets of saphenous fascia shift toward each other and cause compression of the gsv (figure 5). as compression of the fascia compartment takes place, blood is simultaneously pushed out of the gsv segment towards the sapheno-femoral junction (level 1). during the heel off position of the step cycle, fascial tension dissipates, and the saphenous fascia tissue no longer exerts pressure on the gsv (figure 6); this results in the gsv assuming a form resembling a circle. the relaxing fascial compartment allows blood inflow from lower leg segments. each process is repeated during subsequent cycles of the step cycle. changes in the gsv lumen size, in relation to the midstance and heel off positions of the step cycle, are shown in figure 7. formula 2, as previously discussed, was used to calculate the blood volume contained in a 100 mm segment of a theoretically selected gsv, located in the middle of the thigh. figure 8 shows these blood volumes in the midstance and step off positions of the step cycle. the calculation does not include the resting superficial vein flow and its velocity. using this data in formula 3, as previously discussed, we obtain the following result: 198.8±31.2 mm3 of blood flows in, and is pushed out of, a 100 mm gsv segment in the thigh, towards the saphenofemoral junction (level 1) during the step cycle. as a result of this research, we have obtained data proving an active function of the gsv fascial compartment, which is the main part of the active mechanism. one of its purposes is to form, together with the gsv trunk, a venous pump, or the superficial venous pump of the lower extremities. the superficial venous pump was recently described. franceschi and zamboni distinguished this mechanism and its place in venous outflow from the leg.13 gianesini et al.14 determined the flow figure 4. patient examination in the heel off position of the step cycle. figure 5. the sheets of saphenous fascia shift toward each other and cause compression of the gsv. no nco mm er cia l u se on ly article [page 32] [veins and lymphatics 2018; 7:7280] velocities along the venous segments of the lower limb in 26 healthy volunteers. the peak systolic velocity, average time velocity and diameter of the saphenous system were obtained. the investigation provides evidences of the superficial venous pump as the active mechanism of outflow with the venturi effect as a potential factor in the flow aspiration from the superficial to the deeper veins. there was no difference in the results between the group patients with gsv reflux and does without. different risks of its varicose transformation can be assumed depending on the types of gsv location in the thigh (i-type, h-type, s-type). in the htype and s-type of gsv location, in which the trunk lies extrafascially, the sheets of saphenous fascia do not exert pressure on the vein. meanwhile results of our investigation did not represent differences between the patients with different gsv location in the thigh. the pumping mechanism can lower the venous pressures and reduce the volume of blood contained within the superficial veins. the tributaries play the role of reservoirs, from which blood enters the gsv. because of the presence of valves, blood does not return to them during the tension of the saphenous fascia. however, when the valves in the tributaries are incompetent, at the time of compression of gsv in the fascial compartment the blood may overfill them. this can lead to their permanent overstretch and varicose transformation. the h and s anatomical types of gsv location in the thigh also could impair this powerful pump and thus worsen venous return, causing the development of varicose transformation. the main limitations of the present study are represented by the exclusive focus on the mechanic aspects of venous return. although this is the main hemodynamic component, the study does not take into account the effects of the vasoactive agents on the saphenous wall as well as the role of the inflammatory cascade on the veins and the surrounding tissues, including the superficial fascia.15-18 figure 6. the saphenous fascia tissue no longer exerts pressure on the gsv this results in the gsv assuming a form resembling a circle. figure 7. changes in gsv lumen size in relation to measured positions of the step cycle. positions of the step cycle: stage 1 = midstance; stage 2 = step off. figure 8. blood volumes in a theoretically selected gsv segment. stage 1 = midstance; stage 2 = step off. no nco mm er cia l u se on ly article [veins and lymphatics 2018; 7:7280] [page 33] conclusions the conducted research has revealed an active function of the gsv fascial compartment in causing blood outflow. with the alternating tension and relaxation of the fascial compartment surrounding the gsv, blood is pushed out of the vein segment towards the sapheno-femoral junction, and then filled again, by a two-step process: i) when the saphenous fascia becomes tense, venous walls shift towards each other in the long segment, which leads to a rapid increase in blood flow; ii) when the sheets of saphenous fascia are relaxed, the vein, due to its elasticity, becomes round in its cross section. a concurrent increase in vein volume causes suction of blood to this segment. one-way centripetal blood flow is provided by valves. we have called this mechanism the superficial venous pump. it plays the role of a peripheral superficial heart, which combined with venous valves serve to avoid gravitational reflux during fascial diastole. finally this is a further argument in favor of saphenous vein sparing strategies.13,16,19 we are aware that the study was somewhat biased. a wider range of patients might have provided a more precise understanding of our research. nevertheless, we hope that it will help in the further study of venous outflow from superficial structures. references 1. miller jd, pegelow df, jacques ja, dempsey ja. skeletal muscle pump versus respiratory muscle pump: modulation of venous return from the locomotor limb in humans. j physiol 2005; 563:925-43. 2. uhl jf, gillot c. anatomy of the foot venous pump: physiology and influence on chronic venous disease. phlebology 2012;5:219-30. 3. ricci s, moro l, incalzi ar. the foot venous system: anatomy, physiology and relevance to clinical practice. dermatol surg 2014;40:225-33. 4. elsner a, schiffer g, jubel a, et al. the venous pump of the first metatarsophalangeal joint: clinical implications. foot ankle int 2007;8:902-9. 5. staubesand j, heisterkamp t, stege h. use of duplex sonography to investigate the effect of active and passive movement at the ankle joint for promoting venous return. clin anat 1995;2:96101. 6. alimi ys, barthelemy p, juhan c. venous pump of the calf: a study of venous and muscular pressures. j vasc surg 1994;20:728-35. 7. stewart jm, medow ms, montgomery ld, mcleod k. decreased skeletal muscle pump activity in patients with postural tachycardia syndrome and low peripheral blood flow. am j physiol heart circ physiol 2004;286:h1216-22. 8. papadopoulos nj, sherif mf, alberte en. a fascial canal for the great saphenous vein: gross and microanatomical observations. j anat 1981;132:321-9. 9. cavezzi a, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs uip consensus document. part ii. anatomy. eur j vasc endovasc surg 2006;31:288-99. 10. ricci s, caggiati a. echoanatomical patterns of the long saphenous vein in patients with primary varices and in healthy subjects. phlebology 1999;14: 54-8. 11. labropoulos n, tassiopoulos ak, kang ss. prevalence of deep venous reflux in patients with primary superficial vein incompetence j vasc surg 2000;32:6638. 12. coleridge-smith p, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs uip consensus document. part i. basic principles eur j vasc endovasc surg 2006;31:83-92. 13. franceschi c, zamboni p. principles of venous hemodynamics. new york: nova science publishers; 2009. 14. gianesini s, sisini f, di domenico g, et al. lower limbs venous kinetics and consequent impact on drainage direction. phlebology 2018;33:107-14. 15. rizzi a, quaglio d, vasquez g, et al. effects of vasoactive agents in healthy and diseased human saphenous veins. j vasc surg 1998;28:855-61. 16. zamboni p, spath p, tisato v, et al. oscillatory flow suppression improves inflammation in chronic venous disease. j surg res 2016;205:238-45. 17. tisato v, zamboni p, menegatti e, et al. endothelial pdgf-bb produced ex vivo correlates with relevant hemodynamic parameters in patients affected by chronic venous disease. cytokine 2013;63:92-6. 18. zamboni p, lanzara s, mascoli f, et al. inflammation in venous disease. int angiol 2008;27:361-9. 19. mendoza e. primum non nocere. veins and lymphatics 2017;6:6646. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2018; volume 7:7340 [veins and lymphatics 2018; 7:7340] [page 27] brave dreams: an overestimated study, crippled by recruitment failure and misleading conclusions bernhard h.j. juurlink,1 pietro m. bavera,2 salvatore sclafani,3 ivo petrov,4 donald b. reid5 1department of anatomy & cell biology, college of medicine, university of saskatchewan, saskatoon, sk, canada; 2vascular surgeon and diagnostician medick-up vascular lab, milan, italy and member of the italian society for angiology and vascular medicine (siapav) & member of the italian society for vascular investigation (sidv) milan, italy; 3department of radiology, suny downstate medical school, brooklyn, ny, usa; 4department of cardiology, angiology & electrophysiology, cardiovascular center, acibadem city clinic, sofia, bulgaria; 5the edinburgh clinic, edinburgh, scotland, uk a recent study, published in jama neurology, examining whether using percutaneous transluminal angioplasty (pta) to correct chronic cerebrospinal venous insufficiency (ccsvi) in multiple sclerosis (ms) patients concluded: venous pta has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with ms. 1 this is rather a bold statement for a study that was grossly underpowered. not surprisingly, given the history of reaction to the idea that impairment of venous return might influence the progression of ms, the publication of this study was followed by several editorials that bemoaned the power of social media to influence research on and treatment of disease.2,3 the brave dreams clinical trial was a multi-centre, randomized, sham-controlled evaluation of the efficacy and safety of venous pta of extra-cranial and extra-vertebral veins that contributed to ccsvi in patients with ms.1 involved were six centres accredited by the italian national health service. only physicians trained and accredited in functional outcomes, operation of echo colour doppler (ecd) and catheter venography with and without pta participated. patients in the trial were between 18 and 65 years old who had a diagnosis of remitting relapsing (rr) or secondary progressive (sp) ms with extended disability status scale (edss) score between 2 and 5.5, disease duration of 15 years or less, a stable neurology condition for at least 30 days, ccsvi as determined by ecd, not having received msspecific treatment for at least six months, no prior pta nor having a history on being on certain medications such as fingolimod. the primary outcomes measured at 12 months were a functional composite score and mri-detectable lesions. a new functional composite score was developed based upon commonly-experienced functional impairments such as walking control, balance, manual dexterity, post-void residual urine volume, visual acuity, etc. patients were evaluated and placed into improved, stable, worsened or mixed categories. mri analysis grouped patients into categories having new and/or enlarged lesions compared to baseline and those free of lesions. secondary outcomes included annualized relapse rates, changes in edss score and proportion of patients with restored venous flow. a power analysis was performed that determined that to detect 2.1 fewer lesions in rr ms patients at 90% power (an a of 0.05) would require the enrollment of 423 patients and at an 80% power would require enrollment of 300 patients. for sp ms patients a 90% power would require recruiting 222 patients. how many patients were actually enrolled in the clinical trial? only 115 rr ms patients enrolled in the study, of whom 112 completed the study while only 15 sp ms patients were enrolled. herein lies the major problem of the study: gross underpowerment. this incomplete study should not have been published, rather additional centres should have been established to ensure adequate patient enrolment. what the study found was that there were essentially no differences in functional composite score between the pta and sham groups of rr ms. however, 73% of the pta group had no new gadolinium-enhancing lesions compared to 49% in the sham group (p=0.08). for secondary endpoints the study showed that 23% of pta had at least one relapse (annualized rate of 0.32) compared to 31% (annualized rate of 0.39) of the sham group but this was not a significant difference. with sp ms there were no differences in composite functional score between the two groups; however, 100% of the pta group (n=10) developed no new lesions as opposed to 40% in the sham group (n=5). in summary, there was a trend for fewer new lesions in both the rr and sp ms groups if they had pta and fewer relapses in the pta group of rr ms patients. however, there were no differences noted between the two groups for composite functional and edss scores. about 41% of the rr improved compared to 49% of the sham while 12% of the rr and 19% of the sham worsened with the remaining patients showing a mixed outcome. curiously, median edss scores decreased from a median score of 2.5 to 2.0 in both the pta and sham-treated groups. what would the results have been if the study was properly powered? we point out that in a large study where 366 ms patients who had pta to correct for ccsvi were followed up for 4 years, pta resulted in significant clinical improvement, especially in the rr ms patient group.4,5 the patients were divided into rr (264), primary progressive (pp) and sp groups. all patients underwent a duplex exam and filled out a questionnaire that addressed the following symptoms: diplopia, fatigue, headache, upper limb numbness/mobility, lower limb numbness/mobility, altered thermic sensibility, bladder control, balance coordination, quality of sleep, vertigo, mind concentration and working activity. patients with ccsvi then underwent pta and were followed up for 4 years. it is important to note that the researcher carrying out the duplex exams and analyzing the questionnaire data was completely independent of the vascular surgeons carrying out the pta. this large study demonstrated that in rr ms patients that venous blood flow improvements were long-lasting when the abnormalities were not so severe. further, improved venous outflow was correspondence: bernhard h.j. juurlink, department of anatomy & cell biology, college of medicine, university of saskatchewan, 683 butterfield road, mill bay, bc, v0r 2p4, canada. tel: 1-250-815-5656. e-mail: bernhard.juurlink@usask.ca contributions: the initial draft was written by b. juurlink following suggestions of the other authors. this initial draft was then modified according to the further suggestions of each of the authors. conflict of interests: the authors have no conflict of interests to disclose received for publication: 12 february 2018.. revision received: 21 march 2018. accepted for publication: 21 march 2018. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright b.h.j. juurlink et al., 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7340 doi:10.4081/vl.2018.7340 no nco mm er cia l u se on ly editorial [page 28] [veins and lymphatics 2018; 7:7340] associated with long-lasting improvements in clinical symptoms with improvements in: more than 90% with diplopia, fatigue, headache, quality of sleep, vertigo and ability to mentally concentrate; more than 80% in balance control and upper and lower limb functions; and more than 65% in bladder control and thermic sensibility. in contrast, although sp and pp ms patients showed some initial clinical improvements following angioplasty, these disappeared within 212 weeks. a problem with the brave dreams study is that only about half of the patients had improved venous blood flow following pta. clearly, the reasons underlying this surprising failure to improve blood flow in almost 50% of the patients treated for ccsvi must be investigated. the authors are encouraged to publish a review of the technical methodology and outcomes of their study so that the techniques can be analyzed and enhancement in technique be considered. it is equally important to delineate which subset of ms patients respond to pta. we point out that carotid endarterectomy, which now is a well-accepted common stroke prevention technique in a subset of patients, was questioned as recently as 1984.6 the challenge in determining efficacy of endarterectomy was to define which subset of patients benefited from the surgery. this has now been clarified.7 those who have performed angioplasty to correct for ccsvi in ms patients have noted that only a subset of patients benefits from treatment. more research is needed to identify the subset of ms patients with ccsvi that can benefit from the treatment. what also struck us was the lack of composite functional endpoint analysis of the subset of pta-treated patients (54%) where blood flow improved compared to the patients where blood flow was not improved? after all, one of the objectives of pta in treating ccsvi is improvement of venous outflow and cerebrospinal fluid drainage to ultimately enhance cerebrospinal perfusion. and, as noted above, in the bavera follow-up study clinical improvements were noted only if there were improvements in venous outflow following pta.4,5 further, why was no attention paid to the fact that 38% of the sham-treated group had improved blood flow, after all improved blood flow regardless of treatment is desired to improve symptoms of ms. improved blood flow following shamtreatment is, at first glance, surprising; perhaps valvular and other endoluminal alterations resulting from catheterization itself may improve flow. moreover, there is some evidence suggesting that pta may improve autonomic function which may itself improve blood flow.8,9 if this be the case then it becomes important to know whether improved venous blood flow, regardless of treatment, improves outcomes. this was not addressed in the paper. the possibility of technical deficiencies must be considered as a contributor to the poor rate of flow restoration in the brave dreams study. reporting clinical outcomes of a new operative procedure without also reporting the technical parameters of the procedure as was recommended by the international society for neurovascular disease (isnvd) and by the society of interventional radiology prevents real critique of the procedure.10,11 many aspects of this therapy are dependent on the diagnostic findings, such as use of intravascular ultrasound, degree of stenosis, number of extrinsic compressions, incidence of webs, divisum, septum duplication and webs, transit time, stagnation, reflux, and as well upon technique, such as balloon size versus vessel size, end point of angioplasty, pressure of angioplasty, number of inflations, duration of inflation, residual stenosis, incidence of dissection. without this information, proceduralists cannot assess the validity of the results, or learn why almost half of the patients failed to have improved flow after angioplasty, nor can they develop improvement in techniques. one firm conclusion from this randomized, blinded study is that pta to correct for ccsvi is safe.1 this is not a new finding since the safety of pta to correct for ccsvi had been described previously.12 we also note that if one combines the remitting-relapsing and the secondary progressive ms patients in the pta (n=73 and n=10, respectively) and sham (n=37 and n=5, respectively) and examines for absence of new lesion formation, we find that 56/83 pta patients and 21/42 sham patients had no new lesions. a chi squared analysis shows that the probability of the pta treatment having no effect is 0.058. as noted this brave dreams study was greatly underpowered and this statistical analysis suggests that on this basis alone further studies are well-warranted and we urge the investigators to continue to enrol patients into their clinical trial and to, especially, dig deeper into the data. there is an abundance of evidence that co-morbidities have an effect on progression to disability in ms13 and it is, therefore, not unreasonable to hypothesize that problems in venous outflow from the cns would affect progression to disability. references 1. zamboni p, tesio l, galimberti l, et al. efficacy and safety of extracranial vein angioplasty in multiple sclerosis. a randomized clinical trial. jama neurol 2018;75:35-43. 2. green, aj, kamel h, josephson, a. combating the spread of ineffective medical procedures. a lesson learned from multiple sclerosis. jama neurol 2018; 75:15-7. 3. zivadinov r, weinstock-guttman b. extracranial angioplasty is ineffective in treating ms. nature rev neurol 2018; 14:129-30. 4. bavera pm. may symptoms of chronic cerebrospinal venous insufficiency be improved by venous angioplasty? an independent 4-year follow up on 366 cases. veins and lymphatics 2015; 4:5400. 5. bavera pm. chronic cerebrovascular vein insufficiency (ccsvi): how and when can jugular vein pta influence the most frequent symptoms and disturbs in multiple sclerosis. acta phleb 2016;17:27-32. 6. barnett hjm, plum f, walton jn. carotid endarterectomy an expression of concern. stroke 1984;15:941-43. 7. easton jd. history of endarterectomy then and now. stroke 2014;45:e101-3. 8. arata m, sternberg z. transvascular autonomic modulation: a modified balloon angioplasty technique for the treatment of autonomic dysfunction in multiple sclerosis patients. j endovasc ther 2014; 21:417-28. 9. sternberg z, grewal p, cen s, et al. blood pressure normalization post-jugular venous balloon angioplasty. phlebol 2015; 30:280-7. 10. simka m, hubbard d, siddiqui ah, et al. catheter venography for the assessment of internal jugular veins and azygous vein: position statement by expert panel of the international society for neurovascular disease. vasa 2013; 42:168-76. 11. siskin, gp, haskal zj, mclennan g, et al. development of a research agenda for evaluation of interventional therapies for chronic cerebrospinal venous insufficiency: proceedings from a multidisciplinary research consensus panel. j interv radiol 2011;22:587-93. 12. petrov i, grozdinski l, kaninski g, et al. safety profile of endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j endovasc therap 2011; 18:314-23. 13. zhang t, tremlett h, zhu f, et al. effects of physical comorbidities on disability progression in multiple sclerosis. neurol 2018 [epub ahead of print]. no nco mm er cia l u se on ly hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: diameter reduction of the great saphenous vein and the common femoral vein after chiva long-term results by mendoza e. phlebologie 2013;42:65–69. stefano ricci abstract the diameters of the veins are considered to be an indicator of the severity of venous disease. the present paper examines as a retrospective evaluation, the development of the diameter of the gsv and common femoral vein, as well as the small saphenous vein in the patients who were originally enrolled in the long-term investigation on chiva versus stripping and who spontaneously attended the practice over the further course after conclusion of the three-year study. the diameters of the veins were evaluated at the following points: i) common femoral vein immediately distally of the junction of the great saphenous vein; ii) great saphenous vein 15 cm distally of its junction; iii) small saphenous vein 5 cm distally of the knee fold. in addition, the c from the ceap and the refilling time after muscle pump (light reflection rheography, were evaluate. a total of 43 patients presented, 15 men and 28 women. the mean follow-up period was 5.36 years (±1.63 years, range 3–8.6 years). the patients had been operated on the great saphenous vein in 28 cases and on the small saphenous vein in 15 cases. a greater diameter of the common femoral vein was seen preoperatively in the case of disease of the great saphenous vein than in the case of disease of the small saphenous vein [cfv with pathology of the gsv: 16.1 mm (±2.7), cfv with pathology of the ssv 14.1 mm (±3.1)]. the reduction in diameter of the cfv after treatment of the gsv ran from 16.1 mm preoperatively via 15.3 mm after 8 weeks (not significant) to 14.3 mm after 5 years (significant compared with preoperatively and with 8 weeks postoperatively). a significant reduction in diameter results between the preoperative finding and the two postoperative measurements with pathology of the great saphenous vein: the diameter decreased from 7.0 mm (±2.0) preoperatively via 5.0 mm (±1.15) after 8 weeks to 4.4 mm (±1.4) after 5 years. after treatment of the gsv, the c value decreased significantly from 2.6±0.6 preoperatively to 1.8±1.2 postoperatively and was stable after 5 years. the initially significant reduction in the highest c value after treatment of the ssv (from 3.0±1.0 to 1.1±1.0) increased after 5 years (not significant) to 1.6±0.8. the refilling time was only measured in 17 patients with treatment of the great saphenous vein. the values developed from an average of 15.9 s (±6.6) preoperatively to 18.5 s after 8 weeks (±6.5) and further to 21.7 s (±10) after 5 years. in people with healthy veins, a mean diameter at the proximal thigh of 3.7±0.9 mm was demonstrated (mendoza e, blättler w, amsler f. great saphenous vein diameter at the saphenofemoral junction and proximal thigh as parameters of venous disease class. eur j vasc endovasc surg 2012;45:76–83. see abstract and comments on bybliolab 2013:1). the values for the great saphenous vein after 5 years, at an average of 4.4 mm, were within the standard deviation of the people with healthy veins. these data demonstrate that hemodynamic correction after chiva does not place an excessive strain on deep leg veins and that their diameters remain stable or continue to decrease, even after long-term observation. comment by stefano ricci this interesting study is a further step by the same author on analysis of gsv calibers as a parameter of its clinical status. it is demonstrated now that chiva method is able to achieve long-term stable hemodynamic balance (at least in a good number of cases) independently of the inherited evolution tendency of the disease. unfortunately, in the paper all data concerning the shunt classification of pretreated patients are missing and, consequently, the type of operation employed. it is not clear: i) whether all the considered patients (defined as having disease of the gsv) had a crossotomy or alternatively had a tributary disconnection; ii) whether the crossotomy was immediate or has been performed in a second phase; iii) the length of the saphenous incompetence, as well as possible post-operatory phlebitis (recanalized) of the gsv; iv) if all the above-mentioned conditions can have different effects on the gsv behavior. by the way, the treatment of the ssv (junction ligation?) cannot be considered a proper chiva operation. finally, it would be of great interest knowing the specific data related to the 8 patients who received the recommendation of undergoing an intervention, in order to verify the importance of the gsv diameter indication. [top] 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2018; volume 7:7558 [page 48] [veins and lymphatics 2018; 7:7558] the social and aestetical aspects of venous and lymphatics disorders: professor dino de anna vincenzo gasbarro chief vascular surgery unit, azienda ospedaliera universitaria of ferrara, italy speaking of dino de anna it is tough not to be overloaded by personal emotions in order to give to the readers a clear and honest image of him. he was born in cordenons (italy) 72 years ago. he graduated in medicine at the university of ferrara always playing rugby, always at the highest level, both with petrarca padova and sanson rovigo, winning two major series, in 1976 and 1977. as a young resident in surgery he meets mirella, prof. donini’s trusty secretary, who will become his wife. professor donini, a pioneer in venous and lymphatic disease. keen of the physical prowess of the young rugby player and knowing him interested in surgery, after a quick interrogatory, typical of his style, offers him to become an attending physician at the department of surgery at university of ferrara. and so the academic career of dino de anna began. between ‘70 and ‘80’s he completed the specialties in general, pediatric, and vascular surgery. dino, being passionate of venous and lymphatic diseases, picked up and implemented the knowledges of his masters in this specific field. we recognize the intuition to join phlebology and aesthetical medicine, thanks to the close relationship with carlo alberto bartoletti, pioneer of aesthetical medicine in italy.1 moreover, the social aspects related to venous leg ulceration and lymphedema were always a battle horse in his conferences and lectures.2 under the push of prof. donini, in november 1986 dino was one of the founder members of the italian society of phlebolymphology, becoming subsequently the president from 2000 to 2003. he was a mediator in the process of merging the major italian phlebologic societies, culminated in 1996 into the birth of the italian college of phlebology. the international conferences of phlebolymphology he organized in the second half of the eighties are still remembered for the presence of the gotha of phlebology at that time, including stemmer, van deer stricht, simkin, altman canestri, cockett, hobbs, partsch, ouvry. he chaired the institute of surgical pathology at the university of sassari in the half of nineties, and the institute of general surgery at the university of udine a few years later. from eclectic and dynamic man who was, he alternated the academic career to the politics, covering the position of senator of the italian republic from 1996 to 2001. in phlebology are remembered his studies on minimally invasive venous surgery, being a pioneer in the angioscopy of the venous system and of the laser ablation of the greater saphenous vein.3,4 mention should also be made of his numerous scientific contributions in diagnosis and treatment of lymphoedema. president of honor of the italian college of phlebology from 2011. he left us on march 29, 2018. i am certain that these few notes cannot define in exhaustive way the personality and the sensibility of a man who always demonstrated honesty and good sense. everybody remember his frank and direct speech. i will bring me inside his self-irony and modesty, the most characterizing tracts of the strong personality of dino, as well as an indelible memory of man and teacher. references 1. donini i, de anna d, carella g, et al. [mesotherapy in the treatment of lymphedema: histologic and ultrastructural observations]. chir patol sper 1982;30: 25-34. 2. de anna d, corcos i. [social relevance of venous lymphatic diseases]. minerva cardioangiol 2002;50:34-8. 3. zamboni p, feo c, marcellino mg, et al. angiovideo-assisted hemodynamic correction of varicose veins. int angiol 1995;14:202-8. 4. corcos l, dini s, de anna d, et al. the immediate effects of endovenous diode 808-nm laser in the greater saphenous vein: morphologic study and clinical implications. j vasc surg 2005;41: 1018-24; discussion 1025. correspondence: vincenzo gasbarro, chief vascular surgery unit, azienda ospedaliera universitaria of ferrara, italy. e-mail: gsv@unife.it this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright v. gasbarro, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7558 doi:10.4081/vl.2018.7558 figure 1. dino de anna, founder member and past president of the italian society of phlebolymphology. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2018; volume 7:7622 [veins and lymphatics 2018; 7:7622] [page 59] pressotherapy with adjustable high-pressure gradients claude-julien cartier cabinet médical, châtearoux, france abstract our team is presenting a new therapeutic concept based on the important experience acquired around the mercury fluid’s strong internal hydrostatic pressures in vascular and post-traumatic therapy. currently, the objective is to extend the physical recourse to strong pressures without mercury to carry on the advantages and open up to other performances. context when looking for the tissue complications of scuba diving in the literature, we do not find any. yet the soft parts of the body receive 1 bar of extra pressure every 10 meters deep. in apnea, we can easily reach 3 to 10 extra bar. with bottles, we go down much deeper and a lot longer. 1 bar is the atmospheric pressure on the cutaneous surfaces at sea level. 1 extra bar is a familiar pressure for the plantar lymphatics when walking, and this pressure is greatly increased during jogging and jumping. 1 bar is the maximum pressure of the high gradients known and used on the human body (mercury). professor henri boccalon (vascular physician, rangueil university hospital of toulouse), performed isotopic lymphoscintigraphy in 1992 before and after treatment with mercurial pressotherapy of 30 primary and secondary lymphoedemas of the lower limbs by monotherapy: i) 13 flow improvements; ii) 16 unchanged states; iii) 1 single aggravation on recurrence of cancer, with clinical improvement. today, after 30 years of mercurial pressotherapy and more than 2,000,000 patients treated (medical practices, hospitals): no early or late deleterious effects in the usual results on loosening, volume reduction, healing.1-5 therefore, all these data seem to allow us to go further in the use of strong pressures safely applied to vascular diseases in limbs. argumentary how and why apply high-pressure gradients? we know the physiological interest of the continuous diurnal compression stokings on liquid transfers (10 to 40 mmhg). the compression can also be applied in a discontinuous, and even paroxysmal mode: i) equal pressure: nothing happens and the tissue fluids settle in depth; ii) degressive compression with low pressure gradient (=existing pressotherapies, less than 200 mmhg): the action is absorbed quickly in the first support tissues, in proportion to the magnitude of the applied pressure gradient; iii) this explains the major physiological interest of applaing high pressure gradients, between 200 mmhg and 760 mmhg (level of the mercury pressotherapy). in the compressed territories, volume decrease and the relaxation of the interstitium and lymphatic canals restores the necessary flexibility to the physiological action of pumping macro-proteins; as soon as the pressures get stronger, the action is transmitted in depth, where the tissues are the most diversified and the lymphatic vessels are the rarest, physiologically overflowing: all the support tissues, muscular compartments, aponeuroses, neurovascular sheaths, tendons, articular areas, periosteum; this action involves moreover a tightening effect on the arteriolar vasodilator endothelium with reactive hyperaemia and macroscopic permanent erythrosis. here, the vasodilatation takes place in a territory emptied of any venous content to stimulate the increase of the tissue oxygenation turn over. this has been schown by the study carried out at insep by dr. jousselin in 1990, which demonstrates, on the lactate levels decreases, the acceleration of the return to muscular aerobiosis in active sports recovery with strong pressure gradient, which was not atchieved with the low-pressure therapies that have been tested. method the treatment that we propose is a gradual paroxysmal discontinuous compression. initial treatment: 3 to 4 sessions of 30 minutes spaced at intervals of 1 to 8 days. maintenance treatment: 1 session after 1 month, then 3 months, then every 6 months or once a year and when necessary according to evolution. the patient is lying down and relaxed while leaning his torso. equipment we turn to compressed air in a characteristic stack of multiple pockets, using a gradient smoothing method on the limbs. variable pressure gradients ranging from the upper limit of the existing pressotherapy to the studied hydrostatic pressures of mercury are programmed. the maximum peripheral pressures can be reported higher on the limb. in pure lymphatic pathologies, the device dispenses proximal ganglionic pressures. the contention is widely used around treatments. input what is innovative and makes a difference with the existing pressotherapies: the set of pressure macro gradients (0, 2 to 1 bar); the deep action; the transfer of the maximum pressures; the evacuation/vasodilatation conjunction; the induced aerobiosis. compared with mercurial pressotherapy: the performance without mercury; the absence of environmental constraint; the position at rest during treatment; the small size of the device, its mobility, its lightness, its cost. proposed pressure gradients will have 3 possible uses: medical and paramedical (the first to be developed); sports fields, fitness, spas; well-being and aesthetics. target of the medical environment venous and veno-lymphatic pathologies correspondence: claude-julien cartier, cabinet médical, 7 rue albert 1er, 36000 châteauroux, france. e-mail: mlaure.cartier11@yahoo.fr conference presentation: international compression club (icc) meeting, paris, 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright c-j. cartier, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7622 doi:10.4081/vl.2018.7622 no nco mm er cia l u se on ly conference presentation [page 60] [veins and lymphatics 2018; 7:7622] (sequelae of thrombosis, pain, heaviness, edemas, hypodermitis, ulcers); sequelae of trauma (sprains, fractures, tears, algoneurodystrophy); sport pathologies and traumas; primary and secondary lymphedemas, early or old; prevention of late edemas; mixed pathologies; contraindicated arterial surgeries for the elderly. currently, the proof of concept is established and we will produce the prototypes in spring, for technical and then medical experiments. references 1. cartier cj. mercury bath pressotherapy, indications, results. phlebologie-sfp 1988. 2. cartier cj. pressoyherapy by mercury in the treatment of limphedemas. j malad vascul 1990;15. 3. cartier cj. edema physical treatment by mercury. eur j lymphol 1992;3:10. 4. cartier cj. mercury pressotherapy (p.m.). angiologie 2000;52. 5. schadeck m. pressotherapy with bath of mercury in the hypodermitis treatment. phlebologie-sfp 2001;54. no nco mm er cia l u se on ly isnvd scientific meetin 7th annual isnvd scientific meeting 4-6 may 2017 taormina, italy alessia giaquinta department of medical and surgical sciences and advanced technologies, university hospital of catania, catania. correspondence: alessia giaquinta, e-mail: alessiagiaquinta@gmail.com the international society for neurovascular disease (isnvd) is pleased to invite you to attend the 7th annual scientific meeting to be held may 4-6, 2017 in taormina, italy. the international society for neurovascular disease is a professional association devoted to research in the field of neurovascular related diseases. our annual scientific meeting targets medical groups including, but not limited to: vascular surgeons, interventional radiologists, neurologists, neurosurgeons, physicists, and technologists and basic neuroscience, bioengineers and neurovascular researchers. the 3 days scientific programme includes: 13 main sessions, dibates and symposiums and 4 keynotes speakers (mat daemen, alberto figueroa, byung-boong lee, seshadri raju). the main topics are (view attached programme): acute stroke prevention during tavi, aortic arch repair and cas; new horizons in the imaging and treatment of acute stroke; brain hypoperfusion and neurodegeneration; bridging the gap between extracranial flow and brain; update on venous stenting. saturday 6th at 2:00 p.m is scheduled a meeting with international patients associations with a keynote testimonial, nicoletta mantovani, and interactive webinar. for more information and for online registration, please visit www.isnvd2017.it [top] early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. eissn 2279-7483 https://www.pagepressjournals.org/index.php/vl/index publisher's disclaimer. e-publishing ahead of print is increasingly important for the rapid dissemination of science. the early access service lets users access peer-reviewed articles well before print / regular issue publication, significantly reducing the time it takes for critical findings to reach the research community. these articles are searchable and citable by their doi (digital object identifier). veins and lymphatics is, therefore, e-publishing pdf files of an early version of manuscripts that have undergone a regular peer review and have been accepted for publication, but have not been through the typesetting, pagination and proofreading processes, which may lead to differences between this version and the final one. the final version of the manuscript will then appear in a regular issue of the journal. e-publishing of this pdf file has been approved by the authors. all legal disclaimers applicable to the journal apply to this production process as well. veins and lymphatics 2023 [online ahead of print] to cite this article: costantino eretta, elisa tridoni, serena isaia, et al. complex decongestive therapy in lymphedema: report from an interdisciplinary center. veins and lymphatics. 2023;12:11551. doi:10.4081/vl.2023.11551 ©the author(s), 2023 licensee pagepress, italy https://www.pagepressjournals.org/index.php/vl/index early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. complex decongestive therapy in lymphedema: report from an interdisciplinary center costantino eretta,1 elisa tridoni,2 serena isaia,2 arianna pigoni,2 azzurra vatteroni,2 laura impieri,2 claudio bianchi1 1general surgery department, ss lymphatic surgery, san bartolomeo hospital, sarzana; 2sme, medical center, sarzana, italy corresponding author: costantino eretta, general surgery department, ss lymphatic surgery, san bartolomeo hospital, sarzana, italy. e-mail: eretta.costantino@gmail.com key words: lymphedema, disability, complex decongestive therapy (cdt), complex decongestive physiotherapy, manual lymphatic drainage (mld) authors’ contributions: all the authors made a substantive intellectual contribution. all the authors have read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work. conflict of interest: the authors declare no potential conflict of interest. funding: none. mailto:eretta.costantino@gmail.com early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. ethics approval and consent to participate: all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 helsinki declaration and its latest amendment. availability of data and materials: all data generated or analyzed during this study are included in this published article. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. abstract lymphedema is a chronic and worsening disease due to an abnormal accumulation of liquids, with a high protein content in the interstitial space. the disease is characterized by an insufficient flow of lymphatic fluid, which manifests as edema, inflammation, and fibrosis, all the way up to the stiffening of the affected tissues. because it's a chronic and increasing disease, the treatment is highly complex. the literature shows that the treatment must be multidisciplinary and it is necessary to combine multiple techniques, such as manual lymphatic drainage, mechanical lymphatic drainage, elasto-compressive bandages and other complementary techniques up to surgical treatment in the most advanced forms which are not responsive to physical therapy. furthermore, the disease is characterized by episodes of cellulitis, that may lead to infectious complications because the lymphatic function becomes insufficient. a condition of local immunodeficiency is created due to the crucial role that the lymphatic system covers with immune defenses, therefore creates a fertile ground for infections caused by small skin wounds, insect bites, animal scratches, nail fungus, blood draws. therefore, particular attention is paid to skin folds and interdigital spaces for which hygiene is necessary using neutral detergents, drying by dabbing, and applying emollient creams for skin hydration. unfortunately, such practices of prevention and care are often underestimated. we provide education of the patient on self-care, such as the self-bandage and the correct application of the elasto-compressed stoking. for wrapping the bandage, it is advisable to wear a glove or a special sock. the multilayer bandages are used in the first decongestant phase while over time the elastic stocking is the best aid for the management of lymphedema. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. our clinic is a referral center for diagnosis, treatment and surgical therapy, where patients come for surgical evaluation. since 2016 we have systematically collected clinical data and volume evaluation of more than 600 cases affected by lymphedema and lipoedema of all stages. they have been treated with complex decongestive therapy for 4 hours a day, 15 consecutive days, subsequently a maintenance of once a week for 3 months, then once a month for 6 months. of more than 600 patients treated, only 150 were submitted to surgery (lymphatic venous anastomosis, fasciotomy or liposuction, chylothorax and chyloperitoneal shunt, reconstructive plastic of external genitalia). complex decongestive interdisciplinary therapy, when properly performed can stabilize the lymphedema patient situation, reducing the stage and ensuring a good quality of life. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. introduction lymphedema is a chronic disease with a progressively worsening evolution and appearances of recurrent complications, dermato lymphangio adenitis (dla) are responsible for a further rapid increase in the volume and consistency of the edema. the conservative therapeutic methods of medical-physical rehabilitation adopted in the treatment of lymphedema of the limbs allow excellent results to be obtained whether performed by expert hands following precise treatment protocols. only patient refractory to conservative treatment should be referred for surgical treatment, a decision exclusively reserved to an experienced lymphologist. in recent decades, the literature has shown that the advent of surgical techniques such as microsurgery and minimally invasive techniques, including autologous vascularized lymph node microsurgery (vlnt), lymphatic graft (lympholymphatic graft), anastomosis lymphatic venous vein (lva) and the superficial one performed in supermicrosurgery, have allowed positive and constantly prolonged results, but they must be always preceded and followed by medical-physical-rehabilitative therapy. the purpose of the present article is to demonstrate how medical physical rehabilitation therapy is effective in treating lymphedema of the limbs, when is performed in highly experienced centers, so then only a small part of patients need surgery. our clinic is a referral center for the diagnosis, conservative treatment and surgical therapy for lymphedema, where only physiotherapists with a diploma of vodder school can work, and always supervised by an expert lymphologist. since 2016 we have systematically collected the clinical data and centimeter evaluation of more than 600 cases affected by lymphedema and lipoedema of all stages, treated with complex decongestive early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. therapy for 4 hours a day, 15 consecutive days, subsequently a maintenance of once a week for 3 months, then once a month for 6 months. of more than 600 patients treated, only 150 were submitted to surgery (lymphatic venous anastomosis, fasciotomy or liposuction, chylothorax and chyloperitoneal shunt, reconstructive plastic surgery of the external genitalia). complex decongestive physical therapy, when properly performed can stabilize the lymphedema patient situation, reducing the stage and ensuring a good quality of life. materials and methods between 2016 and 2022 our center conducted a clinical study involving 600 patients with primary and secondary lymphoedema of the limbs undergoing intensive treatments (table 1). inclusion and exclusion criteria i) cdt, patients with clinical stage ii or iii of lymphoedema (isl stage), lipoedema all stages; patients with nyha 3 heart failure were excluded from the study; ii) surgery, patients who could not be stabilized after 2 cycles of intensive care or patients who had an absolute indication for surgical therapy, e.g. post-surgical lymphocele, lymphangioma, thoracic duct anomalies, plastic surgery of the external genitalia; patients with lipoedema were excluded from surgery. the study included 606 patients, with middle age of 54 years: 171 with lipoedema, 113 with lower limbs affection (99 women and 14 men), 58 with duplicated lipoedema of upper limbs (56 women and 2 men), 435 with lymphedemas, 125 primary, 119 lower limbs (73 women and 46 men), 6 upper limbs (2 men and 4 women). early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. about primary lymphedemas, 80 cases were certified for rare disease with exemption code rgg020 (in our region we have been authorized to issue specific exemptions since 2018), 25 of which underwent genetic testing. two hundred and ninety-one with secondary lymphedema, 202 lower limbs (123 women and 79 men) for uterin and prostate cancer with lymphadenectomy, a minor part for melanoma with lymphadenectomy, 89 affected by lymphedema of the upper limbs, 82 women (mainly secondary lymphedema to breast cancer) and 7 men (2 for breast cancer and 5 for melanoma surgery). patients were classified according to the isl consensus document: i) primary lymphedema, upper limbs 6 cases stage ii, lower limbs 15 stage i, 92 stage ii and 12 stage iii; ii) secondary lymphedema, upper limbs 69 cases stage ii, 20 stage iii, lower limbs 171 stage ii, 31 stage iii. nineteen patients had other pathologies of the truncular lymphatic system. methods in our center, patients are subjected to a lymphological examination by a specialist with many years of experience. the diagnostic procedure includes the collection of anamnestic data, a clinical examination with venous and arterial doppler ultrasound examination of the limbs, complete ultrasound abdominal scan, and in case of suspected cancer pathology tumor markers are prescribed. each patient is discussed collectively with the members of the staff (physiotherapists with a vodder school diploma). all patients underwent lymphoscintigraphic examination of the limbs, but for selected or complex cases we address them to magnetic resonance imaging (mri) studies. indications on skin care and how to prevent possible infectious episodes are always explained. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. at the beginning of the session, the therapist marks centimeter measurements of limbs, weight and photographic documentation of the patient. a suitable diet is given for overweight or obese patients. our protocol provides an intensive cycle of 15 days of complex decongestive therapy (cdt), each day includes 1 hour of manual lymphatic drainage according to vodder, 1 hour of lpg endermology, 2 hours of intermittent pneumatic compression multichamber therapy and a multilayer bandaging with short-stretch bandages. for patients with facial lymphedema, the protocol included 1 hour of manual lymphatic drainage and the linforoll method for one more hour. patients who also presented web axillar syndrome or lymphatic drainage disturbed by scars, we combined the lymph taping. at the end of the cdt, the patient's measurements are taken again, so the clinical response can be evaluated. the specialist then prescribes the correct elastic stocking with the right compression class, which is supplied by our trusted technician based on accurate measurements, so one or more customized elastic garments are packaged. stabilized patients continue with 1 weekly sessions for a further 3 months and subsequently 1 session a month for 6 months, in our center or with a vodder physiotherapist near the patient's residence. patients refractory after at least 2 intensive cycles of cdt may be cases for surgery indications. in our center, the following surgical procedures are performed based on the residual edema and its component (fibrotic vs adipose) and on the lymphoscintigraphic study: i) one site deep lymphaticvenous anastomosis (lva) in the inguinocrural region for the lower limb and in the middle third of the arm for the upper limb, using the blue patent violet and operating microscope; ii) early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. supermicrosurgery, with the use of indocyanine green, with multiple lymphatic venous anastomoses; iii) minimally invasive endoscopic fasciotomy (mif) for cases where is not possible to perform lymphatic-venous anastomosis or for oncological criteria; iv) fibrolympholiposuction, in patients with a higher percentage of residual adipose tissue; v) resective surgery in those patients where exuberant tissue remains at the end of the decongestant therapy or in patients presenting asymmetrical lipodystrophy, resective plastic surgery of the external genitalia, removal of cystic lymphangioma, lymphocele; vi) treatment of chylothorax and chyloperitoneum in patients with abnormalities of the thoracic duct or of the chili cistern, who are preventively undergoing hospitalization and total parenteral therapy and subsequently laparoscopic or thoracoscopic video surgery; vii) implantation of monoclonal cells, in patients with lymphedema and ulcerations. results in our center, we treated all patients with cdt according to our protocol, and in order to evaluate the response to the treatment we decided to use the icf disability scale. the icf is outlined as a classification that aims to describe the state of people’s health in relation to each field of life (social, family, work) in order to highlight the difficulties that can cause disability in the socio-cultural environment of the patient. the icf disability scale is a framework of predefined tables which each patient is asked to fill out at the beginning and at the end of the cycle of treatments. thanks to this methodology we have highlighted the physical and psychological difficulties of the patient during the various stages of the disease. the aim was to verify the patient's improvements by comparing the results obtained based on the subjective responses they made. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. the questionnaires collected data about the disability degree that they express personally, demonstrating how the proposed treatments were able to improve psycho-physical and social conditions of the patient suffering from lymphedema and lipedema (table 2, table 3). in order to get the disability average score, the patient has to express each skill with a score between 0 and 4. then the professionals calculate the total amount by adding each single score and dividing it by the total number of items. the number obtained is related to an index that describe the degree of disability (table 4). all patients affected by lipoedema have been treated with cdt, and those with bmi higher than 25 had to follow a suitable diet combined with regular physical activity, getting benefits from both decongestant therapy and weight loss (figure 1). all patients reported reduction of pain, volume and sensation of tension. about patients affected by lymphedema of all 435 who underwent cdt, 285 had a good reduction of volume, in some cases up to the complete normalization of the edema and reduction of cellulite episodes. all patients wore elastic stocking in the maintenance phase and still continue to take sessions of vodder manual lymphatic drainage, depending on the residual clinical stage (figures 28). the examples below show patients affected by lymphedema of limbs, before and after cdt. the 135 patients’ refractory to conservative therapy after two intensive cycles, 6 months apart, underwent surgery. the indication was placed on the basis of lymphoscintigraphy, the stage of the edema and the component of the edema itself (fibrotic/adipose tissue), the localization of the edema or the congenital anomalies, e.g. anomalies of thoracic duct or chili cistern (table 5). early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. the patients subjected to the different surgical techniques benefited from the result by stabilizing the residual edema and in many cases improving the measurements of volume. some patients underwent also to a combined technique (figures 9-18). the results collected demonstrate that when the combined complex decongestant therapy is conducted in specialized referral centres, with a qualified team of professionals in collaboration with an expert lymphologist, that is profoundly effective to control the lymphedema and lipoedema process in the majority of cases (less than 20 percent of patients need for surgical therapy). based on the data obtained using the icf score, the subjects under examination were able to express themselves, demonstrating the improvement of the psycho-physical and social conditions of their lives, feeling great satisfaction with the treatments received (table 5, table 6). we integrated the reading of the results also with the radar charts, for a better consultation and understanding, especially for the patients, so they can easily recognize the changes. in this way it’s clear to see in a unique image how the general situation before the treatment located mostly in the area of moderate disability, than after the treatment moved to a new area between minor and absence of disability, thanks to the changes of the data. conclusions lymphedema is a disease which is very difficult to manage for patients, mostly because of the disability that the disease manifest in their life. at the most evident level there are the physical changes of the body, especially with limbs that became swollen, stiff, painful and easy to get infections and complications due to the immunological impairment of a decreased lymph flow. but beyond the physical manifestations there is a huge impact on the psychological level, in private and social life. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. our study has finally demonstrated that a well conducted strategy of therapies, known as complex decongestive therapy (cdt) performed by specialized professionals can lead to astounding results for the patients, in terms of both data and disabilities. a proper decongestive therapy is made first of all by the manual lymphatic drainage that only a vodder professional can execute in a precise way, thanks to the deep knowledge and sensations that is reached by the therapist in order to adapt each time to the different tissue that the hand find. this can make a great difference. vodder manual lmphatic drainage associated with the right compression of bandages and stocking in following stages are the real cdt that a patient has to find in a serious center. the real cdt has a fantastic numbers of demostrations in literature about effectiveness and tangible improvemment of the quality of life found by people affected by lymphedema or lipoedema disease. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. references 1. becker c, arrive l, saaristo a, et al. surgical treatment of congenital lymphedema. clin plast surg. 2012;39:377-84. 2. benda k, lebloch d, bendova m. prevention of primary lymphedema-possible way. lymphology. 1998;31:465-8. 3. bernard p. primary and secondary hospitalization criteria. ann dermatol venereol. 2001; 128:363-7. 4. boccardo f, et al. a pilot. study of prevention of secondary lymphedema. lymphology 2000:33:222-555. 5. boccardo f, bellini c, eretta c, et al. the lymphatics in the pathophysiology of thoracic and abdominal surgical pathology: immunological consequences and the unexpected role of microsurgery. microsurgery. 2007;27:339-45. 6. heal d. improving patient concordance in lymphoedema management with softfit techonology. br j community nurs. 2017;22:s22-7. 7. bruna j. indication for lymphography in the era of new imaging methods. lymphology. 1994;27:319-20. 8. bonnetblanc jm, bedane c. erysipelas: recognition and management. am j clin dermatol. 2003;4:157-63. 9. ba corliss, msazimi, j munson,et al. macrophages: an inflammatory link between angiogenesis and lymphangiogenesis. microcirculation. 2016;23:95-121. 10. campisi c, bellini c, eretta c, et al. diagnosis and management of primary chylous ascites. j vasc surg. 2006;43. 11. campisi c, davini d, bellini c, et al. lymphatic microsurgery for the treatment of lymphedema. microsurgery. 2006;26:65-9. 12. campisi c, davini d, bellini c, et al. is there a role for microsurgery in the prevention of arm lymphedema secondary to breast cancer treatment? microsurgery. 2006;26_70-2. 13. campisi c, eretta c, pertile d, et al. microsurgery for treatment of peripheral lymphedema: long-term outcome and future perspectives. microsurgery. 2007;27:333-8. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 14. campisi c, zilli a, macciò a, et al. la prevenzione del linfedema secondario al trattamento del tumore della mammella: dal caso clinico ad una proposta di protocollo di prevenzione. chir ital. 2004;56:419-24. 15. cooper g.compression of therapy and the management of lower-limb lymphoedema: the male perspective. br j community nurs. 2015;20:122-4. 16. de godoy jm, de godoy mf, valente a, et al. lymphoscintigraphic evaluation in patients after erysipelas. lymphology 2000;33:177-80. 17. dupuy a, benchikhi h, roujeau jc, et al. risk factors for erysipelas of the leg (cellulitis): case-control study. bmj. 1999;318:1591-4. 18. eretta c, ferrarese a, moggia e, et al. surgical treatment of recidivist lymphedema. open med (wars). 2016;11:121-4. 19. executive commitee of the international society of lymphology, the diagnosis and treatment of peripheral lymphedema: 2020 consensus document of the international society of lymphology. lymphology. 2020;53:3-19. 20. földi e. therapy of lymphedema. hautarzt. 2012;63:627-33. 21. földi m. the therapy of lymphedema. european journal of lymphology and related problems. 1993-1994;14:43-9. 22. franz-josef schingale. compliance improvement of compression therapy inpatients with lymphedema. veins and lymphatics 2018;7:7635. 23. g. bonetti, k. dhuli, s. michelini, et al. dietary supplements in lymphedema, 2022;63. 24. honnor a. understanding the management of lymphoedema for patients with advanced disease. int j palliat nurs. 2009;15:166-9. 25. international society of lymphology executive committee. the diagnosis and treatment of peripheral lymphedema. lymphology. 1995;28. 26. international congress of lymphology, chennai, india. general assembly isl consensus document revisited. 1999. 27. isl executive committee meeting, földi klinik, hinterzarten, germany. discussions on modification of the isl consensus document. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 28. ishida o et al. evaluation of lymphatic and non lymphatic edema by mri. in progress in: lymphology xiii, ed.ev cluzan. elsevier sc. publisher,1992. 29. kano y, inaoka m, shiohara t. superficial lymphangitis with interface dermatitis occurring shortly after a minor injury: possible involvement of a bacterial infection and contact allergens. dermatology 2001;203:217-20. 30. lasinski bb; complete decongestive therapy for treatment of lymphedema. semin oncol nurs 2013:29:20-7. 31. leduc a. le drainage lymphatique.7th ed. paris, france, masson. 1991. 32. leduc a, bourgeois p, bastin r. lymphatic reabsorption of proteins and pressotherapies. v congrès du group européen de lymphologie (gel) porto, portugal. 1985. 33. ml lanzi. pedagogia sociale manuale per l’infermiere, carocci faber. 2004. 34. mancini s; trattato di flebologia e linfologia. utet. 2001. 35. marzanna t. zaleska, waldemar l. olszewski, mariusz k. kaczmarek. optimal intermittent pneumat-ic compression in lymphedema. veins and lymphatics 2018;7:7985. 36. michelini s, caldirola r, forner cordero i, et al. “linforoll: a new device for treatment of lymphedema. preliminary experience” eur j lymph. 2013;24-25. 37. michelini s, paolacci s, manara e, et al. genetic tests in lymphatic vascular malformations and lymphedema. j med genet. 2018;55:222-32. 38. mihara m, hara h, kikuchi, et al. scarless lymphatic venous anastomosis for latent and earlystage lymphoedema using indocyanine green lymphography and non-invasive instruments for visualising subcutaneous vein. j plast reconstr aesthet surg. 2012:65. 39. mihara m, murai n, hayashi y, et al. using indocyanine green fluorescent lymphography and lymhatic venous anastomosis for cancer related lymphedema. ann vasc surg. 2012;26:278.e16. 40. the diagnosis and treatment of peripheral lymphedema: 2009 consensus document of the international society of lymphology. lymphology. 2009;42. 41. the diagnosis and treatment of peripheral lymphedema: 2013 consensus document of the international society of lymphology. lymphology. 2013;46. 42. thomson m, walker j. collaborative lymphoedema management:developing a clinical. int j palliat nurs. 2011;17:231-8. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 43. uhara h, saida t, watanabe t, takizawa y. lymphangitis of the foot demonstrating lymphatic drainage pathways from the sole. j am acad dermatol. 2002;47:502-4. 44. vaillant l. diagnostic criteria for erysipelas. ann dermatol venereol. 2001;128:326-33. 45. waldemar l. olszewski, marzanna zaleska, marta cakala. lymphedema is more than excess of fluid; a lympho-fibro-adipo-edema. veins and lymphatics 2018;7:7984 early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. table 1. patients’ characteristics. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. table 2. icf upper limb questionnaire. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. table 3. icf lower limb questionnaire. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. table 4. disability average score. 0 absence of disability 0 – 0,5 patients do their activity with no restrictions in choosing, or problems in any function, even with orthoses 1 minor disability 0,6 – 1,5 patients have minor disability in at least one activity 2 moderate disability 1,6 – 2,5 patients have moderate disability in at least one activity 3 serious disability 2,6 – 3,5 patients have serious disability in at least one activity 4 complete disability 3,6 4 patients have complete disability in at least one activity early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. table 5. characteristics of patients. n° patients type of surgery pathology 89 lva one site lymphedema 9 lva multiple lymphedema 2 vlt chylothorax 13 resective surgery lymphocele post surgery 1 vle chyloperitoneum 5 plastic surgery of genitalia genitalia lymphedema 20 mini-invasive fasciotomy lymphedema 10 fibrolymphosuction lymphedema with fibrotic-adipose tissue 1 monoclonal cell implantation lymphedema with ulcer tot. 150 early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. table 6. results for icf lipoedema. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. table 7. results for icf lymphedema. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 1. patients affected by lipoedema at lower limb in different steps while making cdt. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 2. breast cancer. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 3. hysterectomy. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 4. prostatectomy. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 5. hysterectomy. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 6. primary lymphedema. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 7. primary lymphedema. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 8. stabilization of lymphedema with elastic stocking. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 9. lva one site with microscope. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 10. secondary lymphedema result one site lva + cdt. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 11. mini-invasive fasciotomy (mif). early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 12. secondary lymphedema result multiple lva + cdt. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 13. primary lymphedema mif result. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 14. plastic surgery of genitalia. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 15. resective surgery. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 16. fibrolymphosuction technique with pde. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 17. fibrolymphosuction with cdt. early access veins and lymphatics original article the publisher is not responsible for the content or functionality of any supporting information supplied by the authors. any queries should be directed to the corresponding author for the article. all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. figure 18. monoclonal cell implantation in primary lymphedema with ulcer, with pde. hrev_master veins and lymphatics 2017; volume 6:6910 [page 76] [veins and lymphatics 2017; 6:6910] imaging the lymphatic system paolo zamboni vascular diseases center, university of ferrara, italy in the last decade fascinating advanced techniques in lymphatic imaging, new magnetic resonance imaging (mri) agents created by the development of nano-technologies, as well as gene reported technologies have been developed providing us with new tools to interrogate the function of the lymphatic system. for someone like me, who was born locating and cannulating lymphatic capillaries stained with patent blue in the foot of patients, the novelty in lymphatic diagnostics seems unbelievable. doppler ultrasound for artery and veins permits blood flow imaging depending upon scattering of flowing erythrocytes, while the acellular lymph escapes clinical interrogation using ultrasound. so different imaging strategies have been developed in the challenging field of the lymphatic system. indirect mr lymphangiography can be performed by injection of gadolinium-based contrast dye into the dermal and subcutaneous spaces. for instance indirect mr lymphangiography in the upper and lower extremities of lymphedema patients has excellent resolution and more detailed lymphatic routes visualization as compared to routine lymphoscintigraphy.1-4 moreover, the recent introduction of 3d isotropic fatsuppressed t1weighted fse (vista [volumetric isotropic turbo spin-echo acquisition]; philips medical systems) maybe determined a paradigm shift with change of the current gold standard for imaging lymphedema5,6 (figure 1). fat suppression also permits to overcome the low quality imaging related to the non-homogenous tissue density of the co-existing chronic fibrousedema, or with indurative lipodermatosclerosis when phlebo-lymphedema occurs (figure 1). we know that the current gold standard, lymphoscintigraphy, provides routinely information to assess the lymphatic function and anatomy in humans, although with low spatial and temporal resolution respect to the above described innovative mr techniques. lymphoscintigraphy involves the intradermal administration of radio colloid. imaging is obtained after hours by the means of the gamma camera. this technique permits to assess the lymphatic function by measuring the time from the injection in distant digits and the appearance of the radionuclide tracer in the major lymph nodes, such as inguinal or iliac.7-9 fluorescence micro-lymphangiography (fml) is a fluorescence technique widely used in animal models of disease, but with scarce usage in humans. owing to the limited penetration depth of light at visible wavelengths and tissue scattering, only the initial capillaries within the first 100 to 150 microns of tissue depth can be visualized in humans.10 to improve the use of fluorescence techniques in the human being, nir fluorescence (nirf) has been developed. the latter creates the lymphatic imaging, also termed icg lymphography, through an emerging non-microscopic imaging technology that collects tissue-scattered light to assess conducting and collecting lymphatic vessels at greater penetration depths, but with lower resolution than the initial lymphatic imaged with fml.11 in clinical practice could be useful to assess subclinical lymphedema before chronic worsening. unlike other lymphatic imaging approaches, nirf lymphatic images can be collected rapidly with millisecond acquisitions,12 allowing for the non-invasive interrogation of function and the quantitative assessment of the lymph-pump frequency and apparent velocity in the collecting and conducting the lymph. the rapid development and the rapid acquisition of clinical information with the new techniques above described rapidly will change our clinical assessment of lymphedema and related disorders. however, the discrepancy between the advancement of costs and technologies in diagnostics rages against the empiricism of treatment still based on the principles of compression therapy. references 1. lohrmann c, foeldi e, langer m. indirect magnetic resonance lymphangiography in patients with lymphedema preliminary results in humans. eur j radiol 2006;59:401-6. 2. lohrmann c, foeldi e, langer m. diffuse lymphangiomatosis with genital involvement evaluation with magnetic resonance lymphangiography. urol oncol 2011;29:515-22. 3. lu q, delproposto z, hu a, et al. mr correspondence: paolo zamboni, vascular diseases center, university of ferrara, italy. tel.: +39.0532.237694. e-mail: paolozamboni@icloud.com received for publication: 14 july 2017. accepted for publication: 17 july 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright p. zamboni, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6910 doi:10.4081/vl.2017.6910 figure 1. a) indirect magnetic resonance (mr) lymphangiography in a normal case, with the lymphatic routes of the medial aspect of the lower extremity depicted by the white arrows. b) indirect mr lymphangiography in a primary lymphedema case with aplasia of lymphatic collectors of the lower limb. the white arrow depicts the ecstasies of the lymphatic capillary of the foot. c) indirect mr lymphangiography with 3d isotropic fatsuppressed t1weighted fse. the improved resolution is well apparent thanks to the suppression of fat sclerosis. indirect mr lymphangiography permits also to visualize the deep veins as well as to analyze the temporal opacization of both the lymphatic and the venous system. modified from jeon et al., 20165 and sevick-muraca et al., 2014.6 no n c om me rci al us e o nly editorial [veins and lymphatics 2017; 6:6910] [page 77] lymphography of lymphatic vessels in lower extremity with gynaecologic oncology-related lymphedema. plos one 2012;7:e50319. 4. notohamiprodjo m, weiss m, baumeister rg, et al. mr lymphangiography at 3.0 t: correlation with lymphoscintigraphy. radiology 2012;264:78-87. 5. jeon jy, lee sh, shin mj, et al. threedimensional isotropic fast spin-echo mr lymphangiography of t1-weighted and intermediate-weighted pulse sequences in patients with lymphedema. clin radiol 2016;71:e56-63. 6. sevick-muraca em, kwon s, rasmussen jc. emerging lymphatic imaging technologies for mouse and man. j clin invest 2014;124:905-14. 7. battezzati m, donini i. the use of radioisotopes in the study of the physiopathology of the lymphatic system. j cardiovasc surg (torino) 1964;5:6913. 8. szuba a, shin ws, strauss hw, rockson s. the third circulation: radionuclide lymphoscintigraphy in the evaluation of lymphedema. j nucl med 2003;44:43-57. 9. zimmerman h, fessa ck, rossleigh ma, wegner ea. lymphoscintigraphy of lower limb edema. clin nucl med 2012;37:411-5. 10. modi s, stanton aw, mortimer ps, levick jr. clinical assessment of human lymph flow using removal rate constants of interstitial macromolecules: a critical review of lymphoscintigraphy. lymphat res biol 2007;5:183-202. 11. rasmussen jc, fife ce, sevick-muraca em. lymphatic imaging in humans with near-infrared fluorescence. curr opin biotechnol 2009;20:74-82. 12. sevick-muraca em. translation of near-infrared fluorescence imaging technologies: emerging clinical applications. annu rev med 2012;63:217-31. no n c om me rci al us e o nly hrev_master veins and lymphatics 2018; volume 7:7156 [page 10] [veins and lymphatics 2018; 7:7156] inner-ear circulation in humans is disrupted by extracranial venous outflow strictures: implications for ménière’s disease eleuterio f. toro,1 francesco borgioli,1 qinghui zhang,1 christian contarino,2 lucas omar müller,1,3 aldo bruno4 1laboratory of applied mathematics, dicam, university of trento, trento, italy; 2department of mathematics, university of trento, povo (tn), italy; 3biomechanics group, department of structural engineering, ntnu, trondheim, norway; 4vascular surgery division, gepos clinic, telese terme (bn), italy abstract ménière’s disease (md) is a pathology of the inner ear, the symptoms of which include tinnitus, vertigo attacks, fluctuating hearing loss, and nausea. neither cause nor cure are currently known, though animal experiments suggest that disruption of the inner ear circulation, including venous hypertension and endolymphatic hydrops, to be hallmarks of the disease. recent evidence for humans suggests a potential link to strictures in the extracranial venous outflow routes. the purpose of the present work is to demonstrate that the inner-ear circulation in humans is disrupted by extracranial venous outflow stricture and to discuss the implications of this finding for md. the hypothesis linking extracranial venous outflow strictures to the altered dynamics of central nervous system (cns) fluid compartments is investigated theoretically via a global, closed-loop, multiscale mathematical model for the entire human circulation, interacting with the brain parenchyma and cerebrospinal fluid (csf). the fluid dynamics model for the full human body includes submodels for the heart, pulmonary circulation, arterial system, microvasculature, venous system and the csf, with a specially refined description of the inner ear vasculature. we demonstrate that extracranial venous outflow strictures disrupt inner ear circulation, and more generally, alter the dynamics of fluid compartments in the whole cns. specifically, as compared to a healthy control, the computational results from our model show that subjects with extracranial outflow venous strictures exhibit: altered inner ear circulation, redirection of flow to collaterals, increased intracranial venous pressure and increased intracranial pressure. our findings are consistent with recent clinical evidence in humans that links extracranial outflow venous strictures to md, aid the mechanistic understanding of the underlying features of the disease and lend support to recently proposed biophysically motivated therapies aimed at reducing the overall pressure in the inner ear circulation. more work is required to understand the finer details of the condition, such as the associated dynamics of fluids in the perilymphatic and endolymphatic spaces, so as to incorporate such knowledge into the mathematical models in order to reflect the real physiology more closely. introduction the potential link between anomalous strictures in the main extracranial venous outflow routes, alterations of the dynamics of the cns fluid compartments, including venous hypertension, and cns pathologies is becoming an active subject of interdisciplinary research. alperin et al.1 linked extracranial (as well as intracranial) venous outflow anomalies to idiopathic intracranial hypertension (iih). zamboni et al.2 associated extracranial venous outflow anomalies to multiple sclerosis (ms); they called the venous anomaly chronic cerebrospinal venous insufficiency (ccsvi). more recently, such venous strictures have been associated to md, a pathology of the inner ear.3-7 the present research is motivated by these recent works and by previous experiments on animals8 and humans9 that identify alterations of the inner ear circulation as a distinguishing feature of md. we present results from a theoretical study that show how anomalous strictures in the main extracranial venous outflow routes cause chronic venous hypertension throughout the cerebral venous system, including the inner ear circulation. this study addresses the underlying biophysical mechanisms and provides a partial explanation for i) the empirical association between extracranial venous outflow strictures and md, ii) the apparent success of reported clinical experience. md is a pathology of the inner ear. the inner ear houses and protects the neurological structures employed by the hearing (cochlear apparatus) and equilibrium functions (vestibular apparatus);10,11 it is located in the petrous part of the temporal bone and consists of the external bony labyrinth and the internal membranous labyrinth. the space between these two surfaces is filled with perilymph, a fluid whose ionic composition is similar to that of interstitial fluid (isf) and cerebrospinal fluid (csf), rich in sodium and calcium and poor in potassium. perilymph is in contact with the csf via the cochlear aqueduct, which drains the fluid towards the subarachnoid space. the membranous labyrinth contains endolymph, whose ionic composition is high in potassium, thus more comparable to intracellular fluid. since production of endolymph is continuous, a constant removal from the inner ear is needed. the endolymphatic duct, the canal responsible for this function, runs within the vestibular aqueduct, from the central part of the membranous labyrinth to a terminal swelling known as the endolymphatic sac, which is located between two layers of dura mater and from which endolymph is reabsorbed into the subdural space.12 arterial blood supply of the inner ear is provided by the labyrinthine artery, which usually branches from the anterior inferior cerebellar artery or, more rarely, directly from the basilar artery. the labyrinthine artery is in fact a set of arterioles, whose small diameters contribute to the attenuation of arterial pressure and intense blood correspondence: francesco borgioli, celestijnenlaan 200a, heverlee 3001, belgium. tel.: +32.16322187. e-mail: francesco.borgioli@alumni.unitn.it key words: ménière’s disease; jugular vein strictures; cerebral venous drainage; inner ear; cerebrospinal fluid pressure. acknowledgements: the authors thank ms. federica caforio for her suggestions and feedback on reading an earlier version of the manuscript. contributions: ab proposed the topic of investigation; eft, fb, qz and lom developed the modifications needed by the already existing mathematical model to investigate the new topic; fb, qz and cc carried out the numerical simulations reported in the manuscript; eft and fb wrote the manuscript that has been then substantially revised by lom and cc. conflicts of interests: the authors have no conflicts of interest to declare. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright e.f. toro et al., 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7156 doi:10.4081/vl.2018.7156 no nco mm er cia l u se on ly article [veins and lymphatics 2018; 7:7156] [page 11] flow, thus ensuring smooth blood supply to the inner ear.10,12 the inner ear venous blood drainage is provided essentially by three veins, subject to individual variability: i) the vein of the cochlear aqueduct (vcaq), also known as vein of the cochlear canaliculus. this vein runs parallel to the cochlear aqueduct (endolymph), it drains the basal turn of the cochlea, the saccule and part of the utricle, and empties into the superior bulb of the internal jugular veins (ijvs). ii) the vein of the vestibular aqueduct (vva) is another prominent vessel for venous drainage of the inner ear; sometimes, the anterior and posterior vestibular veins are present, and they all drain blood from the semicircular canals and the utricle, they merge into the vva, which runs within the vestibular aqueduct and parallel to endolymphatic duct, and empties into the inferior petrosal sinus or in the jugular bulb. however these veins are not always present in the inner ear vasculature. iii) the labyrinthine vein (labv), or internal auditory vein. blood from the vestibular aqueduct is mainly drained by the labv, which runs parallel to the labyrinthine artery, drains venules both from the cochlear and the vestibular apparatus and ends in the sigmoid sinus, in the superior petrosal sinus or in the transverse sinus. in this paper we shall assume subjects to lack the vva, which is a possible anatomical variation. md is characterized by attacks of nausea, tinnitus, vertigo and fluctuating hearing loss. the normal onset of md is unilateral, but the condition often extends to the other ear, with a registered 40% of bilateralization cases observed in the first 5 years.5 hearing loss is initially temporal, but frequently worsens to permanent, or severe deafness. the symptoms of md are quite common and typical of many other pathologies. this means that the number of md diagnosed patients is probably smaller than the effective number of md diseased subjects. historically, md was first described in 1861 by the french physician prosper ménière, but its aetiology remains uncertain, up to now. genetic factors, autoimmune mechanisms, environmental conditions, infection consequences and even iatrogenic or psychological causes have all been considered through many decades, without finding a strong or predominant correlation of any of these with md. none of these factors have resulted to be a necessary and sufficient condition for the development of the disease.13 as the origin of md is uncertain, no universally accepted therapy for this pathology has so far been found. in spite of these uncertainties, we believe that biophysical aspects may play an important role in altering the circulation of fluids in the inner ear. a persistent anomalous condition in the inner ear, called endolymphatic hydrops.14-16 has been observed in md patients; such condition is characterised by an increase of the endolymphatic volume and pressure in the membranous labyrinth. the causes of eh are still uncertain, but it seems reasonable to suggest that obstruction of the endolymphatic sac, or duct, produces a backlog of fluid in the endolymphatic space, which leads to the increase in volume and pressure. moreover, it has recently been suggested that a potential origin of md could be the altered cerebral venous flow caused by extracranial venous outflow strictures.3-7 the involvement of vascular mechanisms in md has already been proposed in classical works.14-16 animal experimental research has strengthened the biophysical viewpoint.8,9,17,18 a convincing demonstration of an association between anomalous extracranial blood outflow and md could eventually lead to a well-documented and accepted treatment of md patients; medical doctors have already made inroads in this direction,3-7 with encouraging results. an understanding of the basic mechanisms at work would be useful to provide an explanation for these results and also for possibly optimising the procedures. the first clinical studies of the potential link between md and extracranial venous anomalies are quite encouraging. di berardino and collaborators7 conducted a study on 52 subjects with cochleo-vestibular disturbances. the patients were divided into a first group of 24 patients diagnosed with unilateral md and a second group of 28 subjects suffering from unilateral disturbances but not diagnosed as md patients (not-md). magnetic resonance venography (mrv) and echo-color doppler (ecd) were conducted on all subjects to examine the extracranial venous outflow. the mrv technique revealed anomalous venous drainage in 20 md patients (83%) and in 16 not-md (57%), while the ecd technique detected abnormalities in 15 md cases (62%) and in 6 not-md (21%). most frequently, the observed anomalies were asymmetries of the outflow within ijvs and vertebral veins. one of the first surgery treatments based on the assumed link between md and ccsvi was reported by bruno et al.5 the first step in their procedure included a group of 50 md diagnosed patients, who had previously undergone several conventional therapies, with no benefits. their study also included a healthy control group of 100 subjects. in the md group, 45 out of 50 (90%) were diagnosed with the ccsvi condition, while in the control group only 3 out of 100 subjects (3%) were found to be affected by ccsvi. in the 45 positive md patients, 20 were also examined by means of venography that confirmed in all the cases, bilateral lesions in the ijvs and in three cases, also a lesion in the azygos vein (av). at a later stage, these patients underwent bilateral percutaneous transluminal angioplasty (pta) of the affected ijvs and the av, aimed at enlarging the cross-sectional of the narrowed vessel and restoring venous outflow. six months after the surgery, 19 out of 20 patients showed clear improvement of the symptoms, with more rare episodes of vertigo and higher hearing capacity; 1 patient out of 20 showed restenosed ijvs, which is known to be the disadvantage of pta. a more recent work on the same topic is that of bruno et al.6 the available animal experimental evidence, the indications of an association between md and ccsvi conditions in humans as well as the encouraging results from surgical treatment using pta, warrant a more detailed, quantitative study of the ccsvi link trying to identify the basic mechanisms at work. measurements have revealed altered venous flow in ccsvi affected subjects and invasive pressure measurements in extracranial districts have confirmed the expected result of (local) venous pressure increases caused by the strictures. intracranial pressure measurements in ccsvi subjects, to the best of our knowledge, do not currently exist. we note however that for the iih condition associated to dural sinus anomalies, invasive pressure measurements do actually exist.19,20 these dural sinus pressure measurements show the expected venous sinus hypertension. pressure measurements in other districts, e.g. deep cerebral veins and inner ear fluids, resulting from intracranial or extracranial strictures in humans are, to the best of our knowledge, not available. it is here where mathematical models may also prove useful; potentially, they could provide quantification of relevant haemodynamical variables, including pressure. in the context of disturbed brain haemodynamics, müller and toro21 proposed the first global, closed-loop multiscale mathematical model to study this phenomenon. in this model, the geometry for the cerebral and extracranial venous system is individually defined by means of segmentation of patient-specific mri data. the model was later enhanced22 to include one intracranial compartment and starling resistors to better describe the physiology of cerebral veins, csf dynamics, and to more fully account for the interaction of fluid compartments in the cns. see also the related work of no nco mm er cia l u se on ly article [page 12] [veins and lymphatics 2018; 7:7156] caiazzo et al.23 the enhanced global model of müller and toro22 has been used to study the effect of extracranial venous stenoses on intracranial haemodynamics by müller et al.24 the effect of venous valve malfunction on cerebral haemodynamics25 and to produce some preliminary results on ccsvi and sudden sensorineural hearing loss.26 in these studies, it is demonstrated that disturbed brain haemodynamics and intracranial venous hypertension occur as a result of extracranial strictures in the neck veins and the av. for a review on these works in the broader context of neurological diseases potentially related to extracranial venous anomalies, see the review paper by toro.27 in the present work, we extend the global model of müller and toro21,22 to include submodels for the inner ear circulation. then we apply the extended model to study the fluid dynamics resulting from the ccsvi condition, with special attention given to the inner ear haemodynamics. prior to the specific study of inner ear circulation we perform in vivo validation of the extended global circulation for a specific, healthy subject. comparison of computed and mri measured blood flow is shown; the results are satisfactory. the study of pathological cases then follows by investigating the altered fluid dynamics resulting from extracranial venous strictures. our results show that extracranial outflow venous strictures impede efficient cerebral venous drainage, alter blood flow dynamics, increase csf pressure and cause chronic venous hypertension throughout the cerebral venous system, including the inner ear circulation. the theoretical contribution of the present paper is in line with both extracranial venous strictures and altered intracranial dynamics, as will be discussed later. the rest of this paper is structured as follows. after a section on materials and methods we present our results, which include a validation exercise on a healthy subject and two anomalous cases, namely extracranial venous stenosis and anomalous venous valves. there follows a discussion of results. supplementary material is presented in the appendix. materials and methods in this paper we extend the global, closed-loop, multiscale mathematical model proposed by müller and toro21,22 to include submodels for the inner ear circulation. the original model contained 1d, cross-sectional area averaged equations for 85 major arteries and 188 major veins, as well as 0d compartmental models for microcirculation beds,28 the heart,29 the pulmonary circulation29 and the csf.30 the model also includes submodels for valves in the venous system.25,31 the 1d model describes the space (x) and time (t) variation of vessel cross-sectional area a(x,t), blood flow rate q(x,t) and pressure p(x,t). starling resistors are used in the cerebral venous system to obtain a more realistic description of the haemodynamics in the main regions of interest. in the original model, the vessel geometry for the main arteries and veins of the body is mostly obtained from the literature, while mri data from specific subjects are used to describe the major cerebral and extracranial venous vessels. see utriainen et al.32 for a detailed description of the acquisition process of the mri data. for the purpose of investigating the influence of extracranial venous obstructions on the inner ear circulation we have extended the müller-toro model21,22 by adding inner-ear vessels to the global network, utilising data from the literature.33-35 the anterior inferior cerebellar artery, branching from the basilar artery, is added to account for the inner-ear arterial blood supply. to account for inner-ear venous drainage we have incorprorated 1d representations for the labv and the vcaq. labvs transport blood from the inner ear venules and empty at the insertion of the transverse sinus into the sigmoid sinus. vcaqs, instead, are directly connected to the superior bulbs of the ijvs. moreover, two 0d compartments accounting for the inner ear microcirculation were also inserted into the original vascular network. figure 1 gives a detailed illustration of the cerebral and extracranial venous network implemented in the present version of the model. results here we use the term ccsvi condition in a generic sense to include a wide range of extracranial venous malformations, such as stenosis, hypoplasia, atresia and stenotic or regurgitant venous valves. the anomalies considered in this paper are stenoses and stenotic valves in the ijvs and the av; these are the most frequently found anomalies in ccsvi diagnosed subjects. in this section we first carry out an in vivo validation of the entire model for a healthy control, comparing computed results against in vivo mri measurements. then we simulate pathological cases, which is the main subject of this paper. healthy control an in vivo validation of the complete model for a healthy subject in supine position is performed here. figure 2 depicts computed profiles (full line) for pressure and flow, over a cardiac cycle. the second column shows computed pressure, while the third column shows both computed (line) and mri-measured values for flow (symbols). the comparison between computed and measured values for flow is satisfactory, considering the complexity of the full problem and the modelling simplifications adopted; the agreement is satisfactory both from the point of view of flow average values over the cardiac cycle as well as the waveforms. for pressure, there are no measured values available in the literature, as far as we are aware. recall that pressure measurement is an invasive procedure. however, some estimates can be found in the literature. such estimates are close to the values computed by our model. for example, schaller36 estimates an average value of p=6.6±2 mmhg for blood pressure at the confluence of sinuses; our model predicts an averaged value over the full cardiac cycle of p=6.5 mmhg. more in vivo validation results are available but are not included here. the mri measurements used for the validation are reported in müller et al.24 next, we deal with simulation of pathological cases. extracranial venous stenosis here we apply our mathematical model to simulate the haemodynamics resulting from anomalous extracranial venous strictures. we consider a vessel to be stenotic if a significant narrowing of its cross-sectional area is present. in this work, stenoses are represented as a 2 cm long vessel segment whose equilibrium cross-sectional area as0(x) is restricted as follows: as0(x) = 0.1 a0(x), where a0(x) is the normal equilibrium cross-sectional area of the vessel of interest. in the present study we consider two ccsvi cases defined by zamboni et al.,2 namely cases a and b, schematically represented in figure 3. case a includes a stenosis in the left ijv, above the insertion of the middle thyroid vein, and a stenosis in the av, close to the azygos arch. case b is like case a, except that the right ijv is also stenosed, symmetrically with respect to the left ijv. the presence of strictures in the ijvs and the av causes significant alterations to the normal haemodynamics in the cerebral venous network and in the main blood drainage routes towards the heart, as we shall demonstrate. we first consider the effect of local stenoses on the haemodynamics of extracranial vessels, namely ijvs and av. figure 4 no nco mm er cia l u se on ly article [veins and lymphatics 2018; 7:7156] [page 13] shows computed results for the haemodynamics across the stenoses in both ijvs. the first column depicts the locations of interest, while the second and third columns show computed pressure and venous blood flow, as functions of time, within one cardiac cycle. results are shown for the healthy control and for the two anomalous cases a and b. cardiac-cycle averaged values are displayed in squared brackets. as expected, a very consistent reduction of venous blood flow in the stenotic vessels is observed. in case b for example, bottom row of figure 4, the left ijv blood flow decreases from 10.08 ml s–1 in hc to 3.74 ml s–1, a reduction of about 65%. also, a sizeable increase in venous blood pressure jump ∆p across the stricture is observed, namely dp ≈ 1.5 mmhg, which is about the 25% higher than in the healthy control; this computed result is consistent with measured values reported by zamboni et al.2 furthermore, the literature, e.g. zamboni et al.2 have reported another typical haemodynamical disturbance caused by the ccsvi figure 1. properties of all the 1d arteries and veins not included in appendix table 1, see müller and toro.29,30 triangles (green) represent location of venous valves in both internal jugular veins (ijvs) and external jugular veins (ejvs), included in appendix table 1, see müller and toro.21,22 triangles (green) represent location of venous valves in both internal jugular veins (ijvs) and external jugular veins (ejvs). figure 2. in vivo validation for healthy control. the left column shows the spatial locations on the vessels of interest in the modelled venous network; the middle column shows computed pressure at various locations as function of time for one cardiac cycle; the right column compares the corresponding computed (full line) venous blood flow against the mri flow measurements (symbols). no measured data for pressure is available. no nco mm er cia l u se on ly article [page 14] [veins and lymphatics 2018; 7:7156] condition, that is, redirection of blood flow, in the direction of alternative extracranial routes. this empirical observation is also reproduced by our mathematical model. from the ijvs, blood is mainly redirected towards the external jugular veins (ejvs) via the common facial veins. this results in increased venous blood flow, up to four times that of the hc, in the external jugular (ejv) adjacent to the stenosed ijv. a corresponding pressure rise of about 0.6 mmhg in the ejv is also observed (not shown here). another common consequence of the ccsvi condition, as shown by our model, is the redirection of blood from one side to the other, in case of unilateral stenoses in the ijv (as in case a). many vessels configure 3. extracranial venous stenoses. venous stenoses in the present mathematical model are depicted by red circles. two cases are considered: case a (left) and case b (right) taken from 2. figure 4. extracranial venous stenoses. computed results for pressure and venous blood flow in extracranial venous vessels for one cardiac cycle, at two locations in ijvs, upstream and downstream of the stenoses. three model simulations are shown: healthy control (hc: continuous line) and the two pathological cases a (dashed line) and b (dashed and dotted line). the left column shows the location of the points of interest in the venous network, the central column shows venous blood pressure and the right column shows venous blood flow, all as functions of time within one cardiac cycle. numbers in brackets in legends represent the average of the computed quantity over one cardiac cycle. vessel numbering is consistent with.21,22 no nco mm er cia l u se on ly article [veins and lymphatics 2018; 7:7156] [page 15] tribute to transport this blood, such as inferior and superior petrosal sinuses, intra-cavernous sinus, marginal sinuses and lateral anterior condylar veins (not shown here). figure 5 depicts the computed haemodynamics in the inner-ear vein vessel segments located upstream of the starling resistor. no clear differences in blood flow between the healthy control and the pathological cases are seen; this is presumably due to the fact that these vessels are just connected to 0d models and deliver to the venous network. pressure, however, is substantially increased in the presence of stenoses; in fact the pressure increment is comparable to that for the ijvs in the pathological cases, as seen in figure 5 for segments 226 and 227; results for other neighbouring segments are not shown. figure 6 shows cardiac-cycle averaged pressures in selected vessels. the left panel shows a comparison of computed cardiaccycle averaged pressures for the hc and the two pathological cases a and b, in the following five venous vessels: superior petrosal sinus (sps), inferior petrosal sinus (ips), transverse sinus (ts), superior sagittal sinus figure 5. extracranial venous stenoses. computed results for the right inner ear veins. three model simulations are shown: the healthy case (hc: continuous line) and the pathological cases a (dashed line) and b (dashed and dotted line). the left column shows the location of the vessel of interest in the venous network, the central column shows blood pressure and the right column shows venous blood flow rate. numbers in square bracket represent the average of the computed quantity over the cardiac cycle. figure 6. the two panels represent the computed cardiac-cycle averaged pressures in case of extracranial venous stenoses. left panel summarizes the results in the main dural sinuses of the venous network. sps: superior petrosal sinus, ips: inferior petrosal sinus, ts: transverse sinus, sss: superior sagittal sinus and iss: inferior sagittal sinus. (vessel numbering is consistent with 21,22). right panel summarizes the results in intracranial compartment and veins of the right inner ear. icp: intracranial compartment, vcaq: vein of the cochlear aqueduct, labv: labyrinthine vein. for each vessel and location, the left bar corresponds to the healthy control (hc), the middle bar refers to the pathological case a and the right bar to the pathological case b. no nco mm er cia l u se on ly article [page 16] [veins and lymphatics 2018; 7:7156] (sss) and inferior sagittal sinus (iss). it is seen that the pressure rise generated by the extracranial venous strictures is transmitted back to the intracranial circulation and is computed to be around 1.5 mmhg. however, a corresponding variation of flow is not obvious in these vessels, as blood cannot exploit collateral vessels, as was the case in the ijvs. blood pressure of the sss is particularly important, as reabsorption of csf into the venous vasculature depends linearly on the pressure difference between the intracranial compartment and the sss.21,30 therefore, higher blood pressure in sss leads to reduced csf reabsorption, increased csf pressure and intracranial hypertension. right panel of figure 6 shows a comparison of computed cardiac-cycle averaged pressures for the hc and the two pathological cases a and b, in the intracranial compartment (intracranial pressure, icp) and the inner ear veins considered in this study, namely the vcaq and the labv. our mathematical model assumes that the intracranial pressure icp acts as the external pressure on cerebral veins and inner ear veins. starling resistors are introduced in the middle of all the cerebral veins, as well as in the inner ear veins. part of the function of starling resistors is to prevent automatic backward transmission of pressure waves from external vessels up to the terminal intracranial veins and to prevent cerebral venous collapse due to the action of intracranial pressure. hence, the observed venous hypertension in the inner ear veins is not directly caused by the backward transmitted pressure waves from the obstructed sites, as occurs in the dural sinuses, but is originated by its external pressure increase (icp). indeed, this could be seen explicitly from the tube law:21,22 a higher external pressure acting on the vessel wall induces a higher internal pressure in the same vessel. moreover, it is worth noting that in the inner ear veins, as well as in the intracranial compartment, the pressure increment from the hc and the pathological cases is not significantly different from the respective increments in the dural sinuses. this concludes the study of the effect of extracranial venous stenosis on brain haemodynamics and on inner ear circulation in particular. next we study the effect of another kind of extracranial venous anomaly, namely stenotic venous valves. stenotic venous valves the presence of valves in the human jugular veins has long been established, starting from cadaveric dissection studies, even though their anatomy, prevalence and competence are still the ongoing subject of studies.36 valves in jugular veins are meant to ensure one-way venous blood flow and, apart from stenotic malformations, are the only structures that may modify such venous blood flow as well as pressure wave propagation between the brain and the right atrium. it is therefore reasonable to suppose that valve malfunction may have an effect on intracranial venous haemodynamics. as a matter of fact, toro and collaborators25 found that valve function has a visible effect on intracranial venous haemodynamics, including dural sinuses and deep cerebral veins. they reported that valve obstruction causes venous reflux, redirection of flow and intracranial venous hypertension. two modes of valve functioning were identified in their model,25 namely obstructed or stenotic valves, which cannot reach total opening, and incompetent valves, which cannot reach total closure. they also reported that valve incompetence leads to small alterations of pressure within intracranial veins, while valve obstruction can have more visible effect, depending on the degree of obstruction. obstructions greater than about 75% produce substantial pressure increases, above which the pressure increase grows very sharply with the degree of occlusion. in the study of toro and collaborators,25 the mathematical model used did not include a detailed inner ear circulation network and was therefore not applicable to the topic of concern in the present paper. it is reasonable to suppose that the same mechanism regarding stenoses and the results reported in 37 could be relevant. we may therefore hypothesize that valve malfunctioning would generate pressure increases that would be transmitted up to the intracranial compartment, and to the inner ear circulation. that is, valve incompetence may be a cause for venous blood pressure rise around the inner ear. for the present study we considered two cases of stenotic valves that cannot attain full opening, named case c and case d (figure 7). case c is characterised by a stenotic valve in the left ijv, while case d considers stenotic valves (symmetric) in both left and right ijvs. valves are located in the proximal segment of the vein, downstream of the location of the stenoses considered in cases a and b in the previous section on vein stenosis. in both cases a valve obstruction of 75% of the reference cross-sectional area was assumed, when the valve has achieved its maximum opening. figures 8 and 9 show our computed pressure and venous flow in the ijvs and in the inner ear veins, respectively. the results show the same tendency as those for stenotic veins of the previous subsection, though in general the variation in haemodynamical quantities is less pronounced. the histograms of figure 10 summarise the cardiac cycle averaged pressures in the main dural sinuses, in the intracranial compartment and in the inner ear veins. as for the stenosed vessels, a pressure rise is originated in the ijvs upstream of the stenotic valves, and is transmitted up to the dural sinuses, into the intracranial compartment and deep cerebral veins. also in this case, the increased external pressure acting on the inner ear veins produces a venous blood pressure rise in the inner ear circulation. essentially, a stenotic valve restricts the amount of outflowing blood from the brain and thus it reproduces the behaviour associated to a venous stenosis. in cases c and d we have considered a constriction of 75%, and the pressure rise observed is less severe than that of cases a and b. in fact the figure 7. stenotic venous valves. valves are represented by green triangles and are present in both ijvs and ejvs. the pathological cases characterized by stenotic valves are represented by red circles: cases c (left) and d (right). no nco mm er cia l u se on ly article [veins and lymphatics 2018; 7:7156] [page 17] figure 8. stenotic venous valves. computed results for two locations of each ijv, one upstream and one downstream the stenotic valve. the left colum shows vessel locations of interest, the middle colum shows computed pressure and the right column shows computed venous blood flow. three model simulations are shown: the healthy case (hc: continuous line) and pathological cases c (dashed line) and d (dashed and dotted line). numbers in square brackets in the legends represent the average of the computed quantity over the cardiac cycle. vessel numbering is consistent with 21,22. figure 9. stenotic venous valves. computed results for the right inner ear veins. the left colum shows vessel locations of interest, the middle colum shows computed pressure and the right column shows computed venous blood flow. three model simulations are shown: the healthy case (hc: continuous line) and the pathological cases c (dashed line) and d (dashed and dotted line). numbers square brackets in legend represent the average of the computed quantity over the cardiac cycle. no nco mm er cia l u se on ly article [page 18] [veins and lymphatics 2018; 7:7156] difference in pressure jump across a stenotic valve between the healthy control and the pathological cases c and d is about dp ≈ 0.3 mmhg. as noted in 25, the haemodynamical effect of the degree of valve occlusion rises sharply from about 75%. this means that the case considered here is that of a low-degree valve occlusion and therefore its effect on venous hypertension is less marked than in the case of venous stenoses. also to be noted is the fact that the av has normally a very small cross-sectional area, and therefore its obstruction does not visibly influence the results. moreover, we also note that valves are located below the segments of the ijvs that are stenosed in cases a and b. this means that blood blocked by the stenotic valves can exploit a larger number of collaterals to allow blood flow towards the heart. therefore a smaller amount of blood is collected above the valve, thus a smaller pressure rise is observed. a comment on csf pressure, intracranial hypertension and csf reabsorption is in order. figure 10, right frame, includes results for icp, the pressure in the csf compartment. icp increases in the presence of extracranial venous strictures, even if such increases are modest. our computations show, details omitted, that this is a consequence of increased venous pressure in sss, thereby hampering csf reabsorption and thus favouring csf accumulation. we emphasise that the present version of our global model adopts a single 0d model for the entire csf compartment. this is indeed a limitation of the model, as its local resolution, in the inner ear zone for example, would be poor, though still retaining the trend. discussion and conclusions the reported work in the present paper falls within a wider recently started research effort aimed at studying cerebral venous flow in humans. in particular, the potential consequences of disturbed cerebral venous outflow, broadly represented by ccsvi.2 here ccsvi is interpreted as involving several anomalous patterns of malformations in the neck veins and/or in the av, including venous valve anomalies, that perturbs cerebral venous outflow. besides ms and md, several other neurological diseases have been hypothesized to be related to ccsvi, such as bilateral sudden sensorineural hearing loss38 (ssnhl), transient global amnesia (tga),39 retinal abnormalities40 and idiopathic parkinson’s disease.41 see 27 for a review. the lack of simple and non-invasive techniques capable of measuring intracranial venous pressure has revealed the necessity of alternative methods to examine the effects of strictures on the cerebral venous circulation. the development of mathematical models for the circulation certainly provides promising tools for this kind of research, but not without its own limitations. a major difficulty is the vast intersubject variability, particularly in the venous district, which prevents the adoption of a universal description for a human body. the variability of the head and neck venous system has been demonstrated through the years, in terms of vessel dimensions and geometry; depending on these factors, blood main routes toward the heart can be very different from one individual to another. see, for example, doepp et al.42 for a large study on the most common extracranial routes in the supine position; see valdueza et al.43 for the rearrangement of blood outflow paths in an individual under change of posture. our mathematical model uses detailed patient-specific geometry of the head and neck venous network obtained by means of mri techniques. in this paper we have established two interrelated consequences of ccsvi-like anomalies, namely i) intracranial venous hypertension, with disturbed inner ear circulation and inner-ear venous hypertension and ii) increased csf pressure and associated intracranial hypertension. previous studies have tended to decouple the roles of the venous and csf compartments, when in fact their fluid dynamics and physiology are intimately linked. several reported animal experiments are based on injection of artificial csf to raise intracranial pressure. in our model, intracranial hypertension and intracranial venous hypertension are the physiological consequence of increased intracranial venous volume due to extracranial venous outflow strictures; increased figure 10. the two panels represent the computed cardiac-cycle averaged pressures in case of stenotic venous valves. left panel summarizes the results in the main dural sinuses of the venous network. sps: superior petrosal sinus, ips: inferior petrosal sinus, ts: transverse sinus, sss: superior sagittal sinus and iss: inferior sagittal sinus. (vessel numbering is consistent with 21,22). right panel summarizes the results in intracranial compartment and veins of the right inner ear. icp: intracranial compartment, vcaq: vein of the cochlear aqueduct, labv: labyrinthine vein. for each vessel and location, the left bar corresponds to the healthy control (hc), the middle bar refers to the pathological case c and the right bar to the pathological case d. no nco mm er cia l u se on ly article [veins and lymphatics 2018; 7:7156] [page 19] venous pressure hampers csf reabsoption leading to increased csf pressures. inner-ear venous hypertension has for a long time been regarded as a hallmark of md.8,9,14-16,44 in the animal experiments of friis and qvortrup 8 they blocked the venous flow in the vva that drains into the sigmoid sinus. they visualized the reversed venous blood flow direction (reflux) in the extraosseous part of the vein. they argued that reversed venous flow in the vva toward the inner ear could potentially cause portal circulation in the inner ear, with a range of potential consequences, including risk of thrombosis, local hypoperfusion and accumulation of neurotoxic materials. in the present work the blockage was performed in humans in the extracranial veins, leading to analogous observations, including reversed flow and venous hypertension. our second result regarding increased csf pressure is perhaps more appealing in trying to understand the mechanisms at work. subarachnoid spaces and thus csf are directly in contact with the perilymphatic space through the cochlear aqueduct. increases in csf pressure are transmitted directly and rapidly to the perilymphatic space, as demonstrated by the early animal experiments of carlborg and farmer.44 there is evidence that csf pressure increases are also transmitted, even if more slowly, to the endolymphatic space via the endolymphatic sac and endolymphatic duct. a key issue is the pressure difference dpreiss ≠ 0 (in absolute value) across the endolabyrinthine membrane (the reissner membrane) between the endolymphatic space and and perilympahtic space. while many investigators consider to be incompatible under physiological conditions, there are many investigations in which, even if small, a pressure difference is found e.g.45 some authors have suggested that dpreiss in the range 1.4 to 3.5 mmhg would lead to rupture of the endolabyrinthine membranes.44 at this stage it is worth noting the electrolyte levels of perilymph and endolymph. sensory and neural structures are normally bathed in perilymph, which has electrolyte levels similar to csf, suitable for neural transmission. moreover, the potassium level of endolymph is toxic to sensory and neural structures and blocks neural excitation and transmission.16 on the other hand, histological studies suggest that the acute vertiginous episodes are caused by potassium intoxication following ruptures of the membranous labyrinth. schuknecht16 described the pathophysiology of endolymphatic hydrops, whose cause he ascribes to the occlusion of the endolymphatic duct and that the sudden onset of vertigo episodes is acute vestibular paralysis caused by potassium intoxication following a rupture of the endolymphatic system. vertigo episodes have limited time duration, due to the healing capacity of the membranous labyrinth, whose ability to repair itself has been demonstrated in animal studies. our theoretical results are consistent with the above observations and with the animal experiments of yoshida and uemura,18 in that hypertension is also observable in other fluids in the inner ear, in the perilymphatic and endolymphatic spaces. as already indicated, the perilymphatic space has a relatively free communication with the subarachnoid space via the cochlear aqueduct, through which csf pressure waves are transmitted. the endolymphatic sac and the endolymphatic duct, on the other hand, would also transmit csf pressure waves to the endolymphatic space that in theory would equilibrate pressure across the interface between the endolymphatic space and the perilymphatic space, the reissner membrane. according to these authors,18 both the endolymphatic and perilymphatic pressures rise linearly and proportionally to icp increment, and that a pressure rise in the csf space is associated to an analogous pressure rise in both inner ear fluid spaces. no significant time lag was observed between the csf pressure rise and the alteration of the inner ear fluids. moreover, no hydrostatic pressure gradient was observed between the two inner ear spaces, though this result is at variance with the previously mentioned studies. the experiments in18 suggest that a chronic elevation of the csf pressure due to the extracranial venous occlusions would result in a chronic elevation of the endolymphatic and perilymphatic pressures. from their measurements, a linear relation is observed between the csf pressure increase and the endolymphatic pressure increase, with slope m = 0.89. a similar behaviour is observed between icp and perilympahtic pressure, with slope m = 0.84. they argue that the slopes should be m = 1.0 and that experimental details prevented this from happening. assuming their experimental finding is correct, our computed csf pressure rise dpcsf ≈ 1.3 mmhg in our case b may result, with good approximation, in an increment of dpend ≈ 0.3 mmhg in the endolymphatic space and an increment of dpper ≈ 1 mmhg in the perilymphatic space. another aspect of the experimental work in 18 is the effect of csf pressure rise on the hearing function. to that end, they measured the cochlear microphonic (cm); this is an electric signal generated by the hair cell movement, which is proportional to the displacement of the basilar membrane, a structure of the inner ear responsible for the transduction of sound waves into an electric signal. this displacement is thus proportional to the amplitude of the signal sent to the brain. the authors observed a reduction of the cm intensity, which they ascribed to the decreased cochlear blood flow. a clear consequence of this behaviour was that a low acoustic stimulus was not longer recognized and thus the hearing threshold was raised, in the case of a high csf pressure. furthermore, the mechanism was shown to be reversible, so that the normal acoustic function was restored when csf pressure was set back to normal values. we note that their observations were associated to very high values of csf pressure. such high values cannot be reached in a ccsvi subject on a supine position alone, unless additional factors come into play, such as sudden postural change, valsalva type manoeuvres or external compression of the head. in a study conducted by valk et al.,37 endolymphatic hydrops was induced in guinea pigs by inserting artificial endolymph in the endolymphatic space and thus causing inner ear pressure rise consistent with the increments observed in our simulations. the experiments of silverstein17 support the theory that the onset of vertigo episodes follows the rupture of the membranous labyrinth. he injected artificial endolymph into the perilymphatic space in cats, thus producing a sudden increase in the potassium concentration of the perilymphatic fluid, which is what would happen in the actual rupture of the membranous labyrinth. in reality, after the membrane rupture, potassium ions are pushed towards the perilymphatic space by the osmotic pressure gradient, thus reducing its electric potential and blocking the neural structures, and thus reducing the hearing function. promising biophysically based therapies have recently been put forward; see for example the works of bruno and collaborators.5,6 the present work is a contribution to the study of the basic underlying mechanisms that may explain the encouraging results of these therapies, though much work is still needed. a limitation of the present work is that the simulations were carried out for a subject in the supine position. some challenging algorithmic problems need to be resolved in order to simulate postural changes. these are the subject of current investigations. another limitation is the representation of the csf compartment. the current version assumes a single csf compartment; this is indeed too simple. current developments (toro ef, et al. holistic multi-fluid mathematical model for no nco mm er cia l u se on ly article [page 20] [veins and lymphatics 2018; 7:7156] the central nervous system; 2017 data not published) assume a more detailed csf model that includes the four cerebral ventricles, where csf is actually produced, the aqueduct of sylvius, the cerebral subarachnoid space, the spinal subarachnoid space and the brain parenchyma.46 another possible future extension would be the construction of a submodel for the inner ear that includes the endolymphatic and the perilymphatic spaces, in order to analyse in more detail the pressure variations of these fluids as a result of csf pressure rise. references 1. alperin n, lee sh, mazda m, et al. evidence for the importance of extracranial venous flow in patients with idiopathic intracranial hypertension (iih). acta neurochir 2005;95: 129-32. 2. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:392-99. 3. alpini dc, bavera pm, hahn a, et al. chronic cerebrospinal venous insufficiency (ccsvi) in ménière’s disease. case or cause? sciencemed 2013;4:913. 4. alpini dc, bavera pm, di berardino f, et al. bridging the gap between chronic cerebrospinal venous insufficiency and ménière disease. veins and lymphatics 2016;5:5687. 5. bruno a, califano l, mastrangelo d. chronic cerebrospinal venous insufficiency in ménière’s disease: diagnose and treatment. veins and lymphatics 2014;3:3854. 6. bruno a, napolitano m, califano l, et al. the prevalence of chronic cerebrospinal venous insufficiency in ménière’s disease: 24-month follow-up after angioplasty. j vasc interv radiol 2017;28:388-91. 7. di berardino f, alpini dc, bavera pm. chronic cerebrospinal venous insufficiency in ménière’s disease. phlebology 2014;4:274-9. 8. friis m, qvortrup k. a potential portal flow in the inner ear. the laryngoscope 2007;117:194-8. 9. friberg u, rask-andersen h. vascular occlusion in the endolymphatic sac in ménière’s disease. ann otol rhinol laryngol 2002;111:237-45. 10. gray h, carter hv. gray’s anatomy: the anatomical basis of clinical practice, 40th edition edinburgh: churchilllivingstone; 2008. 11. silverthorn du. human physiology: an integrated approach, 5th edition. san francisco: pearson/benjamin cummings; 2010. 12. moller ar. hearing: anatomy, physiology and disorders of the auditory system, 2nd edition. academic press; 2006. 13. tassinari mt, mandrioli d, gaggioli n, et al. ménière’s disease treatment: a patient-centered systematic review. audiol neurotol 2015;20:153-65. 14. gussen r. vascular mechanisms in ménière’s disease. otolaryngol head neck surg 1983;91:68-71. 15. gussen r. vascular mechanisms in ménière’s disease. theoretical considerations. arch otolaryngol 1982;108: 544-9. 16. schuknecht hf. pathophysiology of the endolymphatic hydrops. arch otolaryngol 1976;212:253-62. 17. silverstein h. the effects of perfusing the perilymphatic space with artificial endolymph. ann otol rhinol laryngol 1970; 9:754-65. 18. yoshida m, uemura t. transmission of cerebrospinal fluid pressure changes to the inner ear and its effect on cochlear microphonics. eur arch otorhinolaryngol 1991;248:139-43. 19. lazzaro ma, darkhabani z, remler bf, et al. venous sinus pulsatility and the potential role of dural incompetence in idiopathic intracranial hypertension. neurosurgery 2012;12:877-84. 20. raper dms, buell tj, ding d, et al. a pilot study and novel angiographic classification for superior sagittal sinus stenting in patients with non-thrombotic intracranial venous occlusive disease. j neurointervent surg 2017 [epub ahead of print]. 21. müller lo, toro ef. a global multiscale mathematical model for the human circulation with emphasis on the venous system. j numer method biomed eng 2014;30:681-725. 22. müller lo, toro ef. an enhanced closed-loop model for the study of cerebral venous blood flow. j biomech 2014;47:3361-72. 23. caiazzo a, montecinos g, müller lo, et al. computational haemodynamics in stenotic internal jugular veins. j math biol 2014;70:745-72. 24. müller lo, toro ef, haacke em, et al. impact of ccsvi on cerebral haemodynamics: a mathematical study using mri angiographic and flow data. phlebology 2016;31:305-24. 25. toro ef, müller lo, cristini m, et al. impact of jugular vein valve function on cerebral venous haemodynamics. curr neurovasc res 2015;12:384-97. 26. tessari m, ciorba a, müller lo, et al. jugular valve function and petrosal sinuses pressure: a computational model applied to sudden sensorineural hearing loss. veins and lymphatics 2017;6:6707. 27. toro ef. brain venous haemodynamics, neurological diseases and mathematical modelling. a review. appl math comput 2016;272:542-79. 28. formaggia l, quarteroni a, veneziani a. cardiovascular mathematics: modeling and simulation of the circulatory system. milano: springer-verlag; 2009. 29. liang fy, takagi s, himeno r, et al. biomechanical characterization of ventricular-arterial coupling during aging: a multi-scale model study. j biomech 2009;42:692-704. 30. ursino m, lodi ca. a simple mathematical model of the interaction between intracranial pressure and cerebral hemodynamics. j appl physiol 1997;82:1256-69. 31. mynard jp, davidson mr, penny dj, et al. a simple, versatile valve model for use in lumped parameter and onedimensional cardiovascular models. int j numer method biomed eng 2012;28:626-41. 32. utriainen d, feng w, elias s, et al. using magnetic resonance imaging as a means to study chronic cerebral spinal venous insufficiency in multiple sclerosis patients. techniques vasc intervent radiol 2012;15:101-12. 33. chen h, yu y, zhong s, et al. threedimensional reconstruction of internal auditory meatus and anatomical study of the inner structures. zhonghua er bi yan hou ke za zhi 2000;35:204-6. 34. habibi z, meybodi at, maleki f, et al. superior and anterior inferior cerebellar arteries and their relationship with cerebello-pontine angle cranial nerves revisited in the light of cranial cephalometric indexes: a cadaveric study. turkish neurosurgery 2011;21:504-15. 35. pellet w, cannoni m, pech a. otoneurosurgery. berlin: springer, verlag; 1990. 36. schaller b. physiology of cerebral venous blood flow: from experimental data in animals to normal function in humans. brain res rev 2004;46:24360. 37. valk wl, wit hp, albers fwj. evaluation of cochlear function in an acute endolymphatic hydrops model in no nco mm er cia l u se on ly article [veins and lymphatics 2018; 7:7156] [page 21] the guinea pig by measuring low-level dpoaes. hear res 2004;192:47-56. 38. alpini dc, bavera pm, di berardino f. bilateral sudden sensorineural hearing loss and chronic cerebrospinal insufficiency: a case report. phebology 2013; 28:231-3. 39. nedelmann m, eicke mb, dieterich m. increased incidence of jugular valve insufficiency in patients with transient global amnesia. j neurol 2005;252: 1482-6. 40. adamczyk-ludyga a, wrobel j, simka m, et al. retinal abnormalities in multiple sclerosis patients with associated chronic cerebrospinal venous insufficiency. veins and lymphatics 2012; 1:e2. 41. liu m, xu h, zhong y, et al. patterns of chronic venous insufficiency in the major cerebral and extracranial draining veins and their relationship with white matter hyperintensities for patients with parkinson’s disease. j vasc surg 2015; 61:1511-20. 42. doepp f, schreiber sj, von münster t, et al. how does the blood leave the brain? a systemic ultrasound analysis of cerebral venous drainage patterns. neuroradiology 2004;46:565-70. 43. valdueza jm, von münster t, hoffmann o. postural dependency of the cerebral venous outflow. lancet 2000;355:200-1. 44. carlborg bir, farmer jc. transmission of cerebrospinal fluid pressure via the cochlear aqueduct and endolymphatic sac. am j otolaryngol 1983;4:273-82. 45. weille fl, o’brien hf, clark l, et al. pressures of the labyrinthine fluids. ann otol rhinol laryngol 1961;70:528-40. 46. linninger aa, xenos m, sweetman b, et al. a mathematical model of blood, cerebrospinal fluid and brain dynamics. j math biol 2009;59:729-59. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2015; volume 4:4650 [veins and lymphatics 2015; 4:4650] [page 11] a novel device for non-invasive cerebral perfusion assessment mirko tessari, anna maria malagoni, maria elena vannini, paolo zamboni vascular diseases center, university of ferrara, italy abstract currently brain perfusion can be assessed by the means of radio-invasive methods, such as single-photon emission computed tomography and positron emission tomography, or by hightech methods such as magnetic resonance imaging. these methods are known to be very expensive, with long examination time, and finally, cannot be used for assessing brain oxygen distribution in relation to exercise and/or cognition-tests. the near infrared spectroscopy (nirs) is a non-invasive diagnostic technique. in real time it is capable of measuring tissue oxygenation using portable instrumentation with a relative low cost. we and other groups previously adopted this instrument for investigation of the oxygen consumption in the muscles at rest and during exercise. nirs can be now used to assess brain perfusion through the intact skull in human subjects by detecting changes in blood hemoglobin concentrations. changes in perfusion can be related to both arterial and venous problems. this novel equipment features allow for a wide field of innovative applications where portability, wearability, and a small footprint are essential. the present review shows how to use it in relation to exercise protocols of the upper and lower extremities, measured in healthy people and in conditions of arterial and chronic cerebro-spinal venous insufficiency. historical background the discovery of the infrared region in 1800 is credited to william f. hershel’s famous work, experiments on the refrangibility of the invisible rays of the sun.1 wheeler2 described the near infrared (nir) region as extending from about 2 microns (m) into the visible at about 0.7 m. goddu and delker3 demonstrated the spectra-structure correlations and average molar absorptivity for a number of functional groups for the nir region, and the maximum recommended path lengths for twelve solvents over the wavelength region 1.0 to 3.1 m. ellis4, kaye5 and goddu6 et al. compiled an extensive review of nir spectrophotometry prior to 1960 and subsequently schrieve et al.7 discussed applications for the short-wave nir region, referring to synonyms such as the far-visible, the near, near-infrared to describe the range of approximately 700 to 1100 nanometers (nm) of the electromagnetic spectrum.8,9 the new decade of the 1960s brought about a prolific series if papers related to direct determination and the measurement of light transmittance and reflectance properties of intact biological materials. early work, most of which used multiple linear regression to identify key calibration wavelengths, used both filter and dispersive scanning instruments to relating nir spectral response to reference analytical data.8,9 near infrared has been used for analysis of gasoline, fine chemicals, polymers and pharmaceuticals, both with dispersive and fouriertransform nir based instruments.10 more recently, medical applications for near-infrared have proliferated into areas of blood analyze monitoring and imaging of materials including tissue.11 near infrared spectroscopy the near infrared spectroscopy (nirs) was recently quoted in annals of the new york academy of sciences12 as one of the most promising technology in the next decade in monitoring finalized to the neuro-protection, being able to measure at regional level parameters such as oxygenation and blood flow within the brain tissue. the nirs is a non-invasive diagnostic technique. in real time it is capable of measuring tissue oxygenation using portable instrumentation and a low cost. the nirs uses a means harmless for studying biological tissues, optical radiation, precisely the spectral band infrared with a wavelength of 700-950 nm.13,14 the photon nir launched in biological tissue through it a second path between source and detector. nir probes have the most used source revealing, that one or more optical fibers which capture the light radiation leaking from the biological tissue after covering a distance of variable depth and shape comparable to a banana shape (figure 1), by same side of the light source. 13,14 the maximum distance between the fiber end and the revealing of the fiber, which emits optical radiation, is usually 3-4 cm, allowing the nir photons penetrate into the biological tissue below up to a maximum depth of 3.5 cm.15 the nir photon in biological tissue undergoes two main processes: diffusion and absorption. the diffusion, dominant process in the nir spectral band, is the basis of the typical zigzag of the photon within the tissue, and is quantized by the scattering coefficient. the absorption by the biological tissue is mainly due to hemoglobin, and quantized by the absorption coefficient, measured by microseconds, with the recent nirs methods.16-18 the oxygenated hemoglobin (hbo2) and deoxygenated hemoglobin (hb) have different absorption spectra in the nir. this feature allows you to measure separately the two forms of hb and therefore the oxygen saturation of hemoglobin (sto2) in the tissues studied.19 the instrumentation for nirs timeresolved, based on the emission of light of variable intensity over time, allows to obtain data that reproduce the real state of oxygenation of the biological tissues investigated, using the dosage absolute hbo2 and hb and then the sto2.17-20 applications of near infrared spectroscopy for assessment of muscular metabolism in peripheral arterial disease peripheral arterial disease (pad) affecting blood flow in the lower limbs is responsible for altered oxygen delivery to tissues and muscles during walking. available methods or techniques to assess the presence or severity of pad are performed mainly in static conditions with the ankle brachial index (abi).21-23 otherwise, dynamic evaluations, such as functional tests, are related to patients symptoms and disease severity.24 nirs measurements have been proposed for pad patients, whose performance depends on both oxygen availability and its use.25-30 manfredini et al.24 have demonstrated that a dynamic assessment of muscle metabolism and cardiovascular response during exercise are useful for the evaluation of patients with claudication or exertional leg pain in order to correspondence: mirko tessari, university of ferrara, via aldo moro 8, 44124 cona (fe), italy. e-mail: mirko.tessari@unife.it key words: near infrared spectroscopy, chronic cerebro-spinal venous insufficiency, cerebral perfusion, oxygenation. received for publication: 1 august 2014. revision received: 11 february 2015. accepted for publication: 16 february 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright m.tessari et al., 2015 licensee pagepress, italy veins and lymphatics 2015; 4:4650 doi:10.4081/vl.2015.4650 no n c om me rci al us e o nly review [page 12] [veins and lymphatics 2015; 4:4650] quantify the degree of metabolic disease and to determine the presence of pad. this muscular test with nirs technology is particularly useful in a clinical setting to exclude vascular diseases.24,31,32 it is known that the exercise training is an effective treatment for claudication,33 and walking sessions performed at a moderate level of pain are recommended for patients with pad.33,34 for this reasons the rehabilitation of pad patients is monitored in dynamic conditions and not in static assessment. in literature it has been shown that using nirs technique guidance we may obtain a significant improvement in dynamic muscle perfusion when the exercise were carried out at a prescribed intensity. these patients exhibited better walking performance, together with a greater capacity to extract oxygen in the calf and improvements in the abi, especially in the worse limb.35 the modifications detected through nirs measurements, when combined with noninvasive parameters including the abi, may explain how adaptations affect training outcomes and may therefore be useful to evaluate rehabilitation programs in patients with pad.35 thus, in summary, a parameter that can be easily measured by the means of nirs is the resting muscle oxygen consumption (rmvo2),36 which allows a quantification of the muscle’s capacity to extract oxygen from blood. we have seen that this parameter was found to be impaired in legs of patients with chronic diseases31,37-40 and modified following exercise training in pad.35 finally, nirs in pad was used to compare pneumatic pumps for the treatment of pad in patients who cannot walk, for foot wound or whatever other concomitant problems. for instance, a novel concept for treating pad patients by a device named gradient pump was found to be more effective as compared to classic pneumatic pump.41 cerebral perfusion disturbances in brain perfusion can have immediate, severe and lifelong consequences.42 monitoring perfusion of the brain holds considerable significance to a broad range of clinical situations.43-45 functional studies have shown that the brain activation produces a spatially distributed and temporally varying response.46-49 an imaging modality that is proving to have significant impact in investigative studies is functional magnetic resonance imaging (fmri). this technique is sensitive to the vascular response resulting from neuroactivation, specifically to the level of deoxyhemoglobin. while the utility of fmri continues to expand, it is also clear that the technique has a number of limitations that are not encountered using nirs technique, like the cost effectiveness as well as the impossibility to evaluate a subject under movement.50,51 in addition, also radio-invasive methods [single-photon emission computed tomography (spect) and positron emission tomography (pet)] or methods with contrast imaging (mri) are used.52-54 these methods prove to be very expensive, very difficult and the examination results to be long. but above all these methods are static and not dynamic. however, all this methods of investigation allowed us to understand that even the venous drainage may lead to cerebral hypoperfusion.55,56 as above described, the primary application of nirs to the human body uses the fact that the transmission and absorption of nir light in human body tissues contains information about hemoglobin concentration changes. when a specific area of the brain is activated, the localized blood volume in that area changes quickly. optical imaging can measure the location and activity of specific regions of the brain by continuously monitoring blood hemoglobin levels through the determination of optical absorption coefficients.16,17 nirs can be used for non-invasive assessment of brain perfusion through the intact skull in human subjects by detecting changes in blood hemoglobin concentrations associated with neural activity, for example, in branches of cognitive psychology as a partial replacement for fmri techniques.57 however, nirs cannot fully replace fmri because it can only be used to scan cortical tissue, where fmri can be used to measure activation throughout the brain. special public domain statistical toolboxes for analysis of stand-alone and combined nirs/mri measurements have been developed.58 nirs provides quantitative data in absolute terms on up to a few specific points. the latter is also used to investigate other tissues such as, for example, muscle,59 breast and tumors.60 nirs can be used to quantify blood flow, blood volume, oxygen consumption, reoxygenation rates and muscle recovery time in muscle.59 in perspective, it will be very interesting to measure oxygen consumption contemporaneously in the brain and in the muscle of patients with neurodegenerative disorders. malagoni et al.61 have demonstrated that the rmvo2 values measured by nirs were found to be significantly higher in multiple sclerosis patients compared to healthy control, and in low versus better performing patients. such parameter might represent a marker of peripheral adaptations occurred to sustain mobility. it might be potentially useful in a clinical setting for assessing the level of skeletal muscle metabolic impairment, and for monitoring the progression of the disease, therapeutic treatments or rehabilitative programs.61 the instrumental development of nirs has proceeded tremendously during the last years and, in particular, in terms of quantification and imaging.62 cerebral near infrared spectroscopy the idea to measure micro-circulatory parameters in the brain of people with neurodegenerative disorders, or with multiple sclerosis (ms), is not new. however, after the description of an association between extracranial venous flow impairment and ms, alzheimer’ and parkinson’ diseases determined a renewed interest in brain perfusion assessment.55,56,63,64 for the reasons above, it is important to assess perfusion also with cheaper and portable instruments. recently, also photoplethysmography has been proposed to measure at cortical venular level deoxygenated hemoglobin in relation to cerebral perfusion in patients affected by ms. the cerebral blood volume increase was significantly smaller in the ms patients (left frontal cortex: �58%, p<0.0001; right frontal cortex: �59%, p< 0.0001) compared with healthy people, again demonstrating a significant low perfusion linked with venous function.65 however, photoplethysmography is less reliable and advanced respect to modern cerebral nirs, which includes also several channel and devoted software for building imaging. the latter instrument66 is a lightweight, freely configurable, multi-channel nirs imaging system that combines led illumination with active detection technology for a truly wearable brain imaging solution. these novel product features allow for a wide field of innovative applications where portability, wearability, and a small footprint are essential. this system allows for non-invasive realtime hemoglobin measurements of the cerebral cortex (figure 2). the available nirs instruments offer more than 8 sources and 8 detectors (16 sources/16 detectors in tandem mode) with a diverse array of available headgear and optical probes.67 the device finds application in many diseases, e.g. autism, intra operative monitoring, language, learning and attention, motor masks, neonatal-infant monitoring, psychiatric disorders, stroke and rehabilitation, traumatic brain injury and of course, in case of problems of cerebral venous drainage.66,67 ours first experiences in brain perfusion assessment in relation to chronic cerebrono n c om me rci al us e o nly review [veins and lymphatics 2015; 4:4650] [page 13] spinal venous insufficiency (ccsvi) were performed by the means of nirsport (nirsport88/2.01, ems medical, bologna). dimensions 105¥170¥40 mm, net weight 660 g, illumination type led, number of illumination sources 8 (16 in tandem mode), number of illumination detector 8 (16 in tandem mode), dual wavelength 760 nm, 850 nm, mode of operation continuous wave.68 software for imaging building starting from hemoglobin signal nirs, as above explained, provides information about the level of hemoglobin/deoxygenated hemoglobin level from the different channels in the scalp of the subject under evaluation. to compare nirs assessment with more complex diagnostic systems such as mri, spect and pet is desirable to transform the biochemical signal into a mapping image. the nirstar software package provides a user friendly graphical user interface for system control (calibration and probe setup), patient monitoring, real-time cortical 2d and 3d display capabilities and a module for hyper-scanning (figure 3). contemporaneously, the instrument may derive real-time hyper-scanning capability of oxygenated, deoxygenated and total hemoglobin69 (figure 4). placement and arrangement of near infrared spectroscopy to position nirs optical sensors (optode), the nirscap are used. the nirscap is a headset that is worn on the head of the subject on which there are holes in which are inserted the optode (source and detector). once worn nirscap, the sensors are inserted into the holes inherent in the motor or the cognitive area to be analyzed. through the nirs maps we can identify the correct holes in the affected area. very important for the graft of the sensors on the nirscap is to remove, through a suitable stick, the hair from the entrance hole (figure 5). figure 1. propagation of the near infrared signal. figure 3. a) 2d graphical interface, b) 3d graphical interface, c) cortical view. figure 5. left image: cap in place; middle image: remove hair; right image: ready for optode insertion. figure 2. the near infrared spectroscopy cup with optode for the non-invasive assessment. figure 4. oxygenated (red line), deoxygenated (blue line) and total hemoglobin (green line) variation during the near infrared spectroscopy measurement. no n c om me rci al us e o nly review [page 14] [veins and lymphatics 2015; 4:4650] cognitive and motor functional assessment by cerebral near infrared spectroscopy the big advantage of nirs assessment of brain perfusion is the repeatability of the assessment, as well as the fantastic opportunity to evaluate perfusion in functional conditions. for example we can analyze the cognitive and motor function of the examined subject. depending on the cerebral area that we want to analyze we must change the position of the sensors in the nirscap. to assess motor function we have to analyze the cerebral motor area (figure 6). once positioned the sensors we can proceed with testing. having a dynamic and not static instrumentation, we can afford to run any motor test to the subject and our protocol of investigation. we can perform the classic finger taping, until the six minute walking tests.46,70,71 in this case, if we previously assess ccsvi, nirs leads us to understand how cerebral venous function may affect brain perfusion in experimental conditions which cannot be assessed by more sophisticated equipment. actually, it is the only way to derive micro-circulatory information during exercise. being the nirs a portable instrumentation and equipped with tablet for recording data, if the subject is an athlete, we can think to do an athletic simulation or physical activity to assess the relative activity of oxygenation during exercise and then adjust the trainability or monitoring the rehabilitation exercise after trauma to measure the consumption of oxygen. to assess cognitive function, we need to change the positioning of the sensors in the nirscap and place them in prefrontal area (figure 7). in this case we can propose cognitive tests, e.g. the static paced auditory serial addition task (pasat test) or dynamic box and block test. 71-73 the advantage of these evaluations with nirsport is the speed of acquisition of the test; the freedom of performing the test; the opportunity to redo the test without constraints of instrumentation and recalibration, the possibility to perform any dynamic test without time and space limit.74 nirs is also so versatile to permit acquisition with finger compression of one carotid and or jugular, so deriving information at bed side of respective value in ensuring the correct perfusion of the organ (figure 8). perspectives in neurodegenerative disease literature describes the first quantification by nirs assessment of neurodegenerative diseases. in particular, the focus is based on alzheimer and parkinson disease.75-78 given the excellent tolerability of measurement by nirs74 and the possibility of repeat figure 6. motor area map to insert the optode. figure 7. prefrontal area map to insert the optode. figure 8. an example of brain perfusion with near infrared spectroscopy: a) the red area corresponds to the oxygenated hemoglobin absorption spectra image. b) the blue area corresponds the deoxygenated hemoglobin absorption spectra image.no n c om me rci al us e o nly review [veins and lymphatics 2015; 4:4650] [page 15] measurements quickly without requiring the patient immobility during the examination as a diagnostic techniques with contrast imaging, we are bringing more and more towards this new method of measuring nir since it allows to evaluate the oxygenation and deoxygenation brain in real time. in addition to the part of the imaging nirs is used to monitor the rehabilitation78,79 and post-surgical treatment, monitor the surgical procedure80,81 and the relative perfusion and the ability to constantly monitor the progress of the patient during daily activities. the life is not static and the perfusion parameters in dynamic approaches to the actual daily activities are to be analyzed. it is known that the ccsvi is a condition leading to cerebral hypoperfusion.55,82 currently for this survey are used spect and mri52,56 to be valued the brain perfusion. these allow us to see deep into the cranial perfusion, but only in a static way. the nirs could help us to complete the perfusion assessment in patients with ccsvi in dynamic condition and then we have global information given by more accurate functional evaluations to the patients. references 1. hershel w. experiments on the refrangibility of the invisible rays of the sun. phil trans r soc lond 1800;90:284-92. 2. wheeler oh. near infrared spectra. a neglected field of spectral study. j chem education 1960;37:234-6. 3. goddu rf, delker da. spectra-structure correlations for the near-infrared region. anal chem 1960;32:140-1. 4. ellis jw. molecular absorption spectra of liquids below 3 m. trans faraday soc 1928;25:888-98. 5. kaye w. near-infrared spectroscopy; a review. i. spectral identification and analytical applications. spectrochimica acta 1954;6:257-87. 6. goddu rf. near-infrared spectrophotometry. adv anal chem instr 1960;1:347-424. 7. schrieve gd, melish gg, ullman ah. the herschel-infrared--a useful part of the spectrum. appl spectrosc 1991;45:711-4. 8. whetsel kb. near-infrared spectrophotometry. appl spectrosc rev 1968;2:1-67. 9. stark e, luchter k, margoshes m. nearinfrared analysis (nira): a technology for quantitative and qualitative analysis. appl spectrosc rev 1986;22:335-99. 10. burns d, ciurczak e. handbook of nearinfrared analysis. 2nd ed. new york: marcel-dekker, inc.; 2001. 11. ciurczak e, drennen j. near-infrared spectroscopy in pharmaceutical and medical applications. new york: marceldekker, inc.; 2002. 12. andrews rj. monitoring for neuroprotection. new technologies for the new millennium. ann n y acad sci 2001;939:101-13. 13. committee for human medicinal products (chmp), committee for veterinary medicinal products (cvmp). guideline on the use of near infrared spectroscopy (nirs). london: european medicines agency; 2012. 14. nirx medical technologies llc, fnirs analysis environment. user’s manual fnirs. optical tomography group; 2012. 15. hirasawa a, yanagisawa s, tanaka n, et al. influence of skin blood flow and sourcedetector distance on near-infrared spectroscopy-determined cerebral oxygenation in humans. clin physiol funct imaging 2014 [epub ahead of print]. 16. strait m, scheutz m. what we can and cannot (yet) do with functional near infrared spectroscopy. front neurosci 2014;8:117. 17. tobias jd. cerebral oxygenation monitoring: near-infrared spectroscopy. expert rev med devices 2006;3:235-43. 18. wylie gr, graber hl, voelbel gt, et al. using co-variations in the hb signal to detect visual activation: a near infrared spectroscopic imaging study. neuroimage 2009;47:473-81. 19. schmitz j, pichler g, schwaberger b, et al. feasibility of long-term cerebral and peripheral regional tissue oxygen saturation measurements. physiol meas 2014;35:1349-55. 20. murkin jm, arango m. near-infrared spectroscopy as an index of brain and tissue oxygenation. br j anaesth 2009;103:3-13. 21. ruff d. doppler assessment: calculating an ankle brachial pressure index. nurs times 2003;99:62-5. 22. doobay av, anand ss. sensitivity and specificity of the anklebrachial index to predict future cardiovascular outcomes: a systematic review. arterioscler thromb vasc biol 2005;25:1463-9. 23. manfredini f, malagoni am, manfredini r. ankle brachial pressure index: faulty or overused? angiology 2013;64:89-92. 24. manfredini f, malagoni am, felisatti m, et al. a dynamic objective evaluation of peripheral arterial disease by nearinfrared spectroscopy. eur j vasc endovasc surg 2009;38:441-8. 25. komiyama t, shigematsu h, yasuhara h, muto t. an objective assessment of intermittent claudication by near-infrared spectroscopy. eur j vasc surg 1994;8:294e6. 26. mccully kk, halber c, posner jd. exercise-induced changes in oxygen saturation in the calf muscles of elderly subjects with peripheral vascular disease. j gerontol biol sci 1994;49:128e34. 27. kooijman hm, hopman mt, colier wn, vliet ja, oeseburg b. near infrared spectroscopy for noninvasive assessment of claudication. j surg res 1997;72:1e7. 28. egun a, farooq v, torella f, et al. the severity of muscle ischemia during intermittent claudication. j vasc surg 2002;36:89e93. 29. comerota aj, throm rc, kelly p, jaff m. tissue (muscle) oxygen saturation (sto2): a new measure of symptomatic lower extremity arterial disease. j vasc surg 2003;38:724e9. 30. watanabe t, matsushita m, nishikimi n, et al. near-infrared spectroscopy with treadmill exercise to assess lower limb ischemia in patients with atherosclerotic occlusive disease. surg today 2004;34:849e54. 31. malagoni am, felisatti m, mandini s, et al. resting muscle oxygen consumption by near-infrared spectroscopy in peripheral arterial disease: a parameter to be considered in a clinical setting? angiology 2010;61:530-6. 32. manfredini f, lamberti n, malagoni am, et al. reliability of the vascular claudication reporting in diabetic patients with peripheral arterial disease: a study with nearinfrared spectroscopy. angiology 2014 [epub ahead of print]. 33. stewart kj, hiatt wr, regensteiner jg, hirsch at. exercise training for claudication. n engl j med 2002;347:1941-51. 34. norgren l, hiatt wr, dormandy ja, et al. inter-society consensus for the management of peripheral arterial disease (tasc ii). j vasc surg 2007;45:s5-s67. 35. manfredini f, malagoni am, mandini s, et al. near-infrared spectroscopy assessment following exercise training in patients with intermittent claudication and in untrained healthy participants. vasc endovascular surg 2012;46:315-24. 36. van beekvelt mc, colier wn, wevers ra, van engelen bg. performance of nearinfrared spectroscopy in measuring local o(2) consumption and blood flow in skeletal muscle. j appl physiol 2001;90:511-9. 37. boushel r, langberg h, olesen j, et al. monitoring tissue oxygen availability with near infrared spectroscopy (nirs) in health and disease. scand j med sci sports 2001;11:213-22. 38. hamaoka t, mccully kk, quaresima v, et al. near-infrared spectroscopy/imaging for monitoring muscle oxygenation and oxidative metabolism in healthy and diseased humans. j biomed opt 2007;12: 062105. 39. grassi b, marzorati m, lanfranconi f, et al. impaired oxygen extraction in metabolic myopathies: detection and quantification by near-infrared spectroscopy. muscle nerve 2007;35:510-20. no n c om me rci al us e o nly review [page 16] [veins and lymphatics 2015; 4:4650] 40. abozguia k, phan tt, shivu gn, et al. reduced in vivo skeletal muscle oxygen consumption in patients with chronic heart failure a study using near infrared spectrophotometry (nirs). eur j heart fail 2008;10:652-7. 41. manfredini f, malagoni am, felisatti m, et al. acute oxygenation changes on ischemic foot of a novel intermittent pneumatic compression device and of an existing sequential device in severe peripheral arterial disease. bmc cardiovasc disord 2014;14:40. 42. henriksen om, jensen lt, krabbe k, et al. resting brain perfusion and selected vascular risk factors in healthy elderly subjects. plos one 2014;9:e97363. 43. le heron cj, wright sl, melzer tr, e al. comparing cerebral perfusion in alzheimer’s disease and parkinson’s disease dementia: an asl-mri study. j cereb blood flow metab 2014;34:964-70. 44. alosco ml, gunstad j, jerskey ba, et al. the adverse effects of reduced cerebral perfusion on cognition and brain structure in older adults with cardiovascular disease. brain behav 2013;3:626-36. 45. mehnert j, akhrif a, telkemeyer s, et al. developmental changes in brain activation and functional connectivity during response inhibition in the early childhood brain. brain dev 2013;35:894-904. 46. perrey s. promoting motor function by exercising the brain. brain sci 2013;3:101-22. 47. liu x, sun g, zhang x, et al. relationship between the prefrontal function and the severity of the emotional symptoms during a verbal fluency task in patients with major depressive disorder: a multi-channel nirs study. prog neuropsychophar macol biol psychiatry 2014;54:114-21. 48. schneider a, minnich b, hofstätter e, et al. comparison of four near-infrared spectroscopy devices shows that they are only suitable for monitoring cerebral oxygenation trends in preterm infants. acta paediatr 2014 [epub ahead of print]. 49. khan mj, hong mj, hong ks. decoding of four movement directions using hybrid nirs-eeg brain-computer interface. front hum neurosci 2014;8:244. 50. sato h, yahata n, funane t, et al. a nirsfmri investigation of prefrontal cortex activity during a working memory task. neuroimage 2013;83:158-73. 51. dunn jf, nathoo n, yang r. a tale of two methods: combining near-infrared spectroscopy with mri for studies of brain oxygenation and metabolism. adv exp med biol 2014;812:65-71. 52. song iu, park jw, chung sw, chung ya. brain spect can differentiate between essential tremor and early-stage tremordominant parkinson's disease. j clin neurosci. 2014 [epub ahead of print]. 53. rahman mt, sethi sk, utriainen dt, et al. a comparative study of magnetic resonance venography techniques for the evaluation of the internal jugular veins in multiple sclerosis patients. magn reson imaging 2013;31:1668-76. 54. utriainen d, trifan g, sethi s, et al. magnetic resonance imaging signatures of vascular pathology in multiple sclerosis. neurol res 2012;34:780-92. 55. zamboni p, menegatti e, weinstockguttman b, et al. hypoperfusion of brain parenchyma is associated with the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a cross-sectional preliminary report. bmc med 2011;9:22. 56. feng w, utriainen d, trifan g, et al. characteristics of flow through the internal jugular veins at cervical c2/c3 and c5/c6 levels for multiple sclerosis patients using mr phase contrast imaging. neurol res 2012;34:802-9. 57. mehagnoul-schipper dj, van der kallen bf, colier wn, et al. simultaneous measurements of cerebral oxygenation changes during brain activation by near-infrared spectroscopy and functional magnetic resonance imaging in healthy young and elderly subjects. hum brain mapp 2002;16:14-23. 58. ye jc, tak s, jang ke, et al. nirs-spm: statistical parametric mapping for nearinfrared spectroscopy. neuroimage 2009;44:428-47. 59. van beekvelt mc, van engelen bg, wevers ra, colier wn. in vivo quantitative nearinfrared spectroscopy in skeletal muscle during incremental isometric handgrip exercise. clin physiol funct imaging 2002;22:210-7. 60. van der sanden bp, heerschap a, hoofd l, et al. effect of carbogen breathing on the physiological profile of human glioma xenografts. magn reson med 1999;42:4909. 61. malagoni am, felisatti m, lamberti n, et al. muscle oxygen consumption by nirs and mobility in multiple sclerosis patients. bmc neurol 2013;13:52. 62. wolf m, ferrari m, quaresima v. progress of near-infrared spectroscopy and topography for brain and muscle clinical applications. j biomed opt 2007;12:062104. 63. wang y, butros sr, shuai x, et al. different iron-deposition patterns of multiple system atrophy with predominant parkinsonism and idiopathetic parkinson diseases demonstrated by phase-corrected susceptibility-weighted imaging. ajnr am j neuroradiol 2012;33:266-73. 64. chung cp, beggs c, wang pn, et al. jugular venous reflux and white matter abnormalities in alzheimer’s disease: a pilot study. j alzheimers dis 2014;39:6019. 65. viola s, viola p, fiorelli l, et al. transcranial brain photoplethysmography to study the venules of cerebral cortex in patients with multiple sclerosis. phlebology 2013 [epub ahead of print]. 66. nirx llc 2014. available from: http://www.nirx.net/imagers/nirsport 67. nirx medical technologies llc. nirsport™ user guide. optical tomography group; 2012. 68. nirx medical technologies llc. nirsport™ nirs imaging system. optical tomography group; 2013. 69. nirx medical technologies llc. nirstar software manual. optical tomography group; 2013. 70. jang sh, jang wh, chang ph, et al. cortical activation change induced by neuromuscular electrical stimulation during hand movements: a functional nirs study. j neuroeng rehabil 2014;11:29. 71. tanaka h, katura t, sato h. task-related oxygenation and cerebral blood volume changes estimated from nirs signals in motor and cognitive tasks. neuroimage 2014;94:107-19. 72. lloyd-fox s, papademetriou m, darboe mk, et al. functional near infrared spectroscopy (fnirs) to assess cognitive function in infants in rural africa. sci rep 2014;4:4740. 73. tando t, kaga y, ishii s, et al. developmental changes in frontal lobe function during a verbal fluency task: a multi-channel near-infrared spectroscopy study. brain dev 2014 [epub ahead of print]. 74. piper sk, krueger a, koch sp, et al. a wearable multi-channel fnirs system for brain imaging in freely moving subjects. neuroimage 2014;85:64-71. 75. sakatani k, katayama y, yamamoto t, suzuki s. changes in cerebral blood oxygenation of the frontal lobe induced by direct electrical stimulation of thalamus and globus pallidus: a near infrared spectroscopy study. j neurol neurosurg psychiatry 1999;67:769-73. 76. kito h, ryokawa a, kinoshita y, et al. comparison of alterations in cerebral hemoglobin oxygenation in late life depression and alzheimer’s disease as assessed by near-infrared spectroscopy. behav brain funct 2014;10:8. 77. quirk bj, desmet kd, henry m, et al. therapeutic effect of near infrared (nir) light on parkinson's disease models. front biosci 2012;4:818-23. 78. viola s, viola p, buongarzone mp, et al. new brain reperfusion rehabilitation therapy improves cognitive impairment in mild alzheimer’s disease: a prospective, no n c om me rci al us e o nly review [veins and lymphatics 2015; 4:4650] [page 17] controlled, open-label 12-month study with nirs correlates. aging clin exp res 2013 [epub ahead of print]. 79. ishikuro k, urakawa s, takamoto k, et al. cerebral functional imaging using nearinfrared spectroscopy during repeated performances of motor rehabilitation tasks tested on healthy subjects. front hum neurosci 2014;8:292. 80. martini m, röhrig a, wenghoefer m, et al. cerebral oxygenation and hemodynamic measurements during craniosynostosis surgery with near-infrared spectroscopy. childs nerv syst 2014 [epub ahead of print]. 81. nielsen hb. systematic review of nearinfrared spectroscopy determined cerebral oxygenation during non-cardiac surgery. front physiol 2014;5:93. 82. zamboni p, sisini f, menegatti e, et al. an ultrasound model to calculate the brain blood outflow through collateral vessels: a pilot study. bmc neurol 2013;13:81. no n c om me rci al us e o nly hrev_master veins and lymphatics 2017; volume 6:6757 [page 56] [veins and lymphatics 2017; 6:6757] initial patterns of unilateral great saphenous vein reflux in women with telangiectasias and varicose veins carlos a. engelhorn,1,2 ana luiza d.v. engelhorn,1,2 sergio x. salles-cunha,2 patricia r. terna,1 karine d. kovalski,1 thaina v. parizotto1 1department of angiology, school of medicine, pontifical catholic university of paraná; 2angiolab noninvasive vascular laboratory, curitiba, pr, brazil abstract telangiectasias and varicose veins have been linked to chronic venous valvular insufficiency causing great saphenous vein (gsv) reflux. gsv diameter-reflux correlations were determined in women c1 and/or c2 and unilateral gsv reflux. subgroups were: i) bilateral c1/c1 (n=106) and ii) refluxing gsv c2/contralateral nonrefluxing c1 or c2 (n=50). gsv included saphenofemoral junction (sfj), gsv, and major veins in and out of the saphenous compartment at knee and calf. prevalence and diameters were compared by chi-square and paired t-test. reflux prevalence at junction, thigh and calf were 5%, 26% and 71% of 106 refluxing c1 extremities, and 18%, 44% and 72% of 50 refluxing c2 extremities (p=0.007, 0.03, 0.87). significant diameter increase compared to contralateral nonrefluxing segment (p<0.05) were at: c2 junction, 7.9±1.8 vs 6.6±1.5 mm, and c2 mid-thigh, junction refluxing or not, 4.8±1.1 vs 3.6±1.0 or 4.1±0.8 vs 3.6±0.7 mm. calf gsv diameters averaged 2.5 to 2.7 mm if reflux was below-knee. unilateral reflux occurred in calf veins without correlation to diameter. enlarged diameters were noted in refluxing sfj and thigh gsv of women with varicose veins. introduction telangiectasias and varicose veins have been linked to chronic venous insufficiency (cvi), or more specifically, to chronic venous valvular insufficiency (cvvi) and great saphenous vein (gsv) reflux.1-3 this investigation focused specifically in women with early stages of cvvi characterized by c1, simple c2 and pr classifications only. in particular, the great saphenous vein system (gsv), comprised of the gsv in the proper compartment and major axial, parallel veins in and out of the saphenous compartment at the knee and calf levels, was evaluated. duplex ultrasonography has become the practical standard for diagnosis, pretreatment mapping, peri-treatment imaging, and patient follow-up of cvvi conditions. international consensus has described basic principles, related anatomy and follow-up protocols.4-6 minimally invasive techniques have expanded the scope of treatment of affected veins, most commonly of superficial varicose veins, telangiectasias, and, in particular, of the refluxing gsv.7-14 gsv diameter measurements have become essential to complement evaluation of reflux and to help in treatment planning.14-17 foam volume should depend on vein diameter, for example.14 our initial report on gsv diameter and prediction of reflux was not based on an early disease, uniform, sample population.15 our analyses for quality control of the vascular laboratory tried to improve precision in relation to female gender and clinical ceap classes c1 and/or c2.2,3,18 this report centered on women with reflux in only one lower extremity. the objectives were to determine patterns of gsv reflux, to relate location of reflux and venous diameter, and to determine possible differences once the extremity developed varicose veins besides spider veins or telangiectasias. materials and methods duplex ultrasound data came from examinations performed at an iso 9001 certified noninvasive vascular laboratory founded in curitiba, state of parana, south of brazil, in 1991. ultrasonography was performed by board certified physicians according to the rules set by vascular, cardiology and radiology brazilian societies. the patients examined in this laboratory were predominantly of european descent, including ancestors of portuguese, italian, polish, german, ukrainian, and slavic origins. this investigation conformed to the ethical guidelines of the 1975 declaration of helsinki and was approved by the ethics committee of the pontificia universidade católica do paraná. inclusion criterion women with unilateral gsv reflux and ceap clinical classification c1 and/or c2 entered the study. men were excluded. seven cases of extremities with non-severe edema but conditional swelling, and two cases with gsv reflux in the c1extremity but non-refluxing gsv in the contralateral c2 extremity were also excluded. individual data were sequentially extracted from 353 archives automatically created according to standard laboratory protocol. sample patient population two subgroups were formed: i) c1 subgroup: actually, a c1/c1 subgroup, with 106 women who had telangiectasias in both legs but gsv reflux in only one. average age of this subgroup was 42±13 years old, ranging from 23 to 79; ii) c2 subgroup: actually, a c2/c1-c2 subgroup with 50 women who had reflux in an extremity with varicose veins but no reflux in the other extremity with telangiectasias and/or varicose veins. average age of this subgroup was higher, 49±12 years old, ranging from 21 to 79 (p=0.001). duplex doppler ultrasonography duplex doppler, color-flow ultrasonography was performed with siemens acuson antares and siemens acuson x700 instruments and 7-10 mhz transducers. patient was examined standing. the great saphenous vein (gsv) was scanned in its entire length, continuously. reflux time greater than 0.5 sec and diameters were measured standing, even if an unsettled patient had to rest for a while to maintain the orthostatic position. hand compression/decompression correspondence: carlos a. engelhorn, angiolab laboratorio vascular não invasivo, rua da paz, 195, sala 2, alto da xv, curitiba, pr, brazil, 80060-160. e-mail: carlos.engelhorn@pucpr.br key words: saphenous vein reflux; women; varicose veins; telangiectasias; doppler ultrasound. contributions: cae, aldve, design, data collection, quality control, manuscript reviewer, lab organization, data storage; sxsc, data analysis, manuscript writer; prt, kdk, tvp: data collection. conflict of interest: the authors declare no potential conflict of interest received for publication: 18 april 2017. revision received: 13 june 2017. accepted for publication: 13 june 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright c.a. engelhorn et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6757 doi:10.4081/vl.2017.6757 no n c om me rci al us e o nly article maneuvers were standard; they provided versatility in studying virtually all venous segments in diverse calf and thigh positions. long palm-finger compression, and fast decompression were the norm. finger-tip compression was avoided. valsalva maneuver was abandoned as nonproductive and cumbersome in patients with low probability of having saphenofemoral reflux. laughing and talking could replace valsalva maneuver as need. source and drainage points of gsv reflux were marked. practical experience recommended that gsv included the major, continuous, refluxing axial vein at the knee and calf level, even if the refluxing segment was not in the saphenous compartment for its entire length. therefore, the gsv system included the saphenofemoral junction (sfj), the gsv proper at the thigh, knee and calf, and/or the major collateral forming the major axis at the knee and calf levels (example: inclusion of the posterior accessory arch as part of the gsv system). refluxing segments in and out of the great saphenous compartment were noted; such information was not provided for veins without reflux. patterns of reflux included: i) diffuse from sfj to ankle; ii) proximal from sfj to thigh, knee or calf; iii) segmental at the thigh, knee and/or calf levels but excluding sfj; iv) multi segmental either including or not the sfj; v) distal from thigh, knee or calf to ankle; and vi) perijunction as a nonfemoral to gsv reflux. detailed mappings were shown in engelhorn et al.19 diameters measured at the junction, proximal, mid and distal thigh, knee and proximal, mid and distal calf were reported. statistical analysis focused on junction, thigh and calf representative measurements. the final reported included a complete saphenous vein diagram with nonsaphenous veins additions as needed. distances related to source, drainage and perforating vein positioning were indicated longitudinally and circumferentially. such diagram was designed to minimize or shorten preoperative mapping. past experience, however, indicated that mapping in the standing and operative or treatment positions may vary slightly but sometimes significantly for precise localization.20 figure 1 is a simplified example of a perforator to tributary gsv calf segment reflux. although the figure shows a case with a perforating vein as source of reflux, our data analysis indicated that tributary veins were the most common source of saphenous vein reflux in c2 patients.21 differences in type of reflux source were not part of this analysis. data analysis prevalence of reflux patterns was estimated. prevalence was compared using chi-square statistics. descriptive statistics included mean, standard deviation, maximum and minimal diameters for each location. average diameters from refluxing versus non-refluxing extremity were compared using paired t-test. results table 1 describes the prevalence of reflux patterns for the two subgroups. subgroup c2 had significantly higher prevalence of sfj and gsv thigh segment reflux than subgroup c1. the most common place of gsv reflux, however, was in the calf segment of both subgroups. table 2 documents diameters of the two subgroups with reflux in c1 and c2 extremities separately. diameters of gsv with reflux in the calf segment of limbs with telangiectasias or with varicose veins were not significantly different than corresponding contralateral diameters in a non-refluxing gsv. significant diameter differences of about 0.3 mm were noted at the gsv thigh segment of c1 women with gsv reflux starting at the thigh level. refluxing gsv mid-thigh to knee segment diameters dilated even more in the varicose vein limbs, the difference to the contralateral vein being about 0.5 to 0.8 mm. junction reflux prevalence was too small, particularly in the c1 subgroup. the differences in junction and thigh diameters in the c2 subgroup, however, were significant to warrant an observation. on average, refluxing veins were 1.3 to 1.1 mm larger in diameter than non-refluxing contralateral gsvs at and above the knee. these differences could be clearly noticed in ultrasonographic practice. discussion and conclusions a few significant concepts were emphasized with this investigation: i) gsv reflux in early cvvi of women with telangiectasias or with simple varicose veins was predominant in the calf segment; ii) saphenofemoral reflux had low prevalence, particularly in the subgroup with telangiectable 1. prevalence of great saphenous vein (gsv) patterns of reflux: unilateral gsv reflux. reflux pattern* c1 group c2 group p diffuse from junction to ankle 0 0 multi segmental, from junction down 1 2 proximal, from junction to calf 2 3 proximal, from junction to knee 2 2 proximal, from junction to thigh 0 2 perijunction, excluding femorosaphenic 0 1 sf junction reflux total 5 (5%) 9 (18%) 0.007 distal, from thigh to ankle 0 0 multi segmental, from thigh down 8 6 segmental, from thigh to calf 2 2 segmental, from thigh to knee 4 2 segmental, thigh only 9 2 thigh segment reflux total 28 (26%) 22 (44%) 0.03 thigh segment and down only 23 (22%) 12 (24%) distal, from knee to ankle 1 1 segmental, from knee to calf 2 1 segmental, knee only 16 5 knee segment reflux total 38 (36%) 24 (48%) 0.15 knee segment and down only 19 (18%) 7 (14%) distal, from calf to ankle 23 6 segmental, calf only 36 15 calf segment reflux total 75 (71%)o 36 (72%) 0.87 calf segment down only 59 (56%) 21 (42%) *c1 subgroup: c1 extremity with reflux, c1 extremity without reflux; c2 subgroup: c2 extremity with reflux, c2 or c1 extremity without reflux. [veins and lymphatics 2017; 6:6757] [page 57] no n c om me rci al us e o nly article [page 58] [veins and lymphatics 2017; 6:6757] tasias; iii) gsv reflux in the calf failed to dilate such vein significantly when compared to the contralateral gsv; iv) diameter dilatations could be detected if reflux affected the thigh segment of the gsv, particularly in the limbs with varicose veins; and v) diameter dilatations could be easily documented if reflux affected the junction of limbs with varicose veins. the total number of patients entered in this analysis represented 44% (156/353) of the reports surveyed for their selection. the percentage of normal extremities, 22%, was not that different from the prevalence of normal great saphenous evaluations reported previously for c2 (23%) subpopulation.3 it may represent a general estimate of normal examinations performed in this vascular laboratory. in contrast, the percentage of normal saphenous previously reported for c1 subpoplations was 56%.2 a word of caution is needed to emphasize that these subpopulations prevalence data from a vascular laboratory does not represent disease prevalence per se. the women studied had questionable veins and complaints leading to an ultrasound examination. relationships, or lack of them, between saphenous reflux and varicose veins or telangiectasias were not investigated. as a curiosity, however, we have already published a color doppler imaging sequence linking a new telangiectasia by history to thrombus inside a previously ablated saphenous vein (confer. figure 3 in salles-cunha et al.22) furthermore, this analysis of saphenous vein reflux in c1 women was dictated by an international consensus classification indicating c1 as a subgroup not at the level of c2 to c6 classes. the primary intention was to study early stages of saphenous vein reflux. the data reemphasized past reports that saphenofemoral junction reflux was relatively rare in this c1 and/or c2 subgroup studied. prevalence of junction reflux at 5% and 18% respectively were comparable to 3% and 12% previously reported for c1 or c2 women.2,3 the supgroup in this analysis did not present what we named peri-junction reflux in the past, either a femoral to a non-great saphenous vein reflux with insufficient terminal valve, or a non-femoral to great saphenous reflux with normal terminal valve but refluxing preterminal valve. a practical conclusion was that duplex ultrasonography of the superficial veins of the lower extremity should be considered even in women with telangiectasias. another conclusion was that diameter measurements could still contribute to treatment type decision making since reflux may occur in either small or significantly dilated calf veins. women studied herein may not have saphenous ablation; there is documentation that most common segmental reflux lose positioning to multisegment reflux as diseases progressed.18 diameters could provide useful data related to the effects of clinical/stocking treatment, possible elimination of reflux by vasoconstriction medications, and dosage of foam or sclerotherapy saphenous injections, for example. paired-t test statistics emphasizes existing differences that may be uneventful in nortable 2. great saphenous vein diameters: from saphenofemoral junction to distal calf. subgroup type of reflux° average diameter (mm)±standard deviation sfj pt mt dt k pc mc dc junction starting reflux in extremities with varicose veins c2 n=9 c2 sfj reflux 7.9±1.8 5.7±1.0 4.8±1.1 4.4±1.0 4.5±1.3 3.2±1.0 2.6±0.5 2.6±0.7 c2 no reflux 6.6±1.5 4.5±1.2 3.6±1.0 3.3±1.1 3.2±0.9 2.9±0.9 2.5±0.6 2.7±0.8 paired t-test 0.04 0.006 0.0002 0.01 0.0008 junction starting reflux in extremities with telangiectasias c1 n=5 c1 sfj reflux 6.5±1.4 4.3±0.4 4.0±0.1 3.3±0.5 3.4±0.3 2.6±0.2 2.6±0.4 2.5±0.3 c1 no reflux 6.8±1.5 4.0±0.9 3.5±0.6 3.3±0.5 3.1±0.7 2.5±0.5 2.5±0.8 2.3±0.7 paired t-test no significant differences, small number of cases thigh starting reflux in extremities with varicose veins c2 n=12 c2 thigh reflux 6.8±1.3 4.3±1.0 4.1±0.8 4.1±1.0 4.1±1.3 3.1±0.9 2.6±0.4 2.7±0.4 c2 no reflux 7.5±1.4 4.6±1.0 3.6±0.7 3.4±0.8 3.3±0.8 2.8±0.7 2.4±0.5 2.6±0.5 paired t-test 0.02 0.009 0.01 thigh starting reflux in extremities with telangiectasias c1 n=23 c1 thigh reflux 7.0±1.5 4.3±1.0 3.4±0.8 3.2±0.7 2.9±0.8 2.5±0.6 2.3±0.7 2.4±0.7 c1 no reflux 6.4±1.3 4.0±1.0 3.1±0.8 3.0±0.6 2.9±0.6 2.4±0.5 2.5±0.6 2.5±0.6 paired t-test 0.004 0.047* 0.037* 0.056* calf reflux only in extremities with varicose veins c2 n=21 c2 calf reflux 6.7±1.0 4.3±0.9 3.4±0.7 3.2±0.5 3.0±0.6 2.7±0.8 2.6±0.6 2.6±0.6 c2 no reflux 6.7±1.0 4.4±0.9 3.4±0.8 3.0±0.5 3.0±0.5 2.6±0.8 2.6±0.6 2.6±0.6 paired t-test no significant differences calf reflux only in extremities with telangiectasias c1 n=59 c1 calf reflux 6.7±1.4 4.2±0.9 3.5±0.8 3.3±0.7 3.2±0.8 2.6±0.7 2.5±0.6 2.6±0.6 c1 no reflux 6.5±1.4 4.2±0.9 3.4±0.8 3.2±0.7 3.1±0.8 2.6±0.6 2.4±0.6 2.5±0.6 paired t-test no significant differences *significant differences detected only with one tail paired t-test.°reflux starting at the junction, thigh or limited to the calf segment. c1: extremities with telangiectasias; c2: extremities with varicose veins. sfj, saphenofemoral junction; p, m, d: proximal, mid, distal; t: thigh; k: knee; c: calf. no n c om me rci al us e o nly article mal clinical environment. the dilatations observed in the thigh segment of limbs with varicose veins, however, were notable and reportable rather easily in the duplex ultrasound examination performed by the most experienced sonographers. actually, a small dilatation of the refluxing saphenous segment compared to the proximal normal saphenous segment can be useful to detect a location of reflux source associated with a tributary or a perforating vein (confer. figure 3 in reference engelhorn et al.3). modern practice has accepted duplex ultrasonography to evaluate chronic venous valvular insufficiency in patients with varicose veins and nagging symptomatology. the gsv has demanded specific attention. evaluation for superficial vein reflux in women with telangiectasias has had continued debates. we have demonstrated that gsv reflux has a significant prevalence in women with telangiectasias that search medical attention.2 this investigation further emphasized the presence of gsv reflux in the calf of such patients. actual differentiation between gsv compartmental and non-compartmental calf segments has yet to be fully implemented in our own diagnostic duplex examinations. in or out compartment locations were described for refluxing segments but not for normal segments. anatomic, secondarily non-functional details could confuse most referring physicians in our practice. presence of dual channels and pre-operative mapping has demanded additional anatomic details. differentiations between gsv proper (still anterior arch for some) versus posterior accessory saphenous (the posterior arch eponym still acceptable) or other major tributaries were made if reflux were present; but again, details were abstained if these veins were not refluxing at the time of the examination. nevertheless, peri-procedural mapping is recommendable. the probability of detecting thigh or junction reflux was higher in legs with varicose veins than in legs with telangiectasias or reticular veins only. such data presented herein suggested that simple varicose veins might represent a step forward in the deterioration of gsv in terms of reflux affecting the thigh and junction locations. patient follow-up is recommended independent of the type of treatment. one objective would be to verify treatment efficacy or disease progression.18 another objective would be to accompany the contralateral extremity that could develop a reflux disorder in the future. the lack of relationship between gsv diameter in the calf and reflux indicated that valvular insufficiency could have many causes yet to be precisely identified on a patient per patient basis. one simple hypothesis is valvular damage. another genetic type hypothesis is that the refluxing vein has no valves or has working valves in ineffective locations. advanced ultrasonography could relate the difference between venous retrograde filling and actual reflux by determining the characteristics of the vein draining the reflux away from the main gsv channel. the hypothesis of reflux in a vein with valves that can work under venoconstriction but not under venodilatation could still be considered and it needs to be tested appropriately. nevertheless, normal extremities in the morning with reflux detected in the afternoon is a history that has been described often. this investigation made the hypothesis that the contralateral gsv was a standard for comparison, including venodilatation under the same conditions for both the non-refluxing and the refluxing vein. duplex dual examinations in conditions of venoconstriction and venodilatation are still needed to follow the precision theory in investigative phlebology. in summary, attention to gsv reflux in the calf and relative increases in gsv diameters at the thigh and junction is recommended when performing duplex ultrasonography in patients with early chronic venous valvular insufficiency represented by limbs with telangiectasias, reticular veins, or simple varicose veins (c1/c2) without edema, skin changes or ulcers (c3/c4/c5-6). this analysis further corroborates the hypotheses that saphenous reflux started at the weakest point of the vein, mostly in the leg, and that vein dilation could probably be associated with valvular insufficiency before valve damage. further, specific research is needed to demonstrate the second statement. references 1. eklöf b, rutherford rb, bergan jj, et al. revision of the ceap classification for chronic venous disorders: consensus statement. j vasc surg 2004;40:124852. 2. engelhorn ca, engelhorn al, cassou mf, salles-cunha s. patterns of saphenous venous reflux in women presenting with lower extremity telangiectasias. dermatol surg 2007;33:282-8. 3. engelhorn ca, engelhorn al, cassou mf, salles-cunha sx. patterns of saphenous reflux in women with primary varicose veins. j vasc surg 2005; 41:645-51. 4. coleridge-smith p, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs--uip consensus document. part i. basic principles. eur j vasc endovasc surg 2006;31:83-92. 5. cavezzi a, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs--uip consensus document. part ii. anatomy. eur j vasc endovasc surg 2006;31:288-99. 6. de maeseneer m, pichot o, cavezzi a, et al. duplex ultrasound investigation of the veins of the lower limbs after treatfigure 1. calf great saphenous vein segmental reflux: a) no saphenofemoral junction reflux; b) no thigh segment reflux; c) reflux source: perforating vein at upper calf; d) reflux drainage: tributary vein at mid-distal calf; e) normal great saphenous vein distal segment. [veins and lymphatics 2017; 6:6757] [page 59] no n c om me rci al us e o nly article [page 60] [veins and lymphatics 2017; 6:6757] ment for varicose veins uip consensus document. eur j vasc endovasc surg 2011;42:89-102. 7. balint r, farics a, parti k, et al. which endovenous ablation method does offer a better long-term technical success in the treatment of the incompetent great saphenous vein? review. vascular 2016;24:649-57. 8. goodyear sj, nyamekye ik. radiofrequency ablation of varicose veins: best practice techniques and evidence. phlebology 2015;30:9-17. 9. gianesini s, menegatti e, zuolo m. laser-assisted strategy for reflux abolition in a modified chiva approach. veins and lymphatics 2015;4:5246. 10. salles-cunha sx, rajasinghe h, dosick sm, et al. fate of great saphenous vein after radio-frequency ablation: detailed ultrasound imaging. vasc endovascular surg 2004;38:339-44. 11. cavezzi a, mosti g, di paolo s, et al. ultrasound-guided peri-saphenous tumescence infiltration improves the outcome of long catheter foam sclerotherapy of the varicose tributaries. veins and lymphatics 2015;4:4676. 12. ricci s, moro l, incalzi ra. ultrasound assisted great saphenous vein ligation and division: an office procedure. veins and lymphatics 2014;3:4428. 13. morrison n, neuhardt dl, rogers cr, et al. incidence of side effects using carbon dioxide-oxygen foam for chemical ablation of superficial veins of the lower extremity. eur j vasc endovasc surg 2010;40:407-13. 14. stücker m, kobus s, altmeyer p, reich-schupke s. review of published information on foam sclerotherapy. dermatol surg 2010;36:983-92. 15. engelhorn c, engelhorn a, sallescunha s, et al. relationship between diameter and great saphenous vein reflux. j vasc technol 1997;21:167-72. 16. ricci s. comment to: great saphenous vein diameter at the saphenofemoral junction and proximal thigh as parameters of venous disease class, by mendoza e, blättler w, amsler f. eur j vasc endovasc surg 2013;45:76-83. veins and lymphatics bibliolab 2013: 1. available from: http://www.pagepressjournals.org/inde x.php/vl/article/view/bybliolab.2013.1 17. mendoza e, blattler w, amsler f. great saphenous vein diameter at the saphenofemoral junction and proximal thigh as parameters of venous disease class. eur j vasc endovasc surg 2013;45:7683. 18. engelhorn ca, manetti r, baviera mm, et al. progression of reflux patterns in saphenous veins of women with chronic venous valvular insufficiency. 19. engelhorn ca, engelhorn al, cassou mf, et al. patterns of reflux in saphenous veins based on color flow duplex ultrasound scanning. vascular ultrasound today 2003;8. available from: http://www.angiolab.com.br/publicacoes/publication/18_lesson6.html 20. engelhorn c, picheth f, castro n jr., et al. color flow localization of insufficient communicating or perforating veins prior to surgical ligation. j vascular technol 1993;17:251-3. 21. engelhorn c, engelhorn a, casagrande c, salles-cunha sx. sources and drainages of saphenous vein reflux in patients with primary varicose veins. poster, final program of the american venous forum 11th annual meeting of the, dana point, ca, february 18-21, 1999, p. 96. 22. salles-cunha sx, commerota aj, tzilinis a, et al. ultrasound findings after radiofrequency ablation of the great saphenous vein: descriptive analysis. j vasc surg 2004;40:1166-73. no n c om me rci al us e o nly hrev_master veins and lymphatics 2013; volume 2:e7 [veins and lymphatics 2013; 2:e7] [page 19] elastic or inelastic compression? reported evidence from clinical trials mieke flour university hospital leuven, belgium abstract evidence for compression therapy found in literature mainly comes from clinical studies, preferably randomized controlled trials (rcts) and systematic reviews (sr), which are often complemented by research data, expert opinion or by data from technology assessment or regularization documents. differences between materials/methods/intervention in clinical trials can be partly explained by variability in focus, or due to country specific issues. results from rcts and srs, and the interpretation of these results may vary depending on definitions used and the adequacy of data. in the first place, the baseline comparability of study groups depends very much on the accuracy of the diagnosis. secondly, results will very much depend on the intervention used, whether compression is used alone, or whether it is part of a more complex management like decongestive treatment including other physical methods, surgery, or pharmacological treatment. a third consideration relates to the outcome parameters, the methods used to measure them, and the length of follow-up. properties of compression materials have been redefined and standardized, and new insights in the physiological effects of compression treatment have shaken existing myths and dogmas in this field. rcts using out-dated definitions and classifications of materials have led to systematic reviews and recommendations based on the same misunderstanding; it is left to the alert reader to interpret their results with caution. introduction evidence for compression therapy found in literature mainly comes from clinical studies, preferably randomized controlled trials (rcts) and systematic reviews (sr), which are often complemented by research data, expert opinion or by data from technology assessment or regularization documents [european com mittee for standardization (cen), reichsausschuss für lieferbedingungen güteze ichengemeinschaft (ral-gzg), british standards institution (bsi)].1-3 grading and definition of the level of the selected evidence vary between publications, and this is usually described in the introduction of the manuscript. either there will be some objective ranking of the quality/reliability of trials and evidence, or the recommendations combine objective ranking of the evidence with other considerations for practice, like the grade tool introduced by the american college of chest physicians.4 there aren’t too many new relevant good quality rcts each year, so there will not be too much difference between the source documents for systematic reviews, and thus most recommendation documents on compression therapy look very much alike indeed. variability in trials’ setup differences between materials/methods/ intervention in clinical trials can be partly explained by variability in focus, or due to country specific issues. focus may be differently accentuated e.g. depending on authorship and target users groups (nurses, versus medical specialties, versus true multidisciplinary groups including patients’ representatives). also, the scope may vary, depending on whether the intervention is purely conservative (compression treatment, education, etc.) versus that the consensus includes additional recommendations on medical/surgical interventions for etiological management and follow-up of the underlying disease (venous, lymphatic, thrombosis, etc.). of course, the scope will also depend on the specific selected indication or goal setting: the trial or his outcomes may be aiming at getting reimbursement from health care institutions (like those from the haute autorité de santé in france, the dutch institute for healthcare improvement in the netherlands), or aiming at setting educational endpoints, or it is meant for implementation of the uniform application of materials and techniques throughout the country (like in the netherlands, or the 4-layer bandaging in the uk). country specific issues may be the selection of bandages/stocking types according to availability or local preferences (stockings preferred above bandages in france? inelastic bandages preferred in the older guidelines in some european countries). national guidelines/recommendations on compression treatment in specific indications exist in countries like france, the netherlands, uk, ireland, italy, germany, canada, australia, new zealand, belgium, and many others. national and international societies have issued consensus documents or best practice documents regarding compression therapy, and this will most probably influence the choice of intervention by investigators. variability in trial outcomes and recommendations results from rcts and srs, and the interpretation of these results may vary depending on definitions used and the adequacy of data. in the first place, the baseline comparability of study groups depends very much on the accuracy of the diagnosis. in still too many trials and reviews the venous ulcer etiology is based on a normal ankle brachial pressure index in a patient with a leg ulcer clinically compatible with a venous ulcer. not only can the diagnosis (based only on clinical examination) be erroneous, it can underestimate the severity and extent of the problem and any relevant co-morbidity. the accuracy of a venous etiological diagnosis increases with the addition of imaging and invasive testing in chronic venous disorders. the american venous forum recommends duplex scanning as the first diagnostic test to all patients with suspected chronic venous obstruction or valvular incompetence. secondly, results will very much depend on the intervention used, be it compression alone (on top of dressing choice), or complex decongestive treatment including other physical methods [physical therapy, intermittent pneumatic compression (ipc)], or a combination of treatments including surgery, or pharmacological treatment. in the materials and methods paragraph of published trials and studies, description of the type of compression treatment should clearly state specific details, such as: what is the definition and classification correspondence: mieke flour, schoonzichtlaan 43, b-3020 herent, belgium. tel. +32.478.566780. e-mail: mie.flour@skynet.be key words: compression treatment, elastic, inelastic, evidence, clinical trials. conference presentation: part of this paper was presented at the international compression club (icc) meeting on stiffness of compression devices, 2012 may 25, vienna, austria (http://www.icc-compressionclub.com/). conflict of interests: the author reports no potential conflict of interests. received for publication: 14 november 2012. revision received: 2 january 2013. accepted for publication: 21 january 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright m. flour, 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e7 doi:10.4081/vl.2013.e7 no nco mm er cia l u se on ly conference presentation [page 20] [veins and lymphatics 2013; 2:e7] used for compression materials (bandages, stockings), is the applied pressure or stiffness measured in vivo, is compression strength described in (country specific) compression classes or in mmhg, are the bandages and stockings named and described so the reader can agree or not with the label used for compression materials (e.g. definitions like in the bsi, or definitions like inelastic, elastic, short stretch, long stretch, superposition of layers, etc.). a third consideration relates to the outcome parameters, the methods used to measure them, and the length of follow-up. interpretation of the results and the recommendations issued from it, are very much dependent on the above listed issues and insights, which themselves have been the topic of several recent consensus documents.5-7 evidence for the effectiveness of compression therapy a comprehensive review of evidence regarding effectiveness of compression therapy in several venous indications following the clinical, etiology, anatomy, pathophysiology (ceap) classification and scoring system, and in lymphoedema can be found in the consensus document published by the international compression club (icc) in 2008.8 these indications are listed in table 1 and include clinical stages of venous disease, treatment following phlebological interventions, venous thrombosis and lymphoedema. the compression devices used in the trials for these indications include bandages, stockings, ortheses [like circaid™ (san diego, ca, usa), tubular elastic cotton sleeves like tubigrip™ (mölnycke health care, gothenburg, sweden), tubulcus™ (innothera ch s.a. service zentrum europa, saint blaise, switzerland)], and ipc. not all indications have been adequately studied regarding effectiveness of compression treatment, partially due to the fact that measurement outcomes are not always easily defined or assessed, and that they will be dictated by the indication at study. in this table the references get a grade-label for the recommendation (e.g. 1b, 1a), and the insertion of weighted/graded references under a specific column head is deducted from the original classes mentioned on the respective documents. also, the pressure values are rounded to simplified ranges. reason for this is the known discordance between several country specific classifications of pressure range for stockings, and variations in definition of expected pressure under bandages when applied according to the manufacturers’ instructions. this table does not distinguish between elastic or inelastic materials. in most trials, measurement of the delivered pressure was not measured in vivo, neither was the stiffness index. duration of follow-up in rcts is understandably limited, variable, and not always representative for the selected disease progression; thus in some indications the deducted recommendation of duration of treatment are decided by consensus or by expert opinion. an example to illustrate this fact is compression therapy in venous disease c4a, c4b, c5. experimental data exist, but clinical trial data are lacking; class iii medical compression stockings said to deliver 30-40 mmhg have been shown to reduce the area of lipodermatosclerosis (lds) in patients with healed venous ulcers.9 accordingly it is also considered to improve areas of atrophie blanche and to reduce the edema and induration in the leg associated with these conditions. there are experimental data supporting effectiveness of distinct levels of compression regarding different aspects of lds: reduction of edema, eczema, iron deposition, area of lds, inflammation and pain, but no rct’s have been found. clinical trials evaluating compression treatment specifically in lipodermatosclerosis are rare, presumably due to the many possible outcome parameters to choose from, of which validation is not established for the specific indication. progression to ulceration, and prevention of this by the specific compression device is difficult to predict and so it is hard to calculate the power needed to demonstrate effectiveness. table 1. indications for compression treatment. reported efficacy of compression therapy stockings, bandages and intermittent pneumatic compression by randomized controlled trials and meta-analyses in patients with chronic venous disorders (clinical, etiology, anatomy, pathophysiology classification), venous thromboembolism and lymphedema. only strong grades of recommendations are indicated: 1a and 1b. adapted from partsch et al., 2008.8 indications ceap compression stockings bandages ipc compression pressure in mmhg 10-20 mmhg 20-30 mmhg 30-40 mmhg c0s, c1s 1b c1 after sclero 1b c2a,s c2s pregnancy 1b 1b c3 prevention 1b c3 therapy c4b 1b c5 1a c6 1b 1a after procedures 1b 1b vte prevention therapy 1a 1a 1b 1b pts prevention therapy 1a 1b lymphedema therapy 1b 1b ceap, clinical, etiology, anatomy, pathophysiology classification; ipc, intermittent pneumatic compression; vte, venous thromboembolism; pts, post-thrombotic syndrome. no nco mm er cia l u se on ly conference presentation [veins and lymphatics 2013; 2:e7] [page 21] indications define the measured outcomes in clinical trials for compression treatment in venous disease, and unfortunately, there is hardly any objective standard assessment method for most outcome parameters in the clinical classes preceding an ulcer. this is one of the reasons why clinical trials are hard to find in these indications. another explanation is that clinical progression and thus effectiveness of compression is difficult to predict during the relatively short time laps of a trial. in the early stages of venous disease, like c1 and c2, subjective symptoms are not always present, they are not always specific nor diagnostic, and clinical progression is unlikely to be influenced by compression treatment of a trial duration. side-effects of compression may be considered as secondary outcome, but then these would not be correlated to the clinical stage of disease. for venous edema c3, symptoms and signs may be measured although there are many different ways to do this. several trials have demonstrated edema reduction with the use of bandages and stockings, but have not been withheld in the abovementioned publication (table 1).8 as mentioned in table 1, compression treatment has been positively evaluated in c5 for the prevention of ulcer recurrence, as compared to surgery. most clinical trials have been performed on c6, venous ulceration, evaluating wound healing as a primary outcome parameter. this is an objectively measurable outcome, and compression materials or application methods can be compared for effectiveness. prevention of recurrence has been studied as well, as mentioned earlier. disease specific quality of life issues have also been evaluated, in contrast to resolution of skin changes for which no clinical trial could be found. the problem here is that dosimetry and characteristics of the compression therapy are debatable, due to outdated or confusing definitions and classification of bandages or stockings. indeed, new insights in the physiological effects of compression treatment and updated consensus documents invite us to re-interpret older trial data. this fact relates to the intervention itself. another consideration is that methodology of selected clinical trials fulfils historical quality requirements. but expectations and quality criteria become more stringent over the years (the rules of the game change while playing). also, good trial-methods do not necessarily guarantee a correct diagnosis or scoring/grading of the clinical disease at study. this will of course apply to the systematic reviews or guidelines and consensus documents derived from these trials. that fact can be named the inherent tragedy of initiatives like the cochrane database and many other institutions gathering evidence and knowledge: a rct perfectly meeting today’s strict requirements may be outdated and rejected in a later systematic review as soon as new insights change the rules. new insights in compression treatment interpretation of the trial results and the recommendations issued from it, are very much dependent on the above listed issues and insights, which themselves have been the topic of several recent consensus documents.5-7 in this issue several other contributions debate the stiffness or elasticity of compression materials and the measured physiological effects on the treated limb. properties of compression bandages have been updated in a publication reviewing the practical aspects and definitions.6 in that article the acronym place is proposed to summarize the essential aspects that impact on the pressure and stiffness of compression materials. these are the sub-bandage pressure range measured at the gaiter area, the number of layers (and the way they overlap), the several components of the bandage each with its own function (like padding, protection, retention, compression), and the elastic properties or behavior of the assembled bandage. this is why pressure and stiffness must (also) be measured in vivo, on the treated limb. appropriate selection and use of these four properties will define the compression treatment characteristics and effectiveness in the several indications. the term dosimetry of compression pressure has been proposed to describe this. in past clinical trials on compression treatment for venous and lymphatic disease, little is known about dosimetry of the applied compression, for how long and at what level it was or should be applied to yield the described results. the different effects of elastic versus inelastic or short-stretch compression are also little understood without considering the principle of stiffness and the resulting dynamic behavior of the compression device, which is rarely discussed in most selected trials and reviews. rcts using out-dated definitions and classifications of materials have led to systematic reviews and recommendations based on the same misunderstanding; it is left to the alert reader to interpret their results with caution. the pressure-range classifications of bandages and stockings are country specific, and so are the brands and trade names. there is yet no universally accepted standard terminology or classification, application technique or methodology to apply compression treatment. the number of publications is steadily growing with research data, but there is no universal estimation of pressurevalues in vivo (which is dependent of the material used, the care giver, and the patient), and therefore there is no consensus yet on the required pressure, stiffness or compression technique to obtain results in specific indications. the abovementioned considerations may provide part of the explanation for the wide variability in the materials and methods section of the several rcts. sound description of the dosimetry must include components, duration, pressure, layers, elasticity, stiffness, all aspects for which internationally accepted definitions are recently published, but not implemented yet, and thus not used in older trials. there is an impressive choice of compression materials and techniques like bandages, stockings, ortheses, intermittent pneumatic compression devices, and combinations of all these. as for the duration of compression therapy, this may be sustained, with or without changes during the day, or it may change over time, possibly in a cross-over study design. of course, the applied pressure values or compression classes must be explicitly mentioned, referring to the methods for the in vivo assessment of pressure and stiffness. blinding cannot be done for the application, but must be used for outcome assessment. practical problems abound when considering clinical trials on compression treatment for chronic venous leg ulcers: even if investigators do manage to agree between centers on a standardized protocol regarding materials and techniques, there is still a wide variation in the limbs under study, and there are many possible outcome parameters to test, which are not always under control or not always objectively measurable. due to the variability of limb morphology, mobility, underlying (co-) morbidities and ulcer etiology, response to treatment will remain an individual characteristic confounding baseline comparability of studied subjects. nevertheless, as stated in almost all guidelines and systematic reviews, it is probably true to conclude that to heal a venous leg ulcer (c6), management that includes compression is more effective than without compression, that higher pressure (stiffness?) is more effective than low pressure values, and that compression should stay in place as long as possible. it is unclear if this means sustained pressure by elastic systems or pressure peaks under inelastic bandaging systems or stiff stockings. some reviewers also recommend applying the highest pressure tolerated by the patient, although this may negatively influence compliance/adherence to treatment, and secondly, this statement has been refuted by recent trials in secondary lymphedema, which strongly suggest that there is a window of optimal pressure values for achieving edema reduction. the same may be true for ulcer healing, effect on skin changes, inflammation, or subjective symptoms.10 no nco mm er cia l u se on ly conference presentation [page 22] [veins and lymphatics 2013; 2:e7] conclusions in order to compare the effectiveness of compression systems and materials, modern terminology (for which consensus exists) shall be used to describe the materials applied, and objective measurement of the dosimetry (pressure/stiffness/dynamic behavior/duration) is an added value in future trials and systematic reviews. recommendations to guide clinicians and researchers hereby have been reported by consensus working groups.11 the methodological validity and quality of selected previous rcts remains, but we may have to re-interpret the results in the light of new insights which have challenged myths and dogmas10 concerning hemodynamic effects of elastic and inelastic compression treatment, and concerning pressure and stiffness, the characteristics of the final compression system more than those of the individual components used. references 1. european committee for standardization (cen). medical compression hosiery. env 12718:2001 e, august 2001. brussels: european committee for standardization; 2001. available from: www.cenorm.be/ catweb/; www.cen.eu 2. ral-gz 387. deutsches institut für gütesicherung und kennzeichnung medizinische kompressionsstrümpfe ralgz 387. neufassung sept 2000. berlin: beuth-verlag; 2000. updated in: ral gz 387 for compression stockings: gütezeichengemeinschaft medizinische kompressionsstrümpfe; january 2008. available from: http://www.gzg-kompressionsstruempfe.de/ 3. british standards institution. specifi cation for the elastic properties of flat, nonadhesive, extensible fabric bandages. bs 7505:1995. updated: january 2011. available from: http://www.standardscentre.co.uk/bs/bs-7505-1995/?s=1 4. guyatt g, gutterman d, baumann mh, et al. grading strength of recommendations and quality of evidence in clinical guidelines. report from an american college of chest physicians task force. chest 2006;129:174-81. 5. clark m. compression bandages: principles and definitions. in: european wound management association. understanding compression therapy; position document of the european wound management association. frederiksberg: medical educational partnership ltd; 2003. available from: http://www.ewma.org 6. partsch h, clark m, mosti g, et al. classification of compression bandages: practical aspects. dermatol surg 2008; 34:600-9. 7. partsch h, clark m, bassez s, et al. measurements of interface pressure and stiffness. dermatol surg 2006;32:224-33. 8. partsch h, flour m, coleridge smith p, et al. indications for compression therapy in venous and lymphatic disease. consensus based on experimental data and scientific evidence; under the auspices of the iup. int angiol 2008;27:193-219. 9. vandongen yk, stacey mc. graduated compression elastic stockings reduce lipodermatosclerosis and ulcer recurrence. phlebology 2000;15:33-7. 10. flour m, clark m, partsch h, et al. dogmas and controversies in compression therapy: report of an international compression club (icc) meeting, brussels, may 2011. int wound j 2012. [epub ahead of print]. 11. rabe e, partsch h, jünger m, et al. guidelines for clinical studies with compression devices in patients with venous disorders of the lower limb. eur j vasc endovasc surg 2008;35:494-500. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2018; volume 7:7625 [page 64] [veins and lymphatics 2018; 7:7625] activities and effects of a qualification system for elastic compression stocking appliers of the japanese society of phlebology makoto mo department of cardiovascular surgery, yokohama minami kyosai hospital, yokohama, japan abstract the japanese society of phlebology established a qualification system for elastic stocking conductors to promote proper usage of elastic compression stocking (ecs) and bandages for the treatment and prevention of venous disease, and also treatment of lymphatic disease in 2002. one hundred fourteen half day hands-on seminars were held all over japan with assistance of manufactures and distributors of ecs and bandages. the number of attendees, mainly nurses, was more than 11,000(!) and 2384 esc conductors certificates were issued after certain clinical experiences. esc conductors are currently working in the outpatient clinics for treatment of venous and lymphatic edema and on inpatients wards for prevention vte. ecs experts with good knowledge of ecs and diseases increase the compliance of ecs by meticulous consultation of the patients regarding compression therapy. introduction not many medical staff members have sufficient knowledge about compression stockings or bandages. even if they know they do not have enough time to educate and consult patients regarding compression therapy. by increasing the number of medical professionals with knowledge of compression therapy we try to increase patients’ compliance. the educational program of the japanese society of phlebology (jsp) to promote proper usage of elastic compression stockings (ecs) and bandages for treatment and prevention of venous disease, and also treatment of lymphatic disease was established by professor masafumi hirai in 2002. then, a japanese guideline for vte prophylaxis was published in 2004, and revised in 2009. reimbursement for prevention of pulmonary embolism prophylaxis was started in 2004. it is 305 points = approximately 30 euro and is applied only for high-risk vte in-hospital patients who were controlled under ecs, elastic bandages or ipc in accordance with the guideline. perioperative pulmonary thromboembolism in japan decreased to half after 2004, based on the results of perioperative pulmonary thromboembolism research by the japanese society of anesthesiologists (jsa-pte research), mainly after introduction of ecs, elastic bandage or ipc but not of anticoagulants.1 management fee of secondary lymphedema was also reimbursed in 2008. it is up to approximately 300 euro per half year. a esc conductor is qualified after attendance of esc conductor seminar, i.e. half-day hands-on seminars, and documentation of 30 cases of clinical experience reports by jsp. esc conductor seminars are half-day course with 100-300 attendees. eight seminars per year are held all around japan more than 140 times. the jsp published an official textbook for esc conductor seminar which covers venous anatomy, physiology, venous disease, prevention of deep vein thrombosis, pulmonary embolism, lymphedema, and includes theory and practical usage of esc/bandage.2 the lectures are based on the textbook. after the lecture, hands-on seminars of ecs & bandages with video viewing lasts about one and half hours. several methods of application of ecs, elastic bandage and ecs donner are practiced with sub-bandage pressure measurement. seminars are operated under independent financial conditions. class fee; approx. 50-80 euro per attendee and exhibition fee from stocking company: 300-500 euro per company are the main source of income. currently, the number of attendees, mainly nurses, is more than 11000 and the number of qualified ecs conductors exceed 2384 by 2016. about 250 ecs conductors are qualified every year. esc conductors are currently working in the outpatient clinic for treatment of venous and lymphedema and inpatients ward for prevention vte. ecs conductors with good knowledge of ecs and diseases increase the compliance of ecs by meticulous consultation on compression therapy. case reports case of increased compliance of compression therapy by meticulous consultations by ecs conductor. eighty years old female was presented with refractory venous leg ulcer (vlu) due to immobilization and knee/ hip arthroplasty (figure 1). no dvt or varicose vein was detected. it was difficult for her to reach her leg because she could not bend over. leg elevation was instructed. compression therapy with pressure guide medium stretch bandage (30 mmhg) was started. compression bandage was changed to pressure guide low stretch bandage (45 mmhg) because of no heeling of vlu. she started to complain of itching and finally rejected compression therapy. vlu worsened after three months (figure 1). ecs conductor (outpatient nurse) consulted her meticulously and found the reason of poor compliance of compression therapy and poor hygiene. she was living alone and depressed. a visiting nurse was introduced and her son living abroad was informed about his mother’s condition. compression therapy was restarted with pressure guided cotton stretch bandage (30 mmhg) and the pressure was increased up to 45 mmhg. compliance was kept well with help of visiting nurses and encouragement of her son. vlu was healed five months after presentation and she was kept on ecs (20 mmhg) without recurrence (figure 1). conclusions ecs conductors with good knowledge of ecs and bandages and diseases help to increase the compliance regarding compression therapy by meticulous consultation. correspondence: makoto mo, department of cardiovascular surgery, yokohama minami kyosai hospital, 1-21-1 mutsuura higashi kanazawa-ku, yokohama 236-0037 japan. tel.: 81.45.782.2101. e-mail: mou-ths@umin.ac.jp conference presentation: international compression club (icc) meeting, paris, 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright m. mo, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7625 doi:10.4081/vl.2018.7625 conference presentation [veins and lymphatics 2018; 7:7625] [page 65] references 1. kuroiwa m, morimatsu h, tsuzaki k, et al. changes in the incidence, case fatality rate, and characteristics of symptomatic perioperative pulmonary thromboembolism in japan: results of the 2002-2011 japanese society of anesthesiologists perioperative pulmonary thromboembolism (jsapte) study. j anesth 2015;29:433-41. 2. iwai t, hirai m ed. elastic stocking conductor. tokyo: health shuppann co.;2010. figure 1. case reports. hrev_master veins and lymphatics 2013; volume 2:e4 [veins and lymphatics 2013; 2:e4] [page 11] terminology: resistance or stiffness for medical compression stockings? andré cornu-thenard, jean-patrick benigni, jean-françois uhl french university group for medical compression, saints peres university, paris, france abstract based on previous experimental work with medical compression stockings it is proposed to restrict the term stiffness to measurements on the human leg and rather to speak about resistance when it comes to characterize the elastic property of compression hosiery in the textile laboratory. introduction pressure and stiffness are the two items which characterize a medical compression stocking (mcs).1-6 the meaning of pressure is easy to understand for a health care professional. the correct meaning of stiffness is less easy to explain, especially since this word can relate to two different concepts. laboratory pressure and interface pressure: definition pressure is defined as a force per unit of surface area, for example newton/m² or cn/cm². for many reasons medical compression manufacturers and doctors prefer using mmhg.7,8 two different pressures should be differentiated: laboratory and in vivo pressures the laboratory (lab) pressure is determined by manufacturers using a dynamometer, a special device made only for these measurements (figures 1 and 2).8 several brands of dynamometers exist and all give measurements in cn/cm² (force/cm²) easily transformed in mmhg.8,9 the stocking to be measured is placed on a model leg so as to locate and mark the different points along the leg (b, c, d, etc.). the b point (ankle region of the stocking) is marked first and then the b-segment is placed in the dynamometer jaws. force is measured during stretch and also in the relaxed phase. results are printed on a rolling chart. hysteresis curves obtained: on the x-axis the circumference of the mcs is plotted in centimeter (which simulates the leg’s perimeter) and on the y-axis the corresponding pressure in mmhg (figure 3). therefore it is easy to identify the mcs pressure depending on its size. this permits to declare the lab pressure in mmhg (or the compression class) on the box of the garment. the pressure on the human leg is measured in clinical studies (or due to personal interest) by using special pressure probes as kikuhïme (tt meditrade, sore, denmark) or picopress® [(microlab elettronica sas, roncaglia di ponte san nicolò (pd), italy]. the sensor is placed on the b1 point where the medial gastrocnemius muscle turns into its tendinous part and the mcs is applied.10 the pressure measured on the leg in mmhg is called the interface pressure.1-5 this method allows the pressure measurement at several levels along a leg. resistance and stiffness: definition in the european prestandard for medical compression hosiery stiffness is defined as the increase in compression per centimeter increase in the circumference of the leg.6 two different types of stiffness exist: the stiffness on the human leg following the above definition and the corresponding parameter derived from the hysteresis curve. in fact the same word is used in two situations: for the lab measurement of stiffness used by the manufacturers and the stiffness measurements on human legs made by investigators in the course of their assessment of the quality of mcs. such a distinction should be made by presenters and authors when discussing this topic. therefore in an oral presentation or publication there may be some confusion: do the author mean lab or in vivo stiffness? proposition pressure is measured in two different situations: in lab and in vivo. the same two situations exist for the measurement of stiffness. the word used by industry to characterize the hardness or rigidity of numerous materials, for example in physics or aeronautics, is the word resistance. the authors and some international compression club (icc) members propose that this word should be used in our medical compression vocabulary which means inelasticity.11 perhaps words similar to resistance or resistance coefficient could be used such as hardness, rigidity, firmness, inelasticity and others. correspondence: andré cornu-thenard, french university group for medical compression, saints peres university, 45 rue des saints pères 75005 paris, france. e-mail: andre.cornuthenard@wanadoo.fr key words: resistance, stiffness, compression stockings. conference presentation: part of this paper was presented at the international compression club (icc) meeting on stiffness of compression devices, 2012 may 25, vienna, austria (http://www.icc-compressionclub.com/). contributions: ac-t, manuscript writing; j-pb, jf, ideas and experience providing. received for publication: 2 november 2012. revision received: 18 february 2013. accepted for publication: 18 february 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright a. cornu-thenard et al., 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e4 doi:10.4081/vl.2013.e4 figure 1. the ifth dynamometer (paris, france). no nco mm er cia l u se on ly conference presentation [page 12] [veins and lymphatics 2013; 2:e4] definition and measurement the resistance (laboratory measurement) the authors suggest the definition of resistance in medical compression as the stiffness measurement performed by a dynamometer. the value should be declared on the packaging for individual compression garments. at present this value is not shown, perhaps to avoid confusion or questions from interested users. the resistance coefficient (rc) number will reflect the hysteresis curve at the mcs size point. in the curve shown in figure 3 the rc is +/-1 mmhg/cm. this means that this mcs is more rigid, firm or resistant than a 0.5 mmhg/cm and less resistant than a 2 mmhg/cm. the stiffness (measurement on the leg) at the b1 point two measurements of the interface pressure are done during two successive different positions of the leg, at rest and during a significant muscle contraction (e.g. dorsiflexion, standing). this will create two different but similar circumferences, one maximum the other minimum. the difference between the two values characterizes the stiffness of the mcs.1,11 the properties of any mcs can therefore be more completely described using the following measurements: the pressure and the rc measured in the lab, and interface pressure and stiffness measured on the leg. arguments to differentiate resistance of a medical compression stocking and its stiffness in summary arguments to differentiate resistance of a mcs and its stiffness are: i) the two measured points are different: b point for resistance and b1 point for stiffness; ii) the two values cannot be compared (for the moment): the resistance results are obtained in mmhg/cm corresponding to the steepness of hysteresis curves using a dynamometer; for stiffness only pressure increase is measured as a routine but not the change of leg circumference. to consider these parameters could yield much useful information: i) mcs characteristics should be completed and recorded on the box; ii) this would allow a useful comparison between different brands of mcs. conclusions to avoid confusions it could be extremely useful if icc members, companies and doctors agree with this proposed terminology: resistance instead of stiffness measured in lab and stiffness measured on the leg. references 1. partsch h, clark m, bassez s, et al. measurement of lower leg compression in vivo. recommendations for the performance of measurements of interface pressure and stiffness. a consensus statement. j dermatol surg 2006;32:224-33. 2. rabe e, partsch h, jünger m, et al. guidelines for clinical studies with compression devices in patients with venous disorders. eur j vasc endovasc surg 2008;35:494-500. 3. partsch h, flour m, coleridge smith p, et al. indications for compression therapy in venous and lymphatic disease a consensus. int angiol 2008;27:193-219. 4. khaburi ja, nelson ea, hutchinson j, dehghani-sanji aa. impact of variation in limb shape on sub-bandage interface pressure. phlebology 2011;26:20-8. 5. hirai m, niimi k, iwata h, et al. comparaison of stiffness and interface pressure during rest and exrecice among various arms sleeves. phlebology 2010;25:196-200. 6. european committee for standardization (cen). non active medical devices. working group 2 env 12718: european pre-standard ‘medical compression hosiery.’ cen tc 205. brussels: cen; 2001. 7. cornu-thenard a. measuring units for elastic stockings: priority to mmhg rather than classes. phlébologie 1992;45: 457-8. 8. partsch h. evidence based compression-therapy. an initiative of the international union of phlebology (iup). vasa 2004;34:3-37. 9. stolk r. quick pressure determining device for medical stockings. swiss med 1988;10:916. 10. stout n, partsch h, szolnoky g, et al. chronic edema of the lower extremities: international consensus recommendations for compression therapy clinical research trials. int angiol 2012;31:316-29. 11. cornu-thenard a. reduction of a venous edema by elastic stockings, unique or superimposed. resistance coefficient notion. phlébologie 1985;38:159-68. [abstract in english]. figure 3. hysteresis curve of a 25 mmhg medical compression stocking (mcs) with a 2324 cm size. the resistance coefficient equals the tangent at the mcs size point. on this hysteresis curve the pressure increases in 1 mmhg between 23 and 24 cm. so the resistance coefficient equals 1 mmhg on 1 cm, equals 1. figure 2. the hosy dynamometer (germany). no nco mm er cia l u se on ly hrev_master veins and lymphatics 2014; volume 3:4195 [page 74] [veins and lymphatics 2014; 3:4195] how to objectively assess jugular primary venous obstruction paolo zamboni department of morphology, surgery, and experimental medicine; vascular diseases center and section of translational medicine and surgery, university of ferrara, italy abstract last january the lancet published the article by traboulsee et al. prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their sibilings, and unrelated healthy controls: a blinded, case control study. these authors confirmed the presence of chronic cerebrospinal venous insufficiency with a high prevalence of about 70% in the canadian population, but without significant differences between patients and healthy controls, yet. however, they used a criterion never published to assess stenosis, in alternative to the classic measurement of the diameter in the segment immediately preceding the narrowest point. traboulsee et al. measure the stenosis along the entire length of the internal jugular vein, by comparing the maximum diameter with the narrowest point. it has been demonstrated, from normal anatomy findings, how the jugular bulb diameter normally exceeds 50% of the minimum diameter of the internal jugular vein, clearly showing the reason why traboulsee et al. did not find significant differences between people with multiple sclerosis, their sibilings, and unrelated healthy controls. furthermore, as the outcome measure of traboulsee et al., wall stenosis is a neglected part of primary venous obstruction, because in the majority of cases obstruction is the consequence of intraluminal obstacles, as a considerable part of truncular venous malformations, and/or compression; rarely of external hypoplasia. finally, several recently published methods can be adopted for objective assessment of restricted jugular flow in course of chronic cerebrospinal venous insufficiency, by the means of non invasive magnetic resonance imaging, ultrasound and plethysmography. this may help us in improving the assessment of cerebral venous return in the near future. introduction the lancet published online in october 2013 the article prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their sibilings, and unrelated healthy controls: a blinded, case control study, by traboulsee et al.1 in that particular circumstance, i felt constrained to reply to traboulsee and colleagues, because the article repeatedly cites me personally, making comparison with the data published by my group. in the name of a transparent scientific debate, i prayed the editor to publish my comment letter to the article, last october 16, 2013. the article of traboulsee et al. was subsequently published last january,1 and approximately 2 weeks later the senior editor of the lancet communicated me to refuse my reply letter. i am still surprised of the editorial decision either because does not permit me to reply despite the article cites me personally, or correspondence: paolo zamboni, vascular diseases center, university of ferrara, ao s. anna, via aldo moro 8, 44124 loc. cona, ferrara, italy. e-mail: paolozamboni@icloud.com key words: jugular primary venous obstruction, editorial. received for publication: 27 may 2014. revision received: 10 november 2014. accepted for publication: 10 november 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright p. zamboni, 2014 licensee pagepress, italy veins and lymphatics 2014; 3:4195 doi:10.4081/vl.2014.4195 figure 1. a) healthy subject catheter venography of the left internal jugular vein (ijv), showing how in normal condition, the jugular bulb exhibits a diameter more than double respect the junction (courtesy of r. galeotti, md); b) autoptic study showing the dilation of the jugular bulb respect to the other segment of the ijv. the table illustrates the average diameter variation measured in an autoptic study modified from furukawa et al., 20109). no n c om me rci al us e o nly editorial [veins and lymphatics 2014; 3:4195] [page 75] because the traboulsee paper presents various scientific inaccuracies that need to be clarified for the benefit of the scientific community. the editor simply stated that asked to the authors to reply me directly. however, eleven months later i did not receive any reply from the authors. on the other hand, on the bases of the lancet article, two comments have been published,2,3 aimed to close rapidly the curtain on the chronic cerebrospinal venous insufficiency hypothesis, despite 13 out of 19 prevalence studies and 3 meta-analysis papers testifies confirming data.4 the concept of primary venous obstruction truncular venous malformations (tvms) are the result of vascular trunk developmental defects occurring during the embryogenesis later stage. when tvms cause a primary venous obstruction, the latter can be subdivided in intraluminal obstacles (septa, webs, fixed and rudimental valves) or in wall stenosis (hypoplasia, agenesis).5 for instance, among tvms, may-thurner syndrome is the consequence of a combination of luminal defect with external compression, whereas primary budd-chiari is characterized by membranous obstruction.6-8 whenever tvms are localized in the internal jugular (ijv) and azygous vein (azy), a condition known as chronic cerebro-spinal venous insufficiency (ccsvi) follows.1,4,5 quite recently, by the means of catheter venography, in a well designed study, traboulsee et al. confirmed the elevated prevalence of venous narrowings in patients with multiple sclerosis. but at the same time, the authors identified this anomaly also in the control population in the same proportion.1 to us, this is not surprising because they measured the stenosis by means of a novel criterion that is not quoted into the reference list. they assessed a greater than 50% wall stenosis by comparing the widest diameter of the vein with the narrowest one, along the entire vessel length, at any point. ijv caliber variations have been described by anatomical studies since a long time, together with the presence of a superior and inferior bulb of the same vein. autopsy evaluations on natural death cases have already demonstrated how the ijv diameter can range from a minimum of 1 cm to a maximum of 2 cm (thus a variability that is greater than 50%) on the right and from 0.4 cm to 1.8 cm (once again greater than 50%) on the left side.9 this is well apparent in figure 1.9 the region of the bulb is a dilation area of the ijv, naturally presents in the human beings. even normal ijv show significant caliber variation, by comparing the bulb with for example j3 or j1 segments. furthermore, figure 2 highlights the coronal diameter in the widest and narrowest tracts, showing how variations bigger than 50% can equally occur both in the physiological (figure 2a) and in the pathological (figure 2b) conditions. thus, by means of the adopted criterion of measuring stenosis >50%, traboulsee et al. confirmed the data of the anatomical ijv caliber variability, rather than providing an assessment to discriminate among healthy and pathological cases. this suggests the possible bias coming out whenever considering the ijv narrowing respect to the maximum diameter along the entire vein trunk the only investigation endpoint. for instance, in our seminal paper, we considered primary venous obstructions from luminal obstacles, as depicted in figure 2b, as stenosis ≥50%, of course.10 anyway, as above stated, primary venous obstruction is something else than just a narrowing of the wall. in the vast majority of ccsvi patients, the venous drainage impairment comes as a consequence of intraluminal obstacles (figure 2b).5,10-12 ccsvi latest investigations demonstrate luminal obstacles in 85% of azy, 50% of right ijv, and 83.3% of left ijv by means of intravascular ultrasound. interestingly, in the same population, catheter venography assessed stenosis of ≥50% just in 50% of azy, 55% of right ijv, and 72% of left ijv.13 external compression is also possible in ccsvi, either isolated or in combination, and easy to demonstrate by the means of ultrasound, but never detected by traboulsee et al, yet.14,15 in our papers, measuring the stenosis by comparing the narrowest tract with the diameter of the immediately preceding segment, as well as a careful evaluation of intraluminal obstacles and compressions, contributed to a better discrimination of ccsvi cases from controls. figure 2. healthy subject (hs) catheter venography (cv) of the left internal jugular vein (ijv). a) the particular shape and caliber variability is well apparent in normal condition. b) chronic cerebro-spinal venous insufficiency (ccsvi) patient cv of the ijv demonstrating complete obstruction of the lumen by a septum (without any narrowing) (black arrows) that leads to a collateral circle activation to by-pass the obstacle (white arrows). in a) and b) the shorter double tip arrow indicates the narrowest tract, the longer one highlights the vein segment presenting a coronal diameter twice as long as the shorter one. ant, anonymous trunk; s, septum; cc, collateral circulation (courtesy of r. galeotti, md). no n c om me rci al us e o nly editorial [page 76] [veins and lymphatics 2014; 3:4195] perspectives the paper of traboulsee testifies the lack of standards to objectively measure the restricted brain outflow characterizing ccsvi. a multimodal diagnosis has been recently proposed in a position statement of the international society for neurovascular disease (isnvd), indicating a group of invasive and non invasive tests giving comprehensive and complementary information leading to a final ccsvi diagnosis.16 the multimodality diagnostic system includes ultrasound, magnetic resonance (mr) venography, catheter venography, and intravascular ultrasound. it is likely the most accurate, but too expensive solution. for the reasons above, an inexpensive and non invasive screening method is highly desirable. from this point of view cervical plethysmography, thoughthe accuracy might be further improved, seems a promising first level approach.17 second level examination might rely upon non invasive and objective parameters derived from ultrasound and/or mr imaging. indeed, new methods objectively assessing cerebral venous outflow by these methodologies have recently been developed.18-21 finally, we need of an accurate third level of investigation. we may agree that the final decision about the surgical approach should be founded on more objective evaluation through catheter venography. quite recently veroux et al. overcome the difficulty linked with the lack of knowledge about rate of stenosis and normality of venograms. they introduced the concept of the clearance time of the contrast dye when injected in the veins by a standardized and reproducible protocol. these authors calculated in a group of healthy controls that a standardized injection of contrast dye is eliminated in less than 2 s through the ijv. the authors measured the clearance time also in a huge group of ccsvi patients, found a significantly increased time of elimination in about 80% of the examined ijvs. i hope that this methodology, highly objective and reproducible, could be rapidly spread and adopted for endovascular procedures on the ijvs.22 despite the traboulsee’ paper, all the above recent references as well as the isnvd position paper testify that the scientific debate is alive and continues. it’s a regret that the group of traboulsee did not find these arguments interesting and at least worthy of a personal response. references 1. traboulsee al, knox kb, machan l, et al. prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their sibilings, and unrelated healthy controls: a blinded, case control study. lancet 2014;383:138-45. 2. paul f, wattjes mp. chronic cerebrospinal venous insufficiency in multiple sclerosis: the final curtain. lancet 2014;383:106-8. 3. barkhof f, wattjes mp. multiple sclerosis: ccsvi deconstructed and discarded. nat rev neurol 2013;9:661-2. 4. paolo zamboni. meta-analysis vs opinions. veins and lymphatics 2013; available from: http://www.pagepressjournals. org/index.php/vl/article/view/cerebvenret urn.2013.2/1369 5. lee bb, baumgartner i, berlien p, et al. diagnosis and treatment of venous malformations consensus document of the international union of phlebology (iup): updated 2013. int angiol 2014. [epub ahead of print] 6. okuda k. membranous obstruction of the inferior vena cava (obliterative hepatocavopathy). j gastroenterol hepatol 2001;16:1179-83. 7. may r, thurner j. the cause of the predominantly sinistral occurrence of thrombosis of the pelvic veins. angiology 1957;8:419-27. 8. raju s, neglen p. high prevalence of nonthrombotic iliac vein lesions in chronic venous disease: a permissive role in pathogenicity. j vasc surg 2006;44:136-43. 9. furukawa s, nakagawa t, sakaguchi i, nishi k. the diameter of the internal jugular vein studied by autopsy. rom j leg med 2010:2;125-8. 10. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:392-9. 11. zamboni p. regarding “no cerebrocervical venous congestion in patients with multiple sclerosis. intraluminal jugular septation”. ann neurol. 2010;68:969. 12. zivadinov r, ramanathan m, dolic k, et al. chronic cerebrospinal venous insufficiency in multiple sclerosis: diagnostic, pathogenetic, clinical and treatment perspectives. expert rev neurother 2011;11:1277-94. 13. karmon y, zivadinov r, weinstockguttman b, et al. comparison of intravascular ultrasound with conventional venography for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency. j vasc interv radiol 2013;24:1487-98. 14. gianesini s, menegatti e, mascoli f, et al. the omohyoid muscle entrapment of the internal jugular vein. a still unclear pathogenetic mechanism. phlebology 2014;29: 632-5. 15. radak dj, tanaskovic s, antonic z, et al. compressive syndrome of internal jugular veins in multiple sclerosis: does it matter? phlebology 2014;29:98-104. 16. zivadinov r, bastianello s, dake md, et al. recommendations for multimodal noninvasive and invasive screening for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency: a position statement of the international society for neurovascular disease. j vasc interv radiol 201425:178594. 17. beggs c, shepherd s, zamboni p. cerebral venous outflow resistance and interpretation of cervical plethysmography data with respect to the diagnosis of chronic cerebrospinal venous insufficiency. phlebology 2014;29:191-9. 18. mancini m, lanzillo r, liuzzi r, et al. internal jugular vein blood flow in multiple sclerosis patients and matched controls. plos one 2014;9:e92730. 19. monti l, menci e, piu p, et al. sonographic quantitative cutoff value of cerebral venous outflow in neurologic diseases: a blinded study of 115 subjects. ajnr 2014. [epub ahead of print] 20. utriainen d, trifan g, sethi s, et al. magnetic resonance imaging signatures of vascular pathology in multiple sclerosis. neurol res 2012;34:780-92. 21. sethi sk, utriainen dt, daugherty am, et al. jugular venous flow abnormalities in multiple sclerosis patients compared to normal controls. j neuroimaging 2014. [epub ahead of print] 22. veroux p, giaquinta a, perricone d, et al. internal jugular veins out flow in patients with multiple sclerosis:a catheter venography study. j vasc interv radiol 2013;24: 1790-7. no n c om me rci al us e o nly 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2014; volume 3:4050 [page 64] [veins and lymphatics 2014; 3:4050] marginal vein is not a varicose vein; it is a venous malformation byung-boong lee center for the lymphedema and vascular malformations, george washington university, washington dc; uniformed services university of the health sciences, bethesda, md, usa abstract marginal vein (mv) is one form of venous malformation (vm); mv is not a varicose vein. mv is the outcome of defective development during the later stage of embryogenesis while the vein trunk is formed. it is an embryonic vein tissue remnant remaining on birth following the failure of normal involutional process. mv is the most common vm involved to klippel-trenaunay syndrome (kts); together with the lymphatic malformation, mv is one of two clinically most important congenital vascular malformation components among kts. mv causes chronic venous insufficiency (cvi) due to a unique condition of avalvulosis (lack of venous valve development) it accompanies with. besides, it accompanies a high risk of venous thromboembolism (vte) due to its structural defect with a lack of smooth muscle cell to form the media properly as a truncular vm infrequently causing fatal pulmonary embolism. therefore, the mv is indicated for the surgical excision whenever feasible not only for the prevention of vte and cvi but also for abnormal long bone growth known as vascular bone syndrome as well as lymphatic complication precipitated by mv. introduction marginal vein (mv)1-4 is often mistakenly considered as a varicose vein since most of mv locates very superficially beneath the skin with a minimum soft tissue coverage although it runs on the lateral aspect of the lower extremity, which is odd/unusual location for common varicose veins. mv is not a matured vein like varicose veins (of superficial vein system); vein; it is an embryonic vein remnant following the failure of normal involutional process through the maturation period of vein trunk formation and remains after the birth. although mv looks like ordinary varicose vein of saphenous/superficial vein especially when it is located in superficially, mv is a lot more clinically serious not only to cause severe chronic venous insufficiency (cvi) but also constant source of intravascular coagulation resulting in venous thrombo-embolism (vte) (figure 1). mv is one of venous malformations (vms);5-8 vm is a common form of congenital vascular malformations (cvms)9-12 and the mv is one form of truncular vms as the outcome of defective development during the later stage of embryogenesis while the vascular/venous trunk is formed. the extent and severity of the mv are variable depending upon the degree of defective development along the last/truncular stage of embryogenesis while forming the vein trunk so that all the mvs present in different lengths as well as different locations; they are also named differently from lateral embryonic vein to sciatic vein.3,13-15 however, all these laterally located embryonic veins have same defective condition of the vein wall with insufficient smooth muscle layers development (cf. varicose vein). besides, as a part of defective development of the venous wall, they accompany a unique condition of the lack of normal venous valves development known as avalvulosis. the mv has a unique clinical significance as the most common form of vm involved to klippel-trenaunay syndrome (kts).16-19 kts is a well known name-based eponym representing a clinical condition of various congenital anomalies affecting not only the vascular system but also the soft tissue as well as the skeletal system. the mv/lateral embryonic vein as a truncular vm lesion1-4,20,21 is potentially most dangerous cvm lesion among various vascular malformation components involved to the kts; together with less common extratruncular vm, mv as a truncular vm belongs to the cvm components of kts. together with this vm group,22-25 the lymphatic malformation (lm) group26-29 affects the clinical condition of the kts as second most serious cvm components, directly and indirectly in various degrees together with capillary malformation (cm);30,31 lm presents in the majority as a truncular lesion known as primary lymphedema and/or extratruncular lesion known as lymphangioma among kts. these two, vm and lm, combined form of cvms are classified as hemolymphatic malformation (hlm) by modified hamburg classification in view of inseparable impact on overall hemodynamic status32-35 (tables 1 and 2). nevertheless, such complicated condition of the mv, often combined with other cvms (e.g. deep vein aplasia/hypoplasia) has been often neglected as a relatively benign condition although the chronic venous hypertension generated by the unique condition of avalvulosis lack of venous valve will give a profound impact on the cvi. lately, mv was found to generate much more serious condition to cause the vte. when this mv is combined with a unique condition of coagulopathy, which is common among the extratruncular vm lesions, it infrequently becomes a source of serious, even fatal, pulmonary embolism (pe) as well.36-39 therefore, proper understanding on the mv is warranted for all the phlebologists who will have more chance to encounter such unique condition mimicking innocuous varicose veins than other clinical specialists. definition the mv is one of the vms, and vm is one of the cvms affecting the venous system alone.9-12 cvm represents a whole group of birth defects caused by the developmental arrest during the embryogenesis to form the vascular system: artery, vein, and lymphatics. depending upon the embryological stage when the defective development occurs, its clinical behavior is affected profoundly by unique embryological characteristics originated from the mesenchymal cells/angioblasts.40-43 therefore, all these inborn vascular defects exist already at birth and the embryonic tissue remnant originated from the defective development in its early stage continues to grow at a rate that is proportional to the growth rate of the body (cf. hemangioma); this unique group originated from the early stage is further defined/sub-classified to the extratruncular type to differentiate from truncular type which represents other group of defective development originated from the late stage. the extratruncular lesions remain as a cluster of malformed vessels since defective development correspondence: byung-boong (b.b.) lee, center for vein, lymphatics and vascular malformation, george washington university school of medicine, washington, dc, usa. division of vascular surgery, department of surgery, george washington university medical center, 22nd and i street, nw, 6th floor, washington, dc 20037 usa. e-mail: bblee38@comcast.net key words: marginal vein, venous malformation, lymphatic malformation, klippel-trenaunay syndrome, venous thromboembolism, vascular bone syndrome. received for publication: 12 may 2014. revision received: 4 july 2014. accepted for publication: 7 july 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright b.-b. lee, 2014 licensee pagepress, italy veins and lymphatics 2014; 3:4050 doi:10.4081/vl.2014.4050 no n c om me rci al us e o nly review [veins and lymphatics 2014; 3:4050] [page 65] occurred while the vascular structure is still in primitive reticular network. this cvm group is classified together with the vascular tumor group under the category of the vascular anomaly; the most of vascular tumor is represented by (neonatal or infantile) hemangioma.44-47 cvm and vascular tumor/ hemangioma represent entire anomalous vascular structures together but both groups are totally different not only its etio-pathogenesis but also its clinical behavior.48 the hamburg classification32-35 has a unique value to provide not only different embryological characteristics of the cvms from different embryonic stages but also its anatomical, histological, patho-physiological, and hemodynamic status for accurate diagnosis to improve its clinical management. the hamburg classification defined the cvms to six groups based on the vascular systems involved: arterial,49,50 venous,51-54 arteriovenous (avm),55-58 lm,59-62 capillary,30,31 and combined vascular malformations.63-65 when lm66-68 is mixed/co-exists with vm or avm69-71 as a combined form of the cvm, they were named to hlm21,65,72 (table 1). based on hamburg classification, each cvm is further sub-classified to two different groups in order to verify unique embryological characteristics certain cvm groups possess: extratruncular and truncular lesions based on the embryological stage when developmental arrest has occurred32-35 (table 2). the extratruncular lesions represent the defective development occurred in the earlier stage of embryonic life retaining the mesenchymal cells (angioblasts) characteristics of mesodermal origin. therefore, they possess evolutional potential to grow when stimulated internally (e.g. menarche, pregnancy, and hormone) or externally (e.g. trauma, surgery).40-43 on contrary, the truncular lesions no longer possess this embryonic characteristics of the mesenchymal cells since they represent the defective development during the later stage of the embryonic development during the vascular trunk formation period.40-43 however, truncular lesions cause more serious hemodynamic consequences related to the type of cvm (e.g. marginal veins) despite minimal risk of recurrence therefore, an extreme variety of the clinical behavior of the cvm lesions is heavily influenced by unique embryological characteristics of different stages of embryogenesis. accordingly, cvm lesions are known as an enigma of modern medicine with a wide range of clinical presentations, unpredictable clinical course, and erratic response to treatment with the potential for high rates of recurrence.73-76 extratruncular vm lesions never involve the main trunk of formed vein itself but remain as an independent lesion from the named/matured vein since they are pre-truncal embryonic lesions occurred before the main vascular trunks are formed. therefore, they represent clinically either as diffuse, infiltrating lesions or localized, limited lesions. but the majority of truncular lesions are directly involved to the vein trunks since the defective development occurs along the late stage while the vascular trunk is formed as post-truncal fetal lesions. therefore, they present as a deformed vein with various degrees of developmental defect (e.g. agenesis/rudimentary deep vein), often as incomplete or immature development (aplasia or hypoplasia) directly affecting the main axial veins. therefore, the truncular lesions no longer possess the evolutional potential with the risk of table 1. hamburg classification of congenital vascular malformations. malformations types according to hamburg classification* predominantly arterial defects predominantly venous defects predominantly arteriovenous shunting defects predominantly lymphatic defects combined vascular defects *based on the consensus on congenital vascular malformation through the international workshop in hamburg, germany, 1988, and subsequently modified. capillary malformation was not included. table 2. hamburg classification of congenital vascular malformations: forms and embryological subtypes. extratruncular forms* infiltrating, diffuse limited, localized truncular forms* aplasia or obstruction hypoplasia; aplasia; hyperplasia stenosis; membrane; congenital spur dilatation localized (aneurysm) diffuse (ectasia) *congenital vascular malformation represents developmental arrest at the different stages of embryonic life: earlier stage extratruncular form; later stage truncular form. both forms may exist together; may be combined with other various malformations (e.g. capillary, arterial, arteriovenous shunting, venous, hemolymphatic and/or lymphatic); and/or may exist with hemangioma. figure 1. a) clinical condition of the marginal/lateral embryonic vein along the lateral aspect of the left lower extremity. this unique vein structure is a persistent foetal remnant vessel following the failure of normal involution/regression; b) angiographic finding of this marginal vein, which remains only major venous drainage route for this patient with a lack of normal development of deep venous system. therefore, surgical excision to control the venous hypertension is contraindicated. from: lee, 2012.3 a b no n c om me rci al us e o nly review [page 66] [veins and lymphatics 2014; 3:4050] recurrence but have varying degrees of hemodynamic consequences due to defective vein trunk either as obstructive77-80 or dilated81-84 lesion often affecting named vein trunk (e.g. femoral, popliteal, iliac veins). in addition to such defective vessel condition presented either as an obstruction (e.g. vein web, spur, annulus, or septum)85-88 or dilatation (e.g. popliteal or iliac vein ectasia/aneurysm)89-92 to cause flow disturbance, another form of hypoplasia causes venous reflux with the absence of valves known as avalvulia/avalvulosis. this unique condition is a hallmark of the mv. together with atresia of the lumen of venous trunks and venous aneurysms, avalvulosis is relatively common vm lesion.93 mv itself is a different form of truncular vm lesion as the outcome of defective maturation; it is an embryonic truncal vein remnant, which failed to undergo normal involutional process and persists/remains as the mv or the sciatic vein.1-4 maturation and development of the main venous system in the primitive lower limb goes through three different stages: the first phase to form lateral peroneal/fibular vein draining into the cardinal vein; second phase to progress to form sciatic vein as a main vessel while medial draining vessel develop; and third/last phase to complete the evolutional process, in which the early lateral veins regresses.3,14 failure of regression of the lateral peroneal vein will result in the existence of the mv at birth. the mv occurs in varying extent and severity (e.g. limited sciatic vein), and they are grouped together as lateral embryonic vein. extension of the mv therefore, may be variable depending upon the limb development stage involved; in mild case it is limited within calf level before it is connected/drained into the proximal deep venous system but its entirety might remain with an extension to the thigh and even to the buttock draining into internal iliac vein. the mv persistence might have a close relationship with a failure of normal development of the deep venous system; more than one third of patients with the mv are known to have a defective deep venous system (e.g. hypoplasia of femoral vein, aplasia of iliac vein). in such case, mv remains as the main draining vein of the limb although it may exist together with normal deep veins. therefore, precise evaluation of the deep venous system is mandated for the assessment of the mv. but in general, mv has a numerous connection with the perforators, sometimes huge in caliber and fragile in consistence to make its management risky. mild/micro av fistula has been described in cases of extensive aplasia of deep veins.78,94,95 valveless condition of mv as an embryonic vein causes a severe reflux resulting in chronic venous hypertension/stasis accompanying various degree of cvi. besides, a defective vessel wall that is deficient in smooth muscle also carries a high risk of thrombo-embolic events and infrequently leads to fatal pe, especially among kts patients.36-39 clinical assessment correct assessment of mv together with the deep venous system is crucial for the treatment planning. clinical examination is often easy to demonstrate the mv. however, collaterals or even the mv itself may not be easy to remain visible by increased subcutaneous fat or combined with extratruncular lm in which thickening of subcutis by lymphatic abnormal tissue may hide the vein.4,93 but in general, the mv can be easily confirmed through the physical examination as an abnormal superficial draining vein of the lower limb which is sited on the lateral edge of the extremity frequently running beneath the coexisting cm known as a port wine stain.1-4 unless it is located within thick subcutaneous fat along the swollen limb, the majority is quite visible as a protruding vein along the lateral aspect of the extremity invariably detected by a light palpation. laboratory evaluation for the diagnosis of the mv is sufficient only with nonto lessinvasive tests based on the duplex ultrasonography (dus), magnetic resonance imaging, and/or computerized tomography. dus is the test of choice to assess the hemodynamic status of the mv and the deep vein system simultaneously (e.g. extent and severity of the reflux and outflow resistance). the deep vein system should be assessed both in lying and standing position to differentiate among normal, aplastic and hypoplastic venous segments. dus is also excellent for the mapping of the mv course to delineate entire length of mv, located supraand sub-fascially, and site and size of perforators besides the extension of reflux.8,22 further evaluation with invasive tests (e.g. direct puncture phlebography together with ascending phlebography) can be deferred till needed as a road map for the surgical intervention8,22,93 (figure 2). figure 2. a) clinical appearance of venous malformation (vm) lesion affecting the right lower extremity as a hemolymphatic malformation, mixed with lymphatic malformation and capillary malformation, often known as klippel-trenaunay syndrome. b) magnetic resonance imaging finding of extratruncular vm lesion diffusely infiltrating in the soft tissue and muscles of right lower extremity. c) whole body blood pool scintigraphy (wbbps) findings of massive abnormal blood pool throughout entire right lower extremity; this wbbps effectively ruled out any additional lesions throughout the body. d) transarterial lung perfusion scintigraphy (tlps) study that is negative for abnormal arteriovenous shunting 2.9% is within normal range. e) radionuclide lymphoscintigraphy findings of anatomically normal, but functionally abnormal double (deep and superficial) lymphatic transporting vessel, visualized along right lower extremity. this finding is consistent with a clinical finding of chronic lymphedema secondary to hypoplasia of the superficial lymphatic system, which is well compensated by deep system. from: lee et al., 2007.21 no n c om me rci al us e o nly review [veins and lymphatics 2014; 3:4050] [page 67] arteriography seldom needed unless needed to rule out the avm involved. proper technique should be known to perform the phlebography correctly in case of a large mv, because standard phlebography may show only the mv itself with poor demonstration of the deep venous system even if this is normal, bringing to a wrong conclusion of aplasia of deep veins. therefore, phlebography should be combined with dus, and phlebography alone should be avoided.1,96 a significant numbers of the mv accompany limb-length discrepancy either as an elongation or shortening of the affected limb. hence, the assessment of the mv among kts patients should be extended to possible involvement of angio-osteohypertrophy/hypotrophy known as vascular bone syndrome.97-100 inconsistent terminology that characterizes the mv with the terms superficial, embryonic etc. has brought significant confusion. from the anatomical stand point the term superficial is a misnomer; although the mv remains in the superficial compartment of the lower extremity, it frequently penetrates the deep fascia and involves muscles of the deep compartment and remains with the high risk of potentially fatal thromboembolic events associated with the mv thrombosis like other major deep vein thrombosis (dvt). from a therapeutic standpoint, evaluation for the mv deserves a special consideration on the hemodynamic alterations associated with blood stasis in these frequently valveless, truncal vm, carrying a high risk for thromboembolic events: dvt and pe. management anticoagulation is critical to the management of the mv due to its natural thrombosis prone condition; prophylactic anticoagulation with the weight adjusted low molecular weight heparin (lmwh) is generally recommended in all patients with the mv whenever possible.101-104 especially when the mv is further combined with an aplastic or hypoplastic iliac-femoral venous system and the mv remains the major venous outflow of the lower extremity where the normal deep venous system is absent, the anticoagulation is essential. in this subgroup, thrombus within the vein would cause serious and often fatal pe.105-108 nevertheless, mv is generally indicated for the removal whenever feasible to prevent if not control various acute as well as chronic complications: cvi, vte, and vascular bone syndrome, as explained in previous section. but the feasibility of the surgical ablation of the mv will depend solely on the deep vein system status; only when the deep system is in normal condition, sudden increase of the venous influx following the removal of the mv can be tolerated by the deep system. if not tolerate, it would precipitate acute venous stasis and subsequent venous hypertension to cause acute venous gangrene. the mv among the children in particular with evidence to cause a limb-length discrepancy should be removed as soon as possible in order to give a sufficient time for natural compensation to correct leg length discrepancy.13,109 in cases with normal deep veins, complete surgical resection of the mv either in a single stage or multiple stages remains the best and most ideal treatment to control the angio-osteodystrophy.97-100,110,111 when the deep vein system is in minimally hypoplastic condition, the mv can be removed in multistages to give a sufficient time for hypoplastic vein to be dilated spontaneously to tolerate new hemodynamic status following the resection of the mv to insure rerouting of venous flow.110,111 in cases of aplasia of the deep veins, the embryonal vein becomes a part of the main draining vessel of the limb and resection is no possible. therefore, surgical excision of the mv remains the treatment of choice in general and should be carried on to correct abnormal hemodynamic condition to cause various morbidities although endoluminal thermal ablation is occasionally technically feasible. even for the patients with mildly hypoplastic deep veins it would be worthy for a trial as long as it would not compromise lower extremity blood return. in this subgroup of patients perioperative anticoagulation with lmwh should be considered. the endovascular obliteration using the laser or radiofrequency is seldom technically applicable for the mv management due to extremely superficial location of the mv right beneath the skin, which makes sufficient tumescent anesthesia difficult. therefore, currently available endovascular ablation by laser or radiofrequency is generally unsuitable for the mv under thin skin because of high risk of skin damage.4,8,22 foam sclerotherapy is also less effective and often difficult due to extremely large venous volume and relatively fast venous flow through the mv. further, it is risky for dvt especially when large perforators are involved with potential extension of thrombosis to the deep vein system without barrier. but the surgical excision is also often technically difficult due to extreme fragility of the defective vein with lack of media, huge and fragile perforators, and/or dense dysplastic lymphatic tissue surrounding the vein to dissect. due to high risk of bleeding, the tourniquet is strongly recommended during the surgical procedure whenever applicable and closed stripping is often contraindicated. mv patients who are candidates for surgical removal, should receive perioperative anticoagulation with lmwh.112 nevertheless, the results of surgical excision are good; recurrence has not been reported.113 conclusions marginal vein is one of venous malformations due to defective development of venous trunk formation during the later stage of embryogenesis. mv is not an ordinary varicose vein but an embryonic vein with defective vessel structure; it therefore, accompanies high risk of venous thromboembolism in addition to chronic venous insufficiency caused by lack of venous valves (avalvulosis). as far as the deep vein system is normal, early ablation should be done whenever feasible especially when complicated with leg length discrepancy. references 1. mattassi r. approach to marginal vein: current issue. phlebology 2007;22:283-6. 2. vollmar j, voss e. vena marginalis lateralis persistens the forgotten vein of the angiologists. vasa 1979;8:192-202. 3. lee bb. venous embryology: the key to understanding anomalous venous conditions. phlebolymphology 2012;19:170-81. 4. lee bb. marginal vein is not a simple varicose vein: it is a silent killer! review. damar cer derg 2013;22:4-14: 5. lee bb, laredo j. editorial. venous malformation: treatment needs a bird’s eye view. phlebology 2013;28:62-3. 6. lee bb, laredo j. chapter 63: venous malformation and tumors: etiology, diagnosis, and managment. part v. congenital venous abnormalities. in: bergan jj, bunke-paquette n, eds. the vein book. 2nd ed. new york, ny: oxford university press; 2014. pp 541-548. 7. lee bb, baumgartner i. contemporary diagnosis of venous malformation. j vasc diagnost 2013;1:25-34. 8. lee bb, baumgartner i, berlien p, et al. diagnosis and treatment of venous malformations consensus document of the international union of phlebology (iup): updated 2013. int angiol 2014 feb 25. [epub ahead of print] 9. lee bb, bergan jj. advanced management of congenital vascular malformations: a multidisciplinary approach. j cardiovasc surg 2002;10:523-33. 10. lee bb. critical issues on the management of congenital vascular malformation. ann vasc surg 2004;18:380-92. 11. lee bb, mattassi r, loose d, et al. no n c om me rci al us e o nly review [page 68] [veins and lymphatics 2014; 3:4050] consensus on controversial issues in contemporary diagnosis and management of congenital vascular malformation seoul communication. int j angiol 2004;13:182-92. 12. lee bb. endovascular management of the congenital vascular malformation (cvm) is not a panacea. damar cer derg 2013;22:1-3. 13. weber j, daffinger n. congenital vascular malformations: the persistence of marginal and embryonal veins. vasa 2006;36:67-77. 14. lewis ft. development of the veins in the limbs of rabbit embryos. am j anat 1906;5:113-20. 15. hochstetter f. g.l.-uilber die' entwicklung der extremitiitsvenen bei den amnioten. morph. jahrb. 1891;7:1-43. 16. klippel m, trenaunay i. du naevus variqueux et ostéohypertrophique. arch gén méd 1900;3:641-72. 17. servelle m. klippel and trénaunay’s syndrome. ann surg 1985;201:365-73. 18. gloviczki p, stanson aw, stickler gb, et al. klippel-trenaunay syndrome: the risks and benefits of vascular interventions. surgery 1991;110:469-79. 19. villavicencio jl. congenital vascular malformations predominantly venous? the syndrome of klippel-trenaunay. scope phlebol lymphol 2000;71:116-25. 20. kim yw, lee bb, cho jh, et al haemodynamic and clinical assessment of lateral marginal vein excision in patients with a predominantly venous malformation of the lower extremity. eur j vasc endovasc surg 2007;33:122-7. 21. lee bb, laredo j, lee ts, et al. terminology and classification of congenital vascular malformations. phlebology 2007;22:249-52. 22. lee bb, bergan j, gloviczki p, et al. diagnosis and treatment of venous malformations consensus document of the international union of phlebology (iup) 2009. int angiol 2009;28:434-51. 23. lee bb. not all venous malformations needed therapy because they are not arteriovenous malformations. dermatol surg 2010;36:347. 24. lee bb. venous malformation is not a hemangioma. flebol linfol lect vascul 2012;7:1021-3. 25. lee bb, laredo j. hemangioma and venous/vascular malformation are different as an apple and orange! acta phlebol 2012;13:1-3. 26. lee bb. chapter 4: lymphedema-diagnosis and treatment. in: tredbar ll, morgan cl, lee bb, et al., eds. lymphatic malformation. london: springer-verlag; 2008. pp 31-42. 27. lee bb, kim yw, seo jm, et al. current concepts in lymphatic malformation (lm). vasc endovasc surg 2005;39:67-81. 28. lee bb. lymphedema-angiodysplasia syndrome: a prodigal form of lymphatic malformation (lm). phlebolymphology 2005; 47:324-32. 29. lee bb, andrade m, antignani pl, et al. diagnosis and treatment of primary lymphedema. consensus document of the international union of phlebology (iup) 2013. int angiol 2013;32:541-74 30. berwald c, salazard b, bardot j, et al. port wine stains or capillary malformations: surgical treatment. ann chir plast esthet 2006;51:369-72. 31. goldman mp, fitzpatrick re, ruiz-esparza j. treatment of port-wine stains (capillary malformation) with the flashlamppumped pulsed dye laser. j pediatr 1993; 122:71-7. 32. belov s. anatomopathological classification of congenital vascular defects. semin vasc surg 1993;6:219-24. 33. belov s. classification, terminology, and nosology of congenital vascular defects. in: belov s, loose da, weber j, eds. vascular malformations. reinbek: einhorn-presse; 1989. pp 25-30. 34. rutherford rb. classification of peripheral congenital vascular malformations. in: ernst c, stanley j, eds. current therapy in vascular surgery. 3rd ed. st. louis, mo: mosby; 1995. pp 834-838. 35. gloviczki p, duncan aa, kalra m, et al. vascular malformations: an update. perspect vasc surg endovasc ther 2009;21:133-48. 36. aggarwal k, jain vk, gupta s, et al. klippel-trenaunay syndrome with a lifethreatening thromboembolic event. j dermatol 2003;30:236-40. 37. walder b, kapelanski dp, auger wr, fedullo pf. successful pulmonary thromboendarterectomy in a patient with klippel-trenaunay syndrome. chest 2000;117:1520-2. 38. ulrich s, fischler m, walder b, et al. klippel-trenaunay syndrome with small vessel pulmonary arterial hypertension. thorax 2005;60:971-3. 39. johnson jn, driscoll dj, christopher ga, mcgregor mb. pulmonary thromboendarterectomy in klippel–trénaunay syndrome. j thorac cardiovasc surg 2010;140:e41-3. 40. leu hj. pathomorphology of vascular malformations: analysis of 310 cases. int angiol 1990;9:147-55. 41. detakats g. vascular anomalies of the extremities. surg gynecol obstet 1932;55:227-37. 42. bastide g, lefebvre d. anatomy and organogenesis and vascular malformations. in: belov s, loose da, weber j, eds. vascular malformations. reinbek: einhorn-presse verlag; 1989. pp 20-22. 43. woolard hh. the development of the principal arterial stems in the forelimb of the pig. contrib embryol 1922;14:139-54. 44. mulliken jb, glowacki j. hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. plast reconstr surg 1982;69:412-22. 45. mulliken jb. classification of vascular birthmarks. in: mulliken jb, young ae, eds. vascular birthmarks: hemangiomas and malformations. philadelphia, pa: wb saunders; 1988. pp 24-37. 46. mulliken jb, zetter br, folkman j. in vivo characteristics of endothelium from hemangiomas and vascular malformations. surgery 1982;92:348-53. 47. mulliken jb. cutaneous vascular anomalies. semin vasc surg 1993;6:204-18. 48. lee bb. venous malformation and haemangioma: differential diagnosis, diagnosis, natural history and consequences. phlebology 2013;28:176-87. 49. agrawal a, whitehouse r, johnson rw, augustine t. giant splenic artery aneurysm associated with arteriovenous malformation. j vasc surg 2006;44:1345-9. 50. miele vj, rosen cl, carpenter j, et al. vertebral artery-to-middle cerebral artery bypass with coil embolization of giant internal carotid artery aneurysm: technical case report. neurosurgery 2005;56:e1159; discussion. 51. lee bb, do ys, byun hs, et al. advanced management of venous malformation (vm) with ethanol sclerotherapy: midterm results. j vasc surg 2003;37:533-8. 52. lee bb. current concept of venous malformation (vm). phlebolymphology 2003;43:197-203. 53. lee bb, kim di, huh s, et al. new experiences with absolute ethanol sclerotherapy in the management of a complex form of congenital venous malformation. j vasc surg 2001;33:764-72. 54. lee bb. les malformations veineuses congénitales: évolution des concepts actuels de diagnostic et de traitement. angéiologie 1998;50:17-9. 55. lee bb, baumgartner i, berlien hp, et al. consensus document of the international union of angiology (iua) 2013. current concept on the management of arteriovenous management. int angiol 2013; 32:9-36. 56. lee bb. chapter 76: mastery of vascular and endovascular surgery. in: zelenock gb, huber ts, messina lm, et al., eds. arteriovenous malformation. phila delphia, pa: lippincott, williams and wilkins; 2006. pp 597-607. 57. lee bb, lardeo j, neville r. arteriono n c om me rci al us e o nly review [veins and lymphatics 2014; 3:4050] [page 69] venous malformation: how much do we know? phlebology 2009;24:193-200. 58. lee bb, laredo j, deaton dh, neville rf. chapter 53: arteriovenous malformations: evaluation and treatment. in: gloviczki p, ed. handbook of venous disorders: guidelines of the american venous forum. 3rd ed. london: a hodder arnold: 2009. pp 583-593. 59. lee bb, laredo j, seo jm, neville r. chapter 29: treatment of lymphatic malformations. in: mattassi r, loose da, vaghi m, eds. hemangiomas and vascular malformations. milan: springer-verlag; 2009. pp 231-250. 60. lee bb, villavicencio jl. primary lymphedema and lymphatic malformation: are they the two sides of the same coin? eur j vasc endovasc surg 2010;39:646-53. 61. lee bb, andrade m, bergan j, et al. diagnosis and treatment of primary lymphedema consensus document of the international union of phlebology (iup) 2009. int angiol 2010;29:454-70. 62. lee bb, laredo j, neville r. chapter 51: primary lymphedema as a truncular lymphatic malformation. section xi lymphedema and congenital vascular malformation. in: lee bb, bergan j, rockson sg, eds. lymphedema: a concise compendium of theory and practice. 1st ed. london: springer-verlag; 2011. pp 419-426. 63. noel aa, gloviczki p, cherry kj jr, rooke tw, stanson aw, driscoll dj. surgical treatment of venous malformations in klippel-trenaunay syndrome. j vasc surg 2000;32:840-7. 64. gloviczki p, hollier lh, telander rl, et al. surgical implications of klippeltrenaunay syndrome. ann surg 1983;197:353-62. 65. lee bb, laredo j. chapter 21: classification: venous-lymphatic vascular malformation. part 3. in: allegra c, antignani pl, kalodiki e, eds. news in phlebology. turin: ed. minerva medica; 2013. pp 91-94. 66. kim kh, kim hh, lee sk, et al. ok-432 intralesional therapy for lymphangioma in children. j. korean assoc pediatr surg 2001;7:142-6. 67. park jh, kim di, huh s, et al. absolute ethanol sclerotherapy on cystic lymphangioma in neck and shoulder region. j korean vasc surg soc 1998;14:300-3. 68. lee bb, kim di, whang jh, lee kw. contemporary management of chronic lymphedema personal experiences. lymphology 2002;35:450-5. 69. lee bb, laredo j, kim yw, neville r. congenital vascular malformations: general treatment principles. phlebology 2007;22:258-63. 70. lee bb, laredo j. multidisciplinary approach in the management of a giant arteriovenous malformation in the right axillary region. j vasc surg 2008;48:775-6. 71. jeon yh, do ys, shin sw, et al. ethanol embolization of arteriovenous malformations: results and complications of 33 cases. j kor radiol soc 2003;49:263-70. 72. lee bb, laredo j. classification of congenital vascular malformations: the last challenge for congenital vascular malformations. phlebology 2012;27:267-9. 73. lee bb, laredo j, deaton d, neville r. chapter 82: endovascular treatment of some congenital diseases hemangioma and vascular malformation. section xi, textbook of peripheral vascular interventions. in: heuser rr, henry m, eds. informa healthcare. 2nd ed. london: informa ltd.; 2008. pp 712-722. 74. lee bb. chapter 41: congenital vascular malformation. in: geroulakos g, van urk h, hobson ii rw, calligaro kd, eds. vascular surgery. 2nd ed.: cases, questions and commentaries. london: springer-verlag; 2006. pp 377-392. 75. lee bb. chapter 40: congenital vascular malformation. in: geroulakos g, van urk h, hobson ii rw, calligaro kd, eds. vascular surgery: cases, questions and commentaries. london: springer-verlag; 2003. pp 315-323. 76. lee bb, beaujean m. nouvelles strategies dans la prise en charge des malformations vasculaires congenitales (mvc): un apercu de l’experience clinique coreenne. angeiologie 2004;56:11-25. 77. eifert s, villavicencio jl, kao tc, et al. prevalence of deep venous anomalies in congenital vascular malformations of venous predominance. j vasc surg 2000;31:462-71. 78. belov s. congenital agenesis of the deep veins of the lower extremity: surgical treatment. j cardiovasc surg 1972;13:594. 79. raju s, hollis k, neglen p. obstructive lesions of the inferior vena cava: clinical features and endovenous treatment. j vasc surg 2006;44:820. 80. lee bb, villavicencio l, kim yw, et al. primary budd-chiari syndrome: outcome of endovascular management for suprahepatic venous obstruction. j vasc surg 2006;43:101-10. 81. gillespie dl, villavicencio jl, gallagher c, et al. presentation and management of venous aneurysms. j vasc surg 1997;26:845-52. 82. sessa c, nicolini p, perrin m, et al. management of symptomatic and asymptomatic popliteal venous aneurysms: a retrospective analysis of 25 patients and review of the literature. j vasc surg 2000;32:902-12. 83. zamboni p, cossu a, carpanese l, et al. the so-called venous aneurysms. phlebology 1990;5:45-50. 84. friedman sg, krishnasastry kv, doscher w, deckoff sl. primary venous aneurysms. surgery 1990;108:92-5. 85. zamboni p, pisano l, mari c, et al. membranous obstruction of the inferior vena cava and budd-chiari syndrome. report of a case. j cardiovasc surg (torino) 1996;37:583-7. 86. nedelmann m, kaps m, mueller-forell w. venous obstruction and jugular valve insufficiency in idiopathic intracranial hypertension. j neurol 2009;256:964-9. 87. wang zg, jones rs. budd-chiari syndrome. in: wang zg, jones rs, eds. current problems in surgery. new york, ny: mosby; 1996. pp 83-211. 88. lee bb, laredo j, deaton d, neville r. chapter 83: endovascular management of budd-chiari syndrome – suprahepatic inferior vena cava occlusive disease. section xii, textbook of peripheral vascular interventions. in: heuser rr, henry m, eds. informa healthcare. 2nd ed. london: informa ltd.; 2008. pp 725-731. 89. ilijevski ns, radak s, novakovic b, et al. images in vascular medicine. jugular vein aneurysm ultrasonographic evaluation. vasc med 2006;11:51. 90. fishman g, derowe a, singhal v. congenital internal and external jugular venous aneurysms in a child. br j plast surg 2004;57:165-7. 91. kersting s, rössel t, hinterseher i, et al. isolated aneurysm of the internal jugular vein. vasa 2008;37:371-3. 92. bush s, khan r, stringer md. anterior jugular venous aneurysm. eur j pediatr surg 1999;9:47-8. 93. lee bb, laredo j, lee sj, et al. congenital vascular malformations: general diagnostic principles. phlebology 2007;22:253-7. 94. loose da. surgical management of venous malformations. phlebology 2007; 22,6:276-82. 95. mattassi r. treatment of venous malformations. in: mattassi r, loose da, vaghi m, eds. hemangiomas and vascular malformations. milan: springer; 2003. pp 223-230. 96. weber j. invasive diagnostik angeborene gefaessfehler (invasive diagnostic of cvm). in: loose da, weber j, eds. angeborene gefäßmissbildungen. luneburg: verlag, nordlanddruck; 1997. pp 127-63. 97. belov s. correction of lower limbs length discrepancy in congenital vascular-bone diseases by vascular surgery performed during childhood. semin vasc surg 1993;6:245-51. 98. dickinson p. venous stasis and bone no n c om me rci al us e o nly review [page 70] [veins and lymphatics 2014; 3:4050] growth. exp med surg 1953;11:49-53. 99. mattassi r. differential diagnosis in congenital vascular-bone syndromes. semin vasc surg 1993;6:233-44. 100. belov s. hemodynamic pathogenesis of vascular-bone syndromes in congenital vascular defects. int angiol 1990;9:155-62. 101. gouin-thibault i, arkam r, nassiri s, et al. markers of activated coagulation in patients with factor v leiden and/or g20210a prothrombin gene mutation. thromb res 2002;107:7-11. 102. cuderman tv, bozic m, peternel p, stegnar m. hemostasis activation in thrombophilic subjects with or without a history of venous thrombosis. clin appl thromb hemost 2008;14:55-62. 103. enjolras o, ciabrini d, mazoyer e, et al. extensive pure venous malformations in the upper or lower limb: a review of 27 cases. j am acad dermatol 1997;36:219-25. 104. mason kp, neufeld ej, karian ve, et al. coagulation abnormalities in pediatric and adult patients after sclerotherapy or embolization of vascular anomalies. ajr am j roentgenol 2001;177:1359-63. 105. poon mc, kloiber r, birdsell dc. epsilonaminocaproic acid in the reversal of consumptive coagulopathy with platelet sequestration in vascular malformation of klippel-trenaunay syndrome. am j med 1989;87:211-3. 106. aronoff dm, roshon m. severe hemorrhage complicating the klippeltrenaunay-weber syndrome. south med j 1998;91:1073-5. 107. katsaros d, grundfest-broniatowski s. successful management of visceral klippel-trenaunay-weber syndrome with the antifibrinolytic agent tranexamic acid (cyclocapron): a case report. am surg 1998;64:302-4 (c36). 108. yamamoto h, muneta t, asahina s, furuya k, suzuki k. lower leg fracture with parkes-weber syndrome complicated by disseminated intravascular coagulation. j orthop trauma 1995;9:449-52. 109. belov s. correction of lower limbs length discrepancy in congenital vascular bone disease by vascular surgery performed during childhood. semin vasc surg 1993;6:245-51. 110. loose, da, lorenz. a die chirurgie der maginalvene (surgery of the marginal vein). in: loose da, weber j, eds. angeborene gefaessmissbildungen (conge nital vascular malformations). lűneburg: nordlanddruck; 1997. pp 230-244. 111. mattassi r. trattamento delle angiodisplasie di tipo venoso (treatment of venous vascular malformations). in: mattassi r, lose da, belov s, vaghi m, eds. malformazioni vascolari ed emangiomi. milan: springer; 2003. pp 116-123. 112. noel a, gloviczki p, cherr k jr, et al. surgical treatment of venous malformations in klippel-trénaunay syndrome. j vasc surg 2000;32:840-7. 113. kim yw, do ys, lee sh, lee bb. risk factors for leg length discrepancy in patients with congenital vascular malformation. j vasc surg 2006;44:545-53. no n c om me rci al us e o nly hrev_master veins and lymphatics 2014; volume 3:717 [veins and lymphatics 2014; 3:717] [page 15] the sapheno-femoral junction valvuloplasty in the post-thrombotic syndrome: a proposal with the use of a new device sante camilli,1 daniele camilli2 1vascular surgery, private office; 2vascular surgery, policlinico di liegro, roma, italy abstract before developing deep venous thrombosis (dvt), most patients suffering from postthrombotic syndrome (pts) have a normal great saphenous vein (gsv). after dvt, the gsv plays a vicarious function, but many patients develop secondary varicose veins (vvs) and the previous positive contribution of the gsv vanishes. in these cases the ablative strategy is generally implemented with positive results in the short-term, but commonly with late varicose recurrences. in two cases the authors preferred a different approach to preserve and recover the gsv vicarious function by sapheno-femoral junction (sfj) valvuloplasty. out of 43 cases we treated with sfj stretching valvuloplasty performed with the new oses device (v-oses), we proposed this operation to two patients (a and b) suffering from pts and secondary vvs at an early stage, classified as c3 and c4 (clinical-etiology-anatomypathophysiology classification, ceap). in the voses operation a gentle stretching force is applied onto the apex of the opposite valve commisures so that the valve cross-section becomes oval and the cusp’s length excess is retrieved. the operation was performed on the sfj valve having incompetent, but floating cusps visible on ultrasound (us) scan. this reparative technique was undertaken under local anesthesia and was combined with disconnection of the incompetent tributaries and/or perforators. the us-duplex scanning showed that the sfj valves were competent at month 16 (b) and 20 (a) follow-up after surgery and the gsv vicarious function was preserved. the stretching valvuloplasty operation is intended to repair the sfj valve incompetence and preserve the gsv vicarious function. this approach may be useful in primary vvs, but especially in pts when superficial reflux appears and secondary vvs are at early stage. the sfj reparative operation may be combined with the conventional gsv conservative strategies, including incompetent tributaries ablation/disconnection. this approach does not seem to have been already reported in the literature and needs further confirmation. introduction since the post-thrombotic syndrome (pts) is a consequence of a deep venous thrombosis (dvt), we cannot neglect that these patients may be suffering from thrombophilia, but, more often, they may have developed dvt as a result of trauma or surgery. in general they have not the stigmata (genetic, hormonal, etc.) of patients with primary varicose veins (vvs). before developing a dvt, these patients usually have a normal great saphenous vein (gsv). however it is a fact that most patients suffering from pts develop secondary vvs. in these cases the ablative strategy is generally implemented with positive results in the shortterm, but commonly with late varicose recurrences, regardless of the type of ablative treatment performed. the gsv system acts anatomically and functionally in parallel to the deep system and therefore plays a vicarious function in case of deep venous hypertension, which leads to the diversion of blood towards the superficial system. the vicarious function of the saphenous system plays a positive role in the early phase of pts, however sooner or later the overload accumulating into the saphenous system causes a progressive dilatation of the vicarious circuit and leads to valve incompetence with a resulting backward flow. then secondary vvs appear and decrease the previous gsv vicarious function with an overall clinical and hemodynamic deterioration. the surgical correction of deep reflux in pts (by valvuloplasty, transposition, bypass, neovalve) involves rather complex procedures, mostly with uncertain or poor results, and has therefore been limited to special cases and performed in highly specialized surgical centres.1 on the contrary the correction of the superficial reflux in pts, in secondary vvs, is commonly treated by ablative techniques (stripping, endovenous thermal or chemical ablation, etc.) to ablate or destroy the gsv and its tributaries. others techniques [stab avulsion, phlebectomy, ablation selective des varices sous anesthesie locale (asval), i.e. selective varicose vein ablation under local anesthesia] aim to reduce the vvs reservoir. others disconnect the saphenofemoral junction (sfj) trying to spare the gsv trunk as a backward draining conduit [cure conservatrice et hémodynamique de l’insuffisance veineuse en ambulatoire (chiva), i.e. outpatient conservative hemodynamic management of varicose veins], etc. (figure 1). all ablative conservative techniques show positive clinical results at short-term follow-up, but in the midor long-term the varicose veins still tend to relapse in many cases. the authors propose a different approach to pts, which envisages sfj stretching valvuloplasty in combination with incompetent tributaries disconnection or ablation to preserve or recover as muchand as long as possible the gsv vicarious function. materials and methods in the case of sfj incompetence with freefloating valve cusps visible on ultrasound (us) scan, the valve may be eligible for repair. the oval-shaped external support (oses a medical device manufactured by assut europe spa, rome, italy) is a new and innovative medical device, especially intended for venous valve repair by a stretching movement (figure 2). being purposely oversized (large diameter about 30 percent greater than the native valve diameter), it is placed outside the vein and sutured at the apex of the opposite valve commissures (figure 3). consequently, the oses device applies an external and gentle stretching force onto the valve’s walls, thus extending the inter-commissural diameter and reducing the cusps excessive length (stretching valvuloplasty), consequently restoring the valve competence in most cases.2,3 out of 43 cases we treated personally with sfj external stretching valvuloplasty with the placement of the oses device (v-oses) to repair the junctional reflux, two patients had pts and secondary vvs. a 36-year-old woman (a) had acute dvt of correspondence: sante camilli, via lombardia 30, 00187 roma, italy. tel. +39.06.482.1244. e-mail: sante.camilli@gmail.com key words: valvuloplasty, valve repair, post-thrombotic syndrome, varicose veins, valve incompetence. contributions: the main contribution is from sante camilli (sc). conflict of interests: the authors declare potential conflict of interests: sc is the inventor of the stretching valvuloplasty technique and the ovalshaped external support (assut europe spa, rome, italy) device. conference presentation: xvii uip meeting 2013, boston (usa). received for publication: 6 june 2013. revision received: 26 february 2014. accepted for publication: 26 february 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright s. camilli and d. camilli, 2014 licensee pagepress, italy veins and lymphatics 2014; 3:717 doi:10.4081/vl.2014.717 no nco mm er cia l u se on ly article [page 16] [veins and lymphatics 2014; 3:717] the right limb, two years before, with femoralpopliteal involvement. the treatment with lowmolecular-weight heparin, oral anticoagulants and elastic stockings offered an initial clinical improvement, but then she started to develop secondary vvs, heaviness and foot edema, and was classified as ceap-c3 (clinical-etiologyanatomy-pathophysiology classification). the ultrasound investigation revealed a femoralpopliteal recanalization with deep reflux, sfj and saphenous trunk incompetence, medial accessory saphenous competence, and incompetence of a perforator in the lower part of the thigh. the other patient was a 45-year-old man (b), who had a femoral-iliac dvt on the right side following a trauma in a car accident and limb immobilization. medical therapy and elastic stockings did not prevent the pts. after 3.5 years, he had skin discoloration, foot edema and secondary infra-genicular vvs classified as ceap-c4. the ultrasound revealed a satisfactory recanalization of the iliac tract, an almost complete obstruction of the femoral vein, sfj and saphenous trunk incompetence in the upper third of the leg. in these two cases, the laboratory tests detected no thrombophilia or hormonal abnormalities; no venous hemodynamic tests [e.g., venous refilling time, ambulatory venous pressure (avp), air plethysmography (apg)] were performed. the two patients agreed with the proposal of intervening on the sfj with the v-oses technique, along with a disconnection of incompetent tributaries and perforators in the same session. they also agreed to undergo us-guided foam sclerosis or stab avulsion of residual incompetent tributaries in a later session, if need be. the surgery was performed under local anesthesia and general sedation in an outpatient setting. the patients were discharged with an elastic stockings prescription with no additional therapy. the postoperative course was simple and uneventful. results after one month, the two patients had relieved symptoms, a better quality of life and were satisfied with the procedure. the sfj was competent at duplex evaluation. some residual varicose veins were reduced in size and some were treated with foam sclerotherapy as planned. during the follow-up, at month 20 (a) and 16 (b), the clinical improvement was evident, both subjectively and objectively. the sfj valves proved to be competent at duplex scanning, while the gsv trunks were incompetent and draining backward as expected. instrumental evaluation tests were not performed. the patients continued to wear elastic stockings, when needed, and tolerated them better than before. figure 1. algorhythm of surgical therapies that can be applied in post-thrombotic syndrome (pts). in advanced-stage pts, a combination of superficial and deep reflux can be detected along with deep obstruction/recanalization. in this case, the superficial one is commonly treated first. the conventional ablative techniques are useful, but they also eliminate the positive vicarious function previously played by the greater saphenous vein (gsv). a strategy for preserving this vicarious function should consider the saphenofemoral junction (sfj) valvuloplasty and the gsv conservative technique at an early stage of superficial reflux. this strategy may be combined with other conservative techniques, such as the cure conservatrice et hémodynamique de l’insuffisance veineuse en ambulatoire (chiva) and ablation selective des varices sous anesthesie locale (asval). indeed, it is a proposal … to be confirmed. figure 2. a picture of the oval-shaped external support (oses) device. it looks like a vascular stent in nitinol alloy submitted to a treatment for biocompatible and super-elastic performance. it comprises two oval arches (a-b), which are active elements, to treat 2 near valves with different diameters. they are provided with multiple eyelets (c,c’ and d,d’) intended for stitching and securing the device to the vein wall. the multiple eyelets, as well as the different device sizes, are intended to achieve a correct stretching action and compliance. the two oval arches (a-b) are connected by a long element (e) giving stability and also elastic flexibility in any direction. for easy positioning of the device, it is equipped with handles (f) to be removed after placement. no nco mm er cia l u se on ly article [veins and lymphatics 2014; 3:717] [page 17] discussion on the basis of the introductory remarks, the authors proposed and then performed the stretching v-oses operation on the incompetent sfj in two cases of young adults suffering from pts and recent secondary vvs with sfj and truncal reflux. the aim was to preserve the gsv vicarious function by sfj repair and refluxive tributaries disconnection or ablation, to restore the gsv positive hemodynamic contribution. although we found a limited number of previous reports concerning primary vvs 4,5 in the medical literature, we couldn’t find any about secondary vvs in pts. in general, the only pre-requisite to perform the v-oses operation is the presence of freefloating valve cusps that are visible at ultrasound investigation. the correct eligibility criteria for valve repair are important, because a positive outcome can be more easily achieved in the case of young adult patients with valve incompetence at an early stage (table 1). for this reason a thorough pre-operative us investigation is mandatory for an accurate evaluation of mobility, consistency, and also symmetry of the valve cusps. this surgical procedure is generally feasible in all eligible cases, is technically simple, is not time consuming (15-30 min in most cases), can be performed under local anesthesia and, if need be, general sedation. a great deal of attention must be paid to the placement of sutures that secure the stretching device to the apex of the opposite commissures, because this is a crucial step that affects the anatomical, hemodynamic and clinical results. these apices are not always easily identifiable, as a reversed v shaped line on the vein wall, and also due to venous spasm induced by usual and even gentle surgical manipulation or to the thickness of the wall. in these cases the surgeon can rely on the images and the measures from the pre-operative duplex scanning that need to be accurately transferred on a paper sketch of the sfj. the learning curve is short for experienced surgeons. the most important requirement is to have a forward-looking mentality and culture and be willing to achieve new goals and use innovative methods. in comparison with the conventional external valvuloplasty techniques, the v-oses operation entails a new and unique approach. we gained extensive experience with the conventional external banding/wrapping techniques,6,7 as well as the sfj plication,8 which are narrowing techniques, thus involving the opposite of the stretching technique. however all of these techniques aim to reduce the vessel area with cusp bundling and implicitly unpredictable erratic or uncertain cusp apposition. this drawback can be overcome by performing the correct stretching operation, which does not involve a cross-sectional area reduction and applies a calibrated, elastic and figure 3. the working concept of the stretching valvuloplasty technique with the oval shaped external support (v-oses) device. the cross-section of the incompetent valve bulb (a) shows circular shape and slackened cusps/leaflets, causing valve incompetence and reflux. a proper oses device should be over-sized by about 30% compared with to the native valve diameter. a correct positioning of the device and its fixation by sutures onto the vein walls (a’, a”) acts like a spring performing a gentle action and modifies the valve bulb that acquires an oval shaped cross-section (b). the stretching action onto the inter-commissural diameter retrieves the slackened cusps and restores the valve competence. figure 4. chart showing a duplex scanning pattern at 1-24-48-month follow-up, after sapheno-femoral junction stretching valvuloplasty by using the oval shaped external support device. among a cohort of 38 consecutive cases of primary varicose veins, 18 were checked at 48 months by ultrasound duplex scanning: 14 (78%) showed a repaired incompetence, 3 (17%) had a reduced incompetence and 1 (5%) was a failure. table 1. inclusion/exclusion criteria for venous valvuloplasty eligibility, in particular for stretching valvuloplasty by using the oval shaped external support device. more extensive experience is needed on the topic to refine criteria and match the best valvuloplasty results. inclusion criteria exclusion criteria valve pattern (us) visibility undetectable free floating cusps frozen cusps symmetrical (substantially) asymmetrical (markedly) varicose disease early stage late stage patient age young-adult short life expectancy us, ultrasound. no nco mm er cia l u se on ly article [page 18] [veins and lymphatics 2014; 3:717] gentle stretching action onto the ideal site, i.e. the opposite commissural apices. the goreexternal valve support9 is also an oval-shaped device, but it has a compressive action as well, acting along the anterior-posterior plane. moreover, depending on its configuration, it could not be used onto the gsv terminal valve and even requires the ligation of the first tributary (the superficial inferior epigastric vein) that is generally competent, while the oses device is adaptive and can spare it. the oses device consists of a slender thread-like material and has a compliant and adaptive behavior and is therefore better than previous devices that might kink in the sitting or crouching position. as to the banding techniques, they have been used by a few groups, mainly in deep venous system, commonly in small groups of patients.8-12 among them, one of the authors obtained deep valve competence in 78 percent of cases at long-term followup,10 but inferior results for sfj valves. others compared airor photo-plethysmography (apg/ ppg) instrumental findings after sfj valvuloplasty vs stripping or vnus ablation (vnus medical techn., inc., san jose, ca, usa), showing an hemodynamic improvement in all cases at a 1 month follow-up.11 the same results after sfj valvuloplasty were found also at a 10 year followup.12 the authors have a cumulative personal experience on 43 patients treated with stretching v-oses operation for primary vvs and on one with bilateral primary deep venous insufficiency. among the patients treated for primary vvs, 18 out of 38 have a 4-year follow-up: 14 (78%) show an excellent valve competence, 3 (17%) have a reduced incompetence and 1 was a failure (figure 4).3 the two patients treated for secondary vvs in pts, described in this report, showed sfj competence at us-duplex evaluation after 20 and 16 months and a sfj forward drainage as well as a preserved gsv vicarious function. indeed, in similar cases we commonly adopt a combination of a reparative operation (sfj valvuloplasty) together with disconnection (like in the chiva strategy) or ablation (like in the asval technique) of the incompetent tributaries. in our opinion this is a reasonable approach, because in some randomized controlled trials (rct) and cochrane reviews, the chiva strategy showed to have better long-term results than stripping.13-18 moreover, the stripping or endovascular techniques give comparable long-term results.19 although these reports may be criticized for some aspects, more rcts should be carried out and give an opposite result, before they can be declared inconsistent. in conclusion, we can reasonably expect that the combination of sfj repair and gsv conservative strategy will have a better mid-term outcome than the individual strategies applied separately. however, in order to assess the actual benefits and the overall strategy to be adopted in these cases, we need to rely on a larger clinical experience, deeper instrumental monitoring (e.g., avp, ppg, apg, etc.) and a longer clinical follow-up. conclusions in case of venous valve incompetence with free-floating us-visible valve cusps, the sfj stretching valvuloplasty by oses device (voses) is technically feasible, simple and safe. it aims to repair the sfj incompetence and preserve the gsv forward flow. in a personal short series of eligible cases in primary vvs, the voses operation has shown clinical and functional effectiveness and good long-term results in most cases.3 if applied in pts, at a relatively early stage or when secondary vvs appear, it may restore the vicarious function of the saphenous system. it may be combined with the conventional conservative strategies for the gsv (e.g. chiva and asval, and also sclerotherapy) with a reasonable expectation that the combination may have a better mid-term outcome than the use of the ablative or conservative strategy applied separately. this proposal does not seem to have been described in previous reports in the medical literature. moreover two clinical positive cases have no statistical significance. therefore it still needs to be validated by a larger clinical experience and instrumental investigation. however, since it is a reconstructive rather than an ablative surgery, it does not preclude the patient from any other therapeutic chance, especially in case of pts. even in case of failure, any other ablative option can still be implemented. furthermore if the effectiveness of sfj valvuloplasty is confirmed, this intervention can be considered the first-choice option in pts, when secondary vvs appear. references 1. henke pk, comerota aj. an update on etiology, prevention, and therapy of postthrombotic syndrome. j vasc surg 2011;53:500-9. 2. camilli d, camilli s. the external stretching valvuloplasty: a new technique for venous valve repair. j vasc endovasc surg 2012; 19:37-40. 3. camilli d, camilli s. venous valve repair by oses technique: results on 39 cases at 4 years f-u. sci med 2012;3:331-6. 4. corcos l, peruzzi gp, romeo v, et al. external valvuloplasty of the sapheno-femoral junction. phlebologie 1991;44:497-508. 5. zamboni p, marcellino mg, cappelli m, et al. saphenous vein sparing surgery: principles, techniques and results. j cardiovasc surg (torino) 1998;39:151-62. 6. hallberg d. a method for repairing incompetent valves in deep veins. acta chir scand 1972;138:143-5. 7. lane rj, graiche ja, coroneos jc, et al. long-term comparison of external valvular stenting and stripping of varicose veins. anz j surg 2003;73:605-9. 8. belcaro g. plication of the saphenofemoral junction. vasa 1989;18:296-300. 9. incandela l, belcaro g, nicolaides an, et al. superficial vein valve repair with a new external valve support (evs). the imes (international multicenter evs study). angiology 2000;51:s39-52. 10. guarnera g, furgiuele s, mascellari l, et al. external banding valvuloplasty of the superficial femoral vein in the treatment of recurrent varicose veins. intl angiol 1998;17:278-71. 11. park uj, yun ws, lee kb, et al. analysis of the postoperative hemodynamic changes in varicose vein surgery using air plethysmography. j vasc surg 2010;51:634-8. 12. joh jh, lee kb, yun ws, et al. external banding valvuloplasty for incompetence of the great saphenous vein: 10-year results. int j angiol 2009;18:25-8. 13. carandina s, mari c, de palma m, et al. varicose vein stripping vs haemodynamic correction (chiva): a long term randomised trial. eur j vasc endovasc surg 2008;35:230-7. 14. parés jo, juan j, tellez r, et al. varicose vein surgery: stripping versus the chiva method: a randomized controlled trial. ann surg 2010;251:624-31. 15. iborra-ortega e, barjau-urrea e, vila-coll r, et al. comparative study of two surgical techniques in the treatment of varicose veins of the lower extremities: results after five years of followup. [estudio comparativo de dos técnicas quirúrgicas en el tratamiento de las varices de las extremidades inferiores: resultados tras cinco años de seguimiento]. angiología 2006;58:459-68. 16. chan cy, chen tc, hsieh yk, huang jh. retrospective comparison of clinical outcomes between endovenous laser and saphenous vein-sparing surgery for treatment of varicose veins. world j surg 2011; 35:1679-86. 17. milone m, salvatore g, maietta p, et al. recurrent varicose veins of the lower limbs after surgery. role of surgical technique (stripping vs. chiva) and surgeon’s experience. g chir 2011;32:460-3. 18. bellmunt-montoya s, escribano jm, dilme j, martinez-zapata mj. chiva method for the treatment of chronic venous insufficiency. cochrane database syst rev 2012;(2): cd009648. 19. rasmussen l, lawaets m, bioern l, et al. randomized clinical trial comparing endovenous laser ablation and stripping of the great saphenous vein with clinical and duplex outcome after 5 years. j vasc surg 2013;58:421-6. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2018; volume 7:7628 [veins and lymphatics 2018; 7:7628] [page 69] a new stocking compression system with a low well-defined resting pressure and a high working pressure andreas nilsson,1 torbjörn lundh1,2 1presscise, herrljunga; 2chalmers university of technology, gothenburg, sweden abstract compression stockings should preferably apply the intended pressure regardless of leg shape and circumference. this may require custom fitting.1 today’s sizing system is focusing on the exerted pressure at the ankle region. a ready-made stocking may therefore exert correct pressure at the ankle, but the pressure at the calf may be well exceeded due to the actual size of the calf, leading to a tourniquet effect, ischemia or even increased risk of thrombosis.2 even with a perfectly-fitted stocking, the problem with changes in leg circumference due to the increase/decrease in oedema is not resolved.3,4 stocking donning problems vary with compression class and elasticity of the material used. added pressure over the calf area has been reported to improve venous pumping function more than graduated compression.5,6 adding stiffness over the calf area may also improve the pumping function.7 häfner et.al. stated that “hemodynamically optimal compression products will make medical compression therapy an even more useful tool in the field of phlebology”.8 with new smart textiles, the pressure can be controlled.9 the aim was therefore to evaluate a prototype of a stocking compression system with specified well-defined target resting pressure and supposedly high working pressure created by stiffness. materials and methods included in this limited study were eight healthy subjects (5 women and 3 men). a novel compression system (lundatex® stocking system, presscise, sweden) consisting of a highly elastic stocking designed for 18 20 mmhg resting pressure without graduated pressure was used as a first layer. the stocking consisted of a patented smart textile with pressure specified to be welldefined regardless of leg circumference and shape. as a second layer, patches consisting of hook-material (similar functionality to velcro) was applied. the second layer converts the system from elastic to stiff. the transformation of an elastic first layer into a stiff system has previously been studied with respect to interface pressure, stiffness, and haemodynamic effectiveness10. the patches were applied from about 5 cm above the malleoli to a point 3 cm below the top of the stocking. interface pressure between stocking and skin were recorded (picopress®, microlab, italy) unilaterally on all subjects. to evaluate the pressure profile as well as the pressure with respect to leg circumference, the interface pressure was measured at the b1 point which is defined as the point where the medial gastrocnemius muscle turns into the tendinous part and the c point at maximum leg-circumference. the static stiffness index (ssi)11 was calculated. a mann-whitney utest was used for comparisons and significance was set at p < 0.05. correlations are given with pearson’s r. unless otherwise stated, all results are given as the mean and standard deviation (sd). results the first layer, the stocking, with specified pressure 18-20 mmhg exerted welldefined target pressure (table1). the pressure was uniform and showed low correlation to leg circumference (r=0.2) despite circumferences varying from 23 to 39.5 cm [fig1]. a pressure increase was noted in supine position when patches were applied, 5 mmhg (p<0.003) at b1 and 6 mmhg (p<0.001) at c. with the second layer the system turned from an elastic system with low ssi (table1) to a stiff product with high ssi (table2). discussion the compression system applies a welldefined resting pressure regardless of the circumference of the leg, despite the fact that the same stocking was used on all subjects. this indicates that a limited number of stocking sizes may cover the whole range of leg sizes, and that custom fitting will not be required. a high working pressure was achieved by the stiff second layer. the low resting pressure and high working pressure gives the system a high ssi. the moderate increase in pressure when the patches were applied may be reduced by instructions to the applier of the system to avoid using extra stretch when putting on the patches. the subjects found the stocking easy to put on. a probable reason for this is the high elasticity of the stocking. there is reason to assume that the low resting pressure and high working pressure may be maintained over time even after reduction of oedema by opening and closing the front patch on the system, since this approach has successfully been used previously.12 future studies should investigate the pressure over time as well as the haemodynamic effectiveness of the system. correspondence: andreas nilsson, presscise, herrljunga, sweden. e-mail: andreas@presscise.com conference presentation: international compression club (icc) meeting, paris, 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright a. nilsson and t. lundh, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7628 doi:10.4081/vl.2018.7628 figure 1. first layer-stocking only. low correlation was found between interface pressure measured in supine position and leg circumference. no nco mm er cia l u se on ly conference presentation [page 70] [veins and lymphatics 2018; 7:7628] conclusions this new prototype stocking compression system shows promising properties, with low defined resting pressure and high working pressure independent of leg circumference and shape, despite a minimum of measuring and fitting requirements. references 1. liu, rong, et al. "stratified body shapedriven sizing system via three-dimensional digital anthropometry for compression textiles of lower extremities." textile research journal (2017): 0040517517715094. 2. classification of compression stockings, icc derived 120118 from: http://www.tagungsmanagement.org/ic c/images/stories/pdf/pressureranges.p df. 3. nørregaard, bermark, and gottrup. "do ready-made compression stockings fit the anatomy of the venous leg ulcer patient?." journal of wound care 23.3 (2014): 128-135. 4. van der wegen-franken, c. p. m., et al. "changes in the pressure and the dynamic stiffness index of medical elastic compression stockings after having been worn for eight hours: a pilot study." phlebology 24.1 (2009): 31-37. 5. mosti and partsch, (2014) "improvement of venous pumping function by double progressive compression stockings: higher pressure over the calf is more important than a graduated pressure profile." european journal of vascular and endovascular surgery 47.5:545-549. 6. mosti and partsch (2012) "high compression pressure over the calf is more effective than graduated compression in enhancing venous pump function." european journal of vascular and endovascular surgery 44.3:332-336. 7. partsch h, mezinger g, mostbeck a. inelastic leg compression is more effective to reduce deep venous refluxes that elastic bandages. dermatol surg. 1999;25:695-700 8. häfner, piche and jünger. the ratio of working pressure to resting pressure under compression stockings: its significance for the development of venous perfusion in the legs. phlebologie 2001;30:88-93. 9. wiklander, erichsen andersson and källman.(2015) "an investigation of the ability to produce a defined ‘target pressure’ using the presscise compression bandage." international wound journal. 10. mosti and partsch (2017). a new two component compression system turning an elastic bandage into an inelastic compression device: interface pressure, stiffness, and haemodynamic effectiveness. european journal of vascular and endovascular surgery. 11. partsch. the static stiffness index: a simple method to assess the elastic property of compression material in vivo. derm surg 2005;31:625e30. 12. damm, lundh, partsch and mosti. an innovative compression system providing low, sustained resting pressure and high, efficient working pressure. veins lymphatics 2017;6:6627. table 1. first layer-stocking only. interface pressures (mmhg) in supine and standing position with ssi. sensor position supine standing ssi mean sd mean sd mean sd b1 18 1.1 18 2.2 0.1 2.4 c 19 1.4 19 1.5 0.4 0.5 table 2. system-stocking with patches. interface pressures (mmhg) in supine and standing position with ssi. sensor position supine standing ssi mean sd mean sd mean sd b1 23 3.3 44 14 21 13 c 25 2.3 40 9.2 23 7 no nco mm er cia l u se on ly hrev_master veins and lymphatics 2017; volume 6:7048 [page 98] [veins and lymphatics 2017; 6:7048] endovascular laser treatment of mixed shunt alvise cavallini private practitioner, verona, italy abstract in this paper we present our endovascular laser treatment of mixed shunts. this technique is built according the chiva’s important principles: diastolic reflux is interrupts at its proximal origin by flush laser obliteration while centripetal systolic reflux is preserved. in this way, the surgeon interrupts a recirculation pressure loop producing the ambulatory venous hypertension critical to the development of varicose vein symptoms. in this paper we explain how to better understand the intricate venous drainage pathophysiology of mixed shunt and the strategy to approach it using an office-based technique. with the correct strategy and the technological support it is possible to achieve a good functional and aesthetic result to prevent varicosity recurrence. introduction if the varicose veins were only caused by diastolic reflux, phlebology would be easy matter; it would be enough to treat escape points (ep) and/or refluxes to solve or improve the hemodynamic pattern. the major problem is when a systolic reflux occurs. this type of reflux, more rare than diastolic one, can generate 2 types of shunt: an open by-passing shunts (obs, also known as open vicarious shunts) or a mixed shunt, i.e. a combination of closed shunt (cs) and obs.1,2 in cs, a vicious circle is created between the ep and the so-called re-entry point (rp). the deviated flow re-circulates at each energy gradient inversion, like in a close circuit. the energy gradient inversion is created every time a calf muscle systole is followed by the muscular relaxation (diastole), which means at every footstep. an obs is a natural bypass, exploited by the venous network to go over an obstacle. the use of a collateral route to by-pass a functional or a thrombotic occlusion is desirable, as it reduces the drainage resistance. for this reason, this type of shunts are not to be treated. in mixed shunt (figures 1 and 2), the two shunt types share the same ep and part of their refluxing pattern toward the corresponding different rp. in this paper we present our officebased technique to treat mixed shunts with escape point originally from the popliteal fossa, using endovascular laser technology (evlt). in figure 1 clinical case is schematized. the obs presented a continuous flow, both is in systoles and diastole (total activation); sometime the activation may be only systolic, if the obstruction causes the opening of the shunt is not complete and therefore a flow rate is still allowed for the physiological route but, upon arrival of the systolic flow wave as a result of the activation of the pumps, drainage also requires an alternative route. if the giacomini’s vein drains into an incompetent gsv and re-entry point is placed below the escape point, a centripetal flow also exist in the giacomini’s vein during muscle relaxation. blood enters the obs for need of drainage, reaching the gsv reflux in diastole in the cs causing a mixed shunt; this pattern may cause signs and symptoms of chronic venous disease, like in our case. figure 2 shows our patient. a musculotendinous band called the vastoadductor membrane, which jointed the adductor tendon to the vastus medialis, can create a notch with a venous stenosis at the outlet of the hunter’s canal, usually located 12-14 cm above the femoral condyle. the vein at this level could be easily compressed in the posterior angle of the hiatus, commonly tightened by a calcified artery. figure 2a: the giacomini’s vein is ectatic and varicose, draining the blood during the muscular systole, in anterograde direction, coming into the gsv in the third distal thigh. figure 2b and c: part of the blood continues to gsv in the anterograde direction reaching the femoral vein (obs), another part overloads the gsv running backwards to the leg (cs), where the reflux moves to the clinically evident varicose tributary which causes hypodermitis and trophic ulceration. case report the popliteal fossa may present various pathological drainage patterns that need to be known to avoid the formation of surgically or sclerotherapic unviable cavernomas if it is an expression of a demolition of obs. it is to be considered that the hemodynamics of the popliteal region differs from the sapheno-femoral one for the particular proximity of this area with one of the primary pumps among all the series pumps we find in the lower limbs: the calf pump. in fact, there are high speed systoles in this area and strong energies are created in the obs in the presence of organic or functional obstacles to popliteal-femoral physiological drainage. the case we present (figure 2) is a mixed shunt and the obs is caused by hunter’s outlet syndrome;3 the patient in fact did not report episodes of deep venous thrombosis (dvt) and no evidence of dvt at doppler-ultrasound (dus) examination were highlighted. compression of the femoral vein inside the adductor’s canal is an underestimated and misdiagnosed cause of postural stenosis of the femoral vein. typically, in these cases, the giacomini’s vein becomes the ep for the obs; the venous blood shunts in a para-physiological pattern aimed to preserve the same limb drainage. in this case, the giacomini’s vein allows an inverted flow (from the deepest popliteal vein toward the more superficial compartment), so overloading the saphenous trunk while by-passing the obstacle (figure 1). the anomalous pathway re-enter into femoral vein by means of the saphenofemoral junction that, in this example, becomes the rp. the terminal valve and the proximal portion of the gsv were competent both with sqeezing and with the valsalva maneuvers.4 in some cases, like the present one, part of the blood below the re-entry of the giacomini’s vein into the gsv flow also in retrograde manner, so dilating the great saphenous vein (gsv) and making it refluxing. this refluxing pattern, constituting a vicious re-circulation, can cause signs and symptoms of chronic venous disease (cvd). because after the digit compression of correspondence: alvise cavallini, private practitioner, lungadige cangrande 10, 37126 verona, italy. tel.: +39.338.6647913 fax: +39.0458341088. e-mail: alvise.cavallini@tiscali.it key words: laser treatment; shunt; endovascular treatment. received for publication: 3 september 2017. revision received: 10 september 2017. accepted for publication: 12 september 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright a. cavallini, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:7048 doi:10.4081/vl.2017.7048 no n c om me rci al us e o nly how i do it [veins and lymphatics 2017; 6:7048] [page 99] the leg varicose tributary (reflux elimination test)4 the reflux in the gsv was still present, our strategy was to perform a laser fragmentation of the hydrostatic column below the re-entry of the giacomini into the gsv, while maintaining the upper outflow point of the obs. technique evlt was performed with a 1470 nm diode laser (ceralas e; biolitec ag, wien, germany) and a commercial kit (elves radial™ kit/venflon™; biolitec ag) containing all the equipment for the procedure (16-gauge needle for percutaneous introduction, 600 µc double radial fiberoptic). evlt was performed in an operating room with an ecg and pressure gauges monitoring. only the short section of gsv with dyastolic reflux was treated (about 10 cm) (figure 3). gsv was accessed percutaneously with dus guidance (vivide, ge healthcare, us). using the 16-gauge introducer needle, the laser fiber tip has been positioned in close proximity to the giacomini’s vein confluence (figure 3). intraoperative dus was used to guide the laser tip position and the delivery of tumescent anesthesia (cold 5°c saline solution 0.9% + 1 fl of lidocaine 2% +1 fl of bicarbonate); this was infiltrated generously around the gsv by using a 25-gauge needle, creating a good halo effect and good compression of the vein. evlt was carried out in a continuous mode with a power of 8 w. the pullback speed on the fiber was calculated to achieve a linear endovenous energy density (leed: energy amount in joules divided by the treated vein length in centimeters) of 80 j/cm. after the procedure, venous outflow was checked immediately in the proximal gsv veins by dus. in the same session all insufficient tributaries were treated by phlebectomy. compression with 20-30 mmhg elastic stocking for two weeks was applied. in addition, as a precaution, low-molecular-weight heparin for six days was given at prophylactic dosage. patient was mobilized immediately after the intervention and were advised to walk regularly during recovery from treatment. we did not observe any particular complication or side effect. after 6 months patient was very satisfied with the method. figure 4 shows results at six months, with the disappearance of the leg varicose veins and the re-epithelialization of the ulcer. giacomini’s vein, although untreated, is less dilated, because the aspiration effect caused by vicious circulation has failed, so the flow rate is reduced. as evident in figure 3, the fiber tip was positioned 1-2 cm below the orifice of the giacomini’s vein under us guidance, also confirmed by direct visualization of the red aiming beam through the skin. figure 1. mixed shunt. figure 3. evlt of refluxing gsv. figure 2. patient 78 years old with mixed shunt which causes severe symptomatic chronic venous insufficiency with trophic ulceration (c2,3,4,5,6sepas+dpr+o13,2,3,5 according to ceap classification). figure 4. medial and posterior aspect of leg and thigh; 1 and 3, before evlt; 2 and 4, 6 months after evlt. no n c om me rci al us e o nly how i do it [page 100] [veins and lymphatics 2017; 6:7048] discussion and conclusions in the last 15 years vein surgery has been largely replaced by percutaneous office-based procedures that can be performed under local or tumescent anesthesia with similar early and midterm results but with less discomfort to the patient, improved early qol, and earlier return to work; saphenous vein thermal ablation is nowadays the gold standard according both american venous forum and the european and american societies for vascular surgery.5,6 as in any field of medicine, however, the correct indication of treatment is crucial; not only technically but also strategically less aggressive approach could reduce the recurrence risk. other authors already reported evlt according to chiva principles with good results.7,8 in our case, performing a standard laser procedure of the gsv would be useless (proximal gsv and terminal valve were competent) and especially harmful, because interrupting obs would meet unavoidable varicose veins recurrence, very difficult to manage. we consider this individualized evlt strategy extremely useful in these complex shunts, because it allows: i) to preserve systolic centripetal reflux in giacomini’s vein; ii) to treat only diastolic vicious circulation without interrupting the centripetal flow; iii) to achieve a good functional and aesthetic result with a mini-invasive and endovascular method, with minimum discomfort to the patient and earlier return to work. we conclude by quoting glauco bassi, an italian phlebology master; he wrote in 1962: the varicose treatment must be polynomial, etiologic, functional and, above all, differentiated, ie different from case to case. under these conditions it provides excellent, lasting and predictable results with remarkable accuracy. we continue to think the same way, technology today makes it easier. references 1. gianesini s, occhionorelli s, menegatti e, et al. chiva strategy in chronic venous disease treatment: instructions for users. phlebology 2015;30:157-71. 2. franceschi c, zamboni p. principles of venous hemodynamics. new york: nova biomedical books; 2009. 3. uhl jf, gillot c. anatomy of the hunter’s canal and its role in the venous outlet syndrome of the lower limb. phlebology 2015;30:604-11. 4. zamboni p, gianesini s, menegatti e, et al. great saphenous varicose vein surgery without saphenofemoral junction disconnection. br j surg 2010;97:8205. 5. gloviczki p, comerota aj, dalsing mc, et al. the care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the society for vascular surgery and the american venous forum. j vasc surg 2011;53:2s-48s. 6. wittens c, davies ah, bækgaard n, et al. editor’s choice management of chronic venous disease: clinical practice guidelines of the european society for vascular surgery (esvs). eur j vasc endovasc surg 2015;49:678737. 7. gianesini s, menegatti e, zuolo m, et al. short endovenous laser ablation of the great saphenous vein in a modified chiva strategy. veins and lymphatics 2013;2:e21. 8. gianesini s, menegatti e, zuolo m, et al. laser-assisted strategy for reflux abolition in a modified chiva approach. veins and lymphatics 2015;4:5246. no n c om me rci al us e o nly 429 too many requests you have sent too many requests in a given amount of time. 429 too many requests you have sent too many requests in a given amount of time. battista agus phlebolymphology giovan battista agus correspondence: giovan battista agus, e-mail: giovanni.agus@unimi.it clinical and scientific data confirm that veins and lymphatics are inseparable in a one veno-lymphatic system. evidently both the venous and lymphatic circulation, in parallel, return fluid to the blood circulation, one would not exist without the other. lymphology is developing fast and cannot exist without phlebology even if most of phlebologists tend to ignore this unintentionally. for v&l it is therefore appropriate to start a new little section with a peculiar culture and history image of medicine regarding this subject. without going back to the italian gaspare aselli with his de lactibus sive lacteis venis, quarto vasorum mesaraicorum genere, novo invento, in the 2017 we can remember il sistema linfatico nella pratica clinica by ippolito donini with his mentor mario battezzati published 50 years ago (1967) (figure 1 and 2). ippolito donini founded the italian society of phlebolymphology opening new perspective in both fields. only recently in the us we assisted to the change of name of an american specialty board from phlebology to venous and lymphatic medicine. figure 1. prof ippolito donini, chairman clinica chirurgica university of ferrara, italy from 1970 to 1999. figure 2. cover of the italian edition of the lymphatic system in clinical practice. padua: piccin ed.; 1967. [top] 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2018; volume 7:7631 [page 74] [veins and lymphatics 2018; 7:7631] increasing public venous awareness, graduated compression stockings compliance and scientific data collection through open events on golf courses: a feasibility study sergio gianesini,1,2 steve zimmet,3 oscar bottini,4 diana neuhardt,5 mark meissner,6 kate gibson,7 eva kalodiki,8 christopher r. lattimer,8,9 paolo spath,10 lorenzo tessari,11 mirko tessari,1 yung wei chi,12 maria grazia sibilla,1 erica menegatti1 1translational surgery unit, university of ferrara, italy;2usuhs university, bethesda, md, usa; 3zimmet vein & dermatology center, austin, tx, usa; 4vascular surgery department, university of buenos aires, argentina; 5compudiagnostics, inc., scottsdale, az, usa; 6vascular surgery department, university of washington, seattle, wa, usa; 7lake washington vascular labs, bellevue, wa, usa; 8josef pflug vascular lab, imperial college, west london vascular & interventional centre, london, uk; 9thrombosis & hemostasis lab, loyola medical centre, maywood, il, usa; 10vascular surgery department, university of bologna, italy; 11bassi foundation, trieste, italy; 12university of california, davis, ca, usa introduction on an international level, public venous awareness is still low.1 campaigns to increase it are needed in order to reduce the clinical and economic burden of venous disease,2,3 and in particular of venous thromboembolism, a leading cause of preventable death in industrialized countries.4 the center for disease control and prevention declared how adequate communication initiatives represent fundamental opportunities to improving health around the world.5 nevertheless, the rapid growth of countless initiatives has led to the need for a deeper analysis in order to determine the real efficacy of these activities.6,7 the aim of the present paper is to evaluate the feasibility of a new format in venous awareness promotion. materials and methods seven international public venous awareness events were developed. these events were twinned with top quality phlebology meetings of the international union of phlebology, american college of phlebology and latin american venous forum. this social project was called game over to leg failure, as the acronym golf and was endorsed by the italian olympics committee and by the italian golf federation. the vision of the project is the promotion of public venous awareness by means of golf and other pleasant activities at the golf course. all events were open to the public. the same field was transformed into an educational pathway. all the participants, before walking onto the field, received a venous awareness questionnaire with 18 true/false questions about chronic venous disease issues. this questionnaire was aimed at testing the actual knowledge on venous disease and graduated compression stockings (gcs). after having walked through the 18 holes and having read all the answers on the banners, golfers and non-golfers were asked to fill out the same questionnaire again, in order to detect the final improvement in their knowledge on the topic. each right answer to the 18 questions scored one point, wrong answers and not reported answers were scored 0. at the field, another set of data collection was related to the effect of an 18-hole walk on lower limb drainage and perceived fatigue following the use of different levels of gcs. a putting green area of 9 holes was dedicated to venous awareness messages too. these educational messages were on the scorecard of all the players, so that they could take home the educational messages. the following services were offered complimentary: i) venous ultrasound scanning; ii) cardiology consultation; iii) nutritional consultation; iv) sport-medicine consultation; v) physiatry consultation; vi) physiotheray; vii) postural evaluation; viii) adapted physical activity on the treadmill; ix) adapted physical activity with an innovative jacket for electrical muscle stimulation training and muscular rehabilitation (miha bodytectm); x) capacitive and resistive energy transfer (tecar) therapy. a workshop about correct prescribing and use of gcs was offered. all the concepts delivered during the day were associated with scientific paper references. a survey was performed to detect an eventual improvement in terms of compliance to gcs 6 months after the event. results among the 7 events, 1684 participants attended the events. three hundred thirtyfour (334) players filled in the venous awareness questionnaire before starting to play the 18-hole course, thus before reading all the banners. among these players, 305 participants filled in the questionnaire also at the completion of the course: the average score improved from 11±2.1 to 16±1.3 (p<0.0001). in 71% of the questionnaires the attendees answered that there is no difference among gcs defined in mmhg or denars. sixty-two (62) lower limb venous ultrasound scans were performed among the participants. seven-hundred-thirtyseven (737) attendees stopped at the educational corner dedicated to gcs. three-hundredfortyfive (345; 46.8%) subjects among the ones who stopped at the gcs corner were already gcs users, nevertheless 35.9% (124/345) of them presented with a previous wrong gcs prescription in terms of size, 20.9% (72/345) with a wrong class of compression (figure 1). at 6 months, 227 subjects of the 345 (65.8%) who were already gcs users replied to the survey about the compliance change after the event attendance: 41.8% (95/227) of them reported an improvement after the change in the prescription. of the remaining 392/737 (53.2%) attendees who have never used gcs before, 37.8% (148/392) begun to use them. the reason for beginning using gcs was prolonged standing work in 70.9% (105/148), and chronic venous disease detected just during one of the screenings offered at the venous awareness event in 29.1% (43/148) (figure 2). in the study population in which lower limb volume was assessed and related to perceived exertion (40 subjects), the use of no hosiery led to a 5% increase in leg volume (p<0.0001), 18-mmhg led to a noncorrespondence: sergio gianesini, university of ferrara, via aldo moro 8, 44128 cona (fe), italy. e-mail: sergiogianesini@hotmail.com conference presentation: international compression club (icc) meeting, paris, 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright s. gianesini et al., 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7631 doi:10.4081/vl.2018.7631 no nco mm er cia l u se on ly conference presentation significant 1% volume reduction, 23mmhg to a significantly reduction by 4%. a significant fatigue reduction was reported only using 23-mmhg gcs.8 conclusions the present investigation reports an innovative format of public venous awareness. in the united states alone, almost 200-health awareness days, weeks and months are reported on the us national health observances calendar. nevertheless, the real impact on the global health status of these noble activities is still questionable, due to limiting factors that can influence the final outcome.5this study potentially solves some of the most common weak points of public health awareness initiatives: adequate attendance, attraction of the public, setting feasibility, knowledge improvement assessment and reliability of the educational message. educational gadgets significantly contributed to continue the health message delivery. an extreme lack of knowledge in the discrimination about figure 1. attendees stopping at the dedicated graduated compression stockings (gcs) workshop. figure 2. new graduated compression stockings users after the dedicated workshop. [veins and lymphatics 2018; 7:7631] [page 75] no nco mm er cia l u se on ly conference presentation [page 76] [veins and lymphatics 2018; 7:7631] every day stockings, self-claimed graduated stockings and certified gcs stockings was reported. this finding is in accordance with a previous analysis by lim, reporting how addressing patients’ concerns, providing adequate information and reassurance can positively impact compliance toward gcs.9,10 another major point in public awareness is the promotion of physical activity, in particular for the elderly.11,12 the present format involved the general public, older ages included, not only on the health topic, but also on the sport practice. a wider data collection is ongoing, in order to precisely depict the socio-economic characteristics of the participants. references 1. wendelboe am. global public awareness of venous thromboembolism. j thromb haemost 2015;13:1365-71. 2. lefebvre p, laliberté f, nutescu ea, et al. all-cause and potentially diseaserelated health care costs associated with venous thromboembolism in commercial, medicare, and medicaid beneficiaries. j manag care pharm 2012;18:363-74. 3. wakefield t. call to action to prevent venous thromboembolism j vasc surg 2009;49:1620-3. 4. editorial. thromboembolism: an under appreciated cause of death. lancet hematol 2015;2:e393. 5. bernhardt jm. communication at the core of effective public health. am j public health 2004;94:2051-53. 6. purtle j, roman la. health awareness days: sufficient evidence to support the craze? am j public health 2015;105:1061-5. 7. ayers jw, westmaas jl, leas ec, et al. leveraging big data to improve health awareness campaigns: a novel evaluation of the great american smokeout. jmir public health surveill 2016;2:e16. 8. gianesini s, tessari m, menegatti e, et al. comparison among 18 mmhg and 23 mmhg elastic stockings effect on leg volume and tiredness after golf. int angiol 2017;36:129-35. 9. lim cs, davies ah. graduated compression stockings. cmaj 2014;186:e391-8. 10. carpentier p, auvert j-f, bensedrine s, et al. compression therapy in everyday life: let the patients have the floor. veins and lymphatics 2017;6:6625. 11. king ac, rejeski wj, buchner dm. physical activity interventions targeting older adults. a critical review and recommendations. am j prev med 1998; 15:316-33. 12. blair sn, franklin ba, jakicic jm, kibler wb. new vision for health promotion within sports medicine. am j health promot 2003;18:182-5. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2018; volume 7:7624 [page 62] [veins and lymphatics 2018; 7:7624] user goals-based approach to identify and prioritise the underlying drivers of low concordance with compression hosiery use jerry hutchinson hutchinson woundtech limited, neston, uk introduction despite evidence that compression hosiery (ch) is effective in chronic venous disease (cvd), concordance is low.1-3 nonconcordance is associated with poorer outcomes.3 there are many underlying reasons for non-concordance some of which also affect the management of type 2 diabetes4 and compression in burn injuries.5 factors differ from the perspectives of the patient, product, and health care professional (hcp). all perspectives must be considered to understand the drivers of low concordance. addressing low concordance from only one perspective is unlikely to generate sustainable improvement in concordance. perspectives related to concordance many patient-related factors affect concordance.6-10 patients lie on a concordance spectrum. some adhere closely to the care plan, some quickly remove ch and never or only occasionally re-apply it. others lie between these extremes. patient beliefs drive concordance. the natural history of cvd is longer than the time scale over which incremental changes can be recognised, perhaps creating the belief that cvd is not serious. consequently, the patient may believe nothing (or little) will happen if they do not wear ch,10 or if they do wear ch. not wearing ch may be seen as permissible. the impact passes unnoticed at the level of conscious perception. the patient may struggle with delivery or understanding of complex education provided by the hcp, or believe that it doesn’t applies to them. patients may be elderly; have limited mobility; reduced strength; comorbidities that impair donning/removing ch; may need the assistance which if not available reduces compliance. there may be reasons for non-concordance associated with design that may be patient-related. low concordance may be psychosocial.9 the wound itself in a c6 patient may impact concordance.11 patients are likely to want their daily life minimally disrupted. activities of daily living (adl) may affect concordance including laundering; replacing/acquiring new ch;12 confidence related to not being informed about how to replace ch;12 divergent priorities for the clinical effects of ch, and adl. co-morbidities may reduce concordance. the patient may have learned to live with the condition. family members/carers may see ch as disruptive, becoming less willing to help. perhaps the carer is elderly and/or infirm and struggles with donning and removing ch. the patient may start concordant but reduce concordance with experience or changing priorities. ch designs may drive non-concordance. the elasticity, stiffness and stretch, which require force to overcome, may be too great. some ch open to aid donning and have closures to overcome donning issues. no alteration to the structure/shape/physical properties of the ch is possible before donning. performance may degrade once worn and repeatedly laundered, but essentially the properties are fixed. ch designs may be highly medical but made to look more like consumer products, perhaps reducing respect for ch making. the comfort of ch is important.12 the hcp expects the condition to be managed by the agreed care plan despite known challenges. the hcp knows that full concordance is unlikely and may identify patients in whom concordance is less likely. the hcp may have history regarding the patient, or general expectations around concordance from the literature and his/her professional experience, or lack knowledge and skills.6-8,13,14 perhaps this uncertainty is communicated to the patient. research proposal identifying the drivers of low concordance is highly amenable to research. a productive method of research is to examine the patient’s goals (user goals). the use of the term goals instead of needs leads to a different mind-set when pursuing the answers. focus on user goals rather than the ch encourages the respondent to consider their drivers and aims. focusing only on ch will generate a list of reasons; without user goals it is difficult to determine how to improve concordance/adoption. the two, being highly inter-related, must co-exist. the users include the patient, the hcp, and the patient’s carer(s)/family members and all should be involved in any research. user goals may be functional, personal, and social. functional goals include managing the condition; reducing oedema; healing the wound; preventing recurrence; reducing pain; minimising need for frequent removal to change or adjust dressings; minimising odour; improving peripheral skin condition. personal goals include donning and removal; comfort; ability to wear normal clothing; impact on adl; quality of life; time spent self-caring; laundering. social goals include outward appearance; social life; group activities; involvement of lay carers; follow up visits to the hcp. the research is structured to identify the underlying drivers of patient behaviour (goals). first, the steps to achieving goals (pathway) are identified. the drivers of concordance could lie anywhere on the pathway. with this focus the findings can be stratified, clearly demonstrating where the main drivers of concordance are. ultimately, user goals are overlaid on the pathway. the pathway is developed by experts, using a structured questionnaire, and validated or developed with patients. pathway step one is the hcp consultation including patient history; assessment and diagnosis; define treatment options; patient/carer education; fit with other parts of the care plan; the care plan; set concordance expectations; initiate care plan; repeat visits to the hcp. the second step is implementation of the care plan away from the clinical setting including removing ch during the day of the consultation; donning and removal on subsequent days (repeated daily); fit with co-morbidities; repeated laundering; ch replacement as required; removal of new ch from packaging. data collection requires user interviews using open questions considering functional/personal/social goals to identify goals for each pathway component and what makes correspondence: jerry hutchinson, hutchinson woundtech limited, neston, uk. e-mail: jhutchinson31@gmail.com conference presentation: international compression club (icc) meeting, paris, 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright j. hutchinson, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7624 doi:10.4081/vl.2018.7624 conference presentation [veins and lymphatics 2018; 7:7624] [page 63] goal achievement easy/difficult. the research should involve ~15 respondents per ch type/condition/hcp/carer to identify the drivers of non-concordance with a high degree of confidence. the number would increase for a study in more than one country to account for national differences. interviews are conducted by an independent, informed interviewer to elicit unfiltered responses. different users will have different foci for using ch; all will have a bearing on concordance. the research should involve patients using different types of ch or with different conditions to increase specificity, likely generating different reasons for non-concordance. this research structure will uncover many stratified reasons for non-concordance and identify main and subordinate drivers. the outcome will inform changes in approach and behaviour by ch manufacturers, hcps, patients and carers. focus on users goals, and understanding why they are or are not being met, will inform new product design, approaches to hcp consultations, enhanced educational materials, and, it is anticipated higher levels of concordance. references 1. arpaia g, milani m, addeo r, et al. clinical validation of a specially sized class ii compression knee-sock for the prevention of recurrent ulcers in patients with chronic venous stasis (ceap 5). int angiol 2008;27:507-11. 2. palfreyman sj, michaels ja. a systematic review of compression hosiery for uncomplicated varicose veins. phlebology 2009;24:13-33. 3. clarke-moloney m, keane n, o’connor v, et al. randomised controlled trial comparing european standard class 1 to class 2 compression stockings for ulcer recurrence and patient compliance. int wound j 2014;11: 404-8. 4. lie ss, karlsen b, ellen renate oord er, et al. dropout from an ehealth intervention for adults with type 2 diabetes: a qualitative study. j med internet res 2017;19:1-11. 5. coghlan n, copley j, aplin t, strong j. patient experience of wearing compression garments post burn injury: a review of the literature. j burn care res 2017;38:260-9. 6. moffatt, c, kommala, d, dourdin, n, choe, y. venous leg ulcers: patient concordance with compression therapy and its impact on healing and prevention of recurrence. int wound j 2009;6:386-93. 7. annells, m, oneill, j, flowers, c. compression bandaging for venous leg ulcers: the essentialness of a willing patient. j clin nurs 2008;17:350-9. 8. field h. fear of the known? district nurses’ practice of compression bandaging. br j community nurs 2004;9:s6s15. 9. finlayson k, edwards h, courtney m. the impact of psychosocial factors on adherence to compression therapy to prevent recurrence of venous leg ulcers. j clin nurs 2010;19:1289-97. 10. harker j. influences on patient adherence with compression hosiery. j wound care 2000;9:379-82. 11. miller c, kapp s, newall n, et al. predicting concordance with multilayer compression bandaging. j wound care 2011;20:101-12. 12. scheer r. clinical innovation: compression garments for managing lymphoedema. wounds int 2017;8:34-8. 13. schofield j, flanagan m, fletcher j, et al. the provision of leg ulcer services by practice nurses. nurs stand 2000;14:54-60. 14. french, l. community nurse use of doppler ultrasound in leg ulcer assessment. br j community nurs 2005;10:s6-13. 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2018; volume 7:7196 [page 34] [veins and lymphatics 2018; 7:7196] nanobiomaterials for vascular biology and wound management: a review ajay vikram singh,1 donato gemmati,2 anurag kanase,3 ishan pandey,4 vatsala misra,5 vimal kishore,1 timotheus jahnke,6 joachim bill6 1max planck institute for intelligent systems, stuttgart, germany; 2hemostasis & thrombosis center, university hospital of ferrara, ferrara, italy; 3molecules in motion pvt. ltd, pune, india; 4department of microbiology, motilal nehru medical college, allahabad, india; 5department of pathology, motilal nehru medical college, allahabad, india; 6institute for materials science, university of stuttgart, stuttgart, germany abstract nanobiomaterials application into tissue repair and ulcer management is experiencing its golden age due to spurring diversity of translational opportunity to clinics. over the past years, research in clinical science has seen a dramatic increase in medicinal materials at nanoscale those significantly contributed to tissue repair. this chapter outlines the new biomaterials at nanoscale those contribute state of the art clinical practices in ulcer management and wound healing due to their superior properties over traditional dressing materials. designing new recipes for nanobiomaterials for tissue engineering practices spanning from micro to nano-dimension provided an edge over traditional wound care materials those mimic tissue in vivo. clinical science stepped into design of artificial skin and extracellular matrix components emulating the innate structures with higher degree of precision. advances in materials sciences polymer chemistry have yielded an entire class of new nanobiomaterials ranging from dendrimer to novel electrospun polymer with biodegradable chemistries and controlled molecular compositions assisting wound healing adhesives, bandages and controlled of therapeutics in specialized wound care. moreover, supportive regenerative medicine is transforming into rational, real and successful component of modern clinics providing viable cell therapy of tissue remodeling. soft nanotechnology involving hydrogel scaffold revolutionized the wound management supplementing physicobiochemical and mechanical considerations of tissue regeneration. moreover, this chapter also reviews the current challenges and opportunities in specialized nanobiomaterials formulations those are desirable for optimal localized wound care considering their in situ physiological microenvironment. introduction nanomedicine is providing explosive development to complement and augment clinical and biomedical practices in wound healing and ulcer management due to its better therapeutic outcome.1 atomic level control of nanobiomaterials exhibit quantum characteristics compared to their bulk materials and when combined with biological properties, biomolecules exhibit entire new phenomenon in this magic dimension. this is the main reason that nanomedicine is preferred over traditional biomedical practices in recent years. by national institute of health (nih) definition, nanomedicine describes use of nanotechnology in biology and medicine ranging from biomedical applications to molecular nanotechnology and nanoelectronics in developing biosensors for diagnosis and therapeutics.2,3 lately, nanoparticles (nps) have been variously used in targeted drug delivery to improve bioavailability and systemic circulation of drug and an insight into this is reflected by the fact that annual investment in nanobiomaterials has increased to 3.8 billion usd.4 in past, targeted drug delivery was one of most sought nightmare of pharmaceutical industry. dendrimer polymer and lipid based drug delivery system had contributed immensely in this regard. dimensional benefits of nps provide an opportunity to adapt in systemic circulation and move through the cell membranes and are concentrated and accumulated inside cytoplasm. design of biodegradable nps, e.g. nanoliposomes, nanospheres, nanocapsule, hollow nanostructures, ceramic nps, dendrimers and polymeric micelles have their own advantages over traditional drug delivery system5,6 (figure 1). they provide sustained release of drug at target sites and can be maintained for longer period in systemic circulations.7 most important characteristic that attracted these nanomaterials to ambitious researchers for drug delivery, emerges from their easy and reliable surface modification for tissue/organ specific targeting.8 in this context, to catalyze the pharmaceutical innovation in vascular biology, a strategic and legislative effort was made via interviewing patients by the consulting physicians to highlight most transformative medicine in last 25 years. out of 941 patient, 513 voted the drugs with superior efficiency as most transformative medicine. this could be future logic for vascular nanotherapeutics design as well since nanotechnology has provided tremendous efficacy via vascular nanomedicine9 (table 1). question related with the efficacy: this drug had a huge impact on our ability to treat osteoporosis; spectacular impact on b cell malignancies, and on autoimmune diseases; the most potent class of agents to lower intraocular pressure; actually modified the course of multiple sclerosis, although difficult to use, has proven life-saving for many patients with arrhythmias. novel mechanism of action: introduced a new set of compounds for treatment of psychosis; prototype of an antibody directed to a growth factor receptor that re-energized breast cancer tumour biology as well as proved highly curative as a treatment of selected subsets. tnf blockers; rheumatology: these drugs first established the paradigm of biological intervention, represented the first class of biological in rheumatology and have made a significant difference in the treatment of rheumatoid arthritis and spondyloarthro pathies; medication that had significant impact on treatment of insulin resistance and helped elucidate underlying mechanism. impact on practice in field: remarkable... for a development strategy correspondence: ajay vikram singh, max planck institute for intelligent systems, heisenbergstr. 3, 70569 stuttgart, germany. e-mail: avsingh@is.mpg.de key words: venous leg ulcer; nanomaterials; hydrogel; dendrimers; organ-on-chip. acknowledgments: avs thanks max planck society for the grass root project grant 2017 (m10335) and 2018 (m10338). conflict of interests: the authors declare no potential conflict of interests. received for publication: 16 november 2017. revision received: 28 january 2018. accepted for publication: 29 january 2018. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright a.v. singh et al., 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7196 doi:10.4081/vl.2018.7196 no nco mm er cia l u se on ly review featuring molecular biomarkers for stratification (bcr-abl rearrangements) and for pharmacodynamics (receptor autophosphorylation). imatinib; oncology: first drug to modify immune response by enhancing it. this is a sentinel therapeutic approach. cinacalcet; nephrology: a unique addition to the armamentarium of drugs for renal bone disease. grew directly out of knowledge gained in basic science research and shows how transformative such work can be. nitisinone; medical genetics: first example of substrate depletion as a therapeutic mechanism for an inborn error of metabolism [disease]. improved safety: when introduced in 2001, overcame many of the severe toxicities associated with combination art regimens before this (tenofovir; infectious diseases). temozolomide; neurology:although the effects are modest, it is clear that the ability to have access to a tolerable treatment for gliomas is important and driving future drug table 1. justifications used by study participants to indicate a drug as transformative. justification freq. (n = 941); n: %* illustrative remarks improved efficacy 513; 55% alendronate; endocrinology rituximab; rheumatology and oncology latanoprost; ophthalmology interferon beta-1a; neurology amiodarone; cardiology novel mechanism of action 345; 37% clozapine; psychiatry sildenafil; urology trastuzumab; oncology tnf blockers; rheumatology metformin; endocrinology impact on practice in field 143; 15% imatinib; oncology imiquimod; dermatology cinacalcet; nephrology nitisinone; medical genetics improved safety 139; 15% tenofovir; infectious diseases temozolomide; neurology fluoxetine; psychiatry propofol; anaesthesiology widespread use and impact 110; 12% fluoxetine; psychiatry enalapril; nephrology sildenafil; urology omeprazole; gastroenterology ease of patient use 109; 12% etanercept; rheumatology combination fluticasone/salmeterol; pulmonary medicine zithromax; infectious diseases tamsulosin; urology application to multiple diseases 63; 7% infliximab; rheumatology onabotulinumtoxina; neurology rituximab; rheumatology/oncology leuprolide; endocrinology acei, angiotensin-converting enzyme inhibitor; anca, anti-neutrophil cytoplasmic antibody; art, antiretroviral therapy; ckd, chronic kidney disease; pde5, phosphodiesterase 5; ssri, selective serotonin reuptake inhibitor; tnf, tumor necrosis factor. *round 1 responses only. answers do not sum to 100% because they were not mutually exclusive. reproduced from kesselheim and avorn, 20139 with permission. [veins and lymphatics 2018; 7:7196] [page 35] figure 1. nanotechnology based translational quest for next generation biomaterials for vascular biology applications (reproduced with permission from ref.6). no nco mm er cia l u se on ly review development. fluoxetine; psychiatry: transformed treatment of depression providing effective agent with far fewer side effects and toxicity risks in overdose than tricyclic antidepressants and monoamine oxidase inhibitors. more rapid recovery with less delirium and less postoperative nausea. fluoxetine; psychiatry: widespread use and impact: first [ssri] to have a major impact worldwide. ushered in a new era of novel antidepressants. enalapril; nephrology: the primary agent that has spawned the widespread use of acei in ckd over 25 years. sildenafil; urology: it is obvious that this was the number one transforming drug not only in urology but in all of medicine and society in last 25 years. omeprazole; gastroenterology: perhaps the most important proton pump inhibitor; more than 60 million americans have gastroesophageal reflux disease, many on a daily basis. ease of patient use: huge impact because of the ability to administer the drug at home (in addition to its efficacy). combination fluticasone/salmeterol; pulmonary medicine: inhaled steroids modify natural history but have poor compliance. adding salmeterol improves compliance. zithromax; infectious diseases: the first antibiotic to have both massive use and once daily dosing. first specific alpha-blocker; no dose titration needed. infliximab; rheumatology: application to multiple diseases: first anti-tnf monoclonal antibody approved for multiple clinical indications, including inflammatory bowel disease. onabotulinumtoxina; neurology: this drug completely altered the treatment for focal dystonia. it has also been useful for many conditions outside of dystonia. rituximab; rheumatology/oncology: [established] the central pathogenic role of b cells in multiple autoimmune diseases including some (rheumatoid arthritis, anca vasculitis, type 1 diabetes, multiple sclerosis) not typically considered b cell diseases despite the expression of autoantibodies. vascular biology and nanomedicine a recent development in material synthesis has given an edge to synthesize biological structures in vitro under ambient lab conditions. these developments coupled with tissue engineering have put forth enormous capabilities of these materials in vascular biology and regenerative medicine. in biomedicine, vascular biology is one of very advance field that seldom needs technical expertise since this field comprises vast cardiovascular premises surrounded by blood vessel and associated structures.10 advances in nanomedicine have given a languishing hope to future promises in this field due to ground level cooperation between various fields of basic sciences comprising engineering, medicine, physics, chemistry and biology. an in vitro study had revealed that biocompatible nanosurfaces promote growth and proliferation of vascular cells viz. endothelial and smooth muscle cells that paved the way for future vascular stents applications in designing endothelial monolayer.11,12 application of nanomedicine in vascular biology advent and increased sophistication of nanotechnological tools provided us an understanding to develop in vitro biological circuits using smart carbon materials that can be used for neuronal prosthesis in vivo.with the discovery of conductive carbon nanotubes and nanofibres with the excellent biocompatibility, a new hope in muscle and brain neuro-vascular biology has aroused specially in neurodegenerative disorders such as parkinson (pd), alzheimer’s (ad) and multiple sclerosis (ms),13,14 where such developments will bring million dollar smile.15 major problem with neuronal vascular biology is their poor capability to proliferate and their nasty requirement for growth and interaction with the surrounding cells maintaining their neuronal plasticity.16 nanofibres-polycarbonate urethanes (pu) composite have provided a novel solution to gliotic scar formation in tissues that was a major challenge in neuronal prosthesis and functionality. this composite also provides positive interaction and cooperation among cells in vitro.17 lately, researchers have shown that neuronal and bone forming stem cell associated with clinical disorder had shown reversal in terms of neuronal/osteopathic anatomy and functionality when cultured in biocompatible environment of composite carbon nanofibers18,19 (figure 2). [page 36] [veins and lymphatics 2018; 7:7196] figure 2. schematic illustration of nanomaterials used for skin wound therapy: from nanoparticles to nanoparticulate composites. abbreviations: fms, films and membranes; hgs, hydrogels; mcs, multicomposites; nfs, nanofibers; nps, nanoparticles (reproduced with permission from ref.18 with free use creative commons attribution 4.0 international license). no nco mm er cia l u se on ly review nanobiomaterials: new beginning in wound healing and ulcer management as updated convention, biomaterials can be defined as substances composed of biologically derived moieties (other than drugs and food) those can be successfully used for therapeutic or diagnostic purposes irrespective of their applications.20 in recent years, biomaterials research has gained momentum due to their significant contribution in biology and medicine.21,22 use of biomaterials in tissue engineering is revolutionary rather than evolutionary due to their capabilities to synthesize artificial connective, epithelial, or neuronal tissues. one of major breakthrough supporting nanobiomaterials in medicine is their dimensional versatility that ranges from equiaxed symmetrical gold,7,23,24 platinum, titanium nanoparticles (nps), quantum dots (qds) to one dimensional fibrous forms (carbon nanotubes/fibers)25 that make them a suitable choice for wound dressing materials. this dimensional profitability makes them materials of choice in various implants and prosthetic applications where dimensional stability is most important features. for example nanobiomaterials have been used in zirconium based joints (hip, knee, shoulder), cochlear/dental and breast implants, ear and glaucoma drainage tube, mechanical heart valve and articular graft, intra ocular lens,26-33 etc. nanoclay and nanohdyroxyapatite are used to fillers and reinforce agents to strengthen the mechanical stability of polymers in various prosthetic processes.27,34 the smart aspect of nanobiomaterials can be evaluated by their smart application in bioelectronics that they not only can touch, feel or stimulate the biological system but also can transmit the information as sensors, biofuels or circuitry elements for versatile biomedical applications that could be another promising approach in design of electronic skin.28,30 these could be used in wound management with supported antimicrobial agents as filling materials in deep cuts and burn cases where we need to cover large surface areas to protect skin and promote rapid healing.29,30 the biggest advantages of nanomaterials are their large surface to volume ratio i.e. they can cover large surface area applied. this characteristic provides a unique opportunity in surface healing process where we need minimal therapeutic to cover large area. challenges in designing biomaterials for wound healing and ulcer management challenging aspects that might be considered during design of nanobiomaterials for wound healing must consider required biodegradability, surface properties, mechanical properties, shapability to sculpt finer details31 (figure 3). some of the challenges in the designing nanobiomaterials are discussed with following areas: i) progress and challenges mimicking ecm biologically and structurally; ii) actively interaction nanostructures, which promote mammalian cell interaction and inhibit bacterial growth;32-34 iii) detail list of biomaterials used for biomedical applications (e.g., soft [veins and lymphatics 2018; 7:7196] [page 37] figure 3. evolution of resolving versus nonresolving inflammation at a cellular level. (a) typical features of a normal acute inflammatory response to infection that is detected by presentation of pamps to pattern recognition receptors. eradication of the pathogen eliminates the stimulus, along with causing some reversible collateral tissue damage, and sets the stage for the resolution/repair phase, leading to restoration of normal tissue homeostasis. (b) typical features of a chronic inflammatory disease caused by a nonimmune pathophysiologic process that in one way or another triggers an initial sterile inflammatory response, often indolent and likely through production of damage-associated molecular patterns (damps). this initial response then becomes amplified by cytokines and chemokines. because this response does not eradicate the initial stimulus, persistent nonresolving inflammation occurs, ultimately resulting in tissue damage. the inflammatory response itself may positively influence the production of damps, which provides an additional positive feedback loop. for example, in the case of atherosclerosis, reactive oxygen intermediates (roi) and reactive nitrogen intermediates (rni) may modify subendothelial lipoproteins in a manner that amplifies their ability to promote inflammation. adapted with permission from ref.36 tabas et al. no nco mm er cia l u se on ly review nanomaterials, hydrogels, fiber scaffold mimicking ecm, dendrimers and electro spun polymers and their advantages);35 iv) corneal wound healing, bladder wall and vascular biology applications: a special use of biomaterials is required due to complex inflammatory cascade depending upon chronic and acute cases;36 v) details of advantageous factors those give an edge to nanomaterials for use over traditional one e.g., surface modifications to prohibit nonspecific protein adsorption, pinpoint and accurate immobilization of signaling molecules over required surface, biologically inspired nanofibres to mimic natural ecm structures, arduous and vociferous design of 3-d architecture to develop in vitro blood vessels with supported angiogenesis;15 vi) unique surface energy of nanomaterials: protein-mediated cell interactions. artificial skin: emerging concept for regenerative medicine designing materials for wound healing and ulcer management had taken one-step forward from traditional materials dissecting the conventional thinking to design dressings and antimicrobial supplement.37 the concept and realization of initial steps of designing artificial skin had given a great hope to regain price and prejudice of aesthetic value in burn cases where often patients has to lose a lot in terms of social values due to lost skin textures that leave a scar after treatment. natural skin transplant will be the first choice for clinicians and surgeons to replace scarred skin in burn cases, nonetheless designing artificial skin will enhance the scope of regenerative, and transplant medicine to underscore the conundrum of success of manmade organ over natural one. fundamentals of designing artificial skin skin with integument system makes primary defense barrier against microbes and keeps body surface in tune with the external environment. histology of skin comprises epidermis composed of stratified squamous epithelium, a dermis having dense connective tissue and fibroblasts with underlying hypodermis with adipose and connective tissue fibers.38among above two, epidermis is home of ecm forming keratinocyte, melanin producing melancholy and epithelial cells. considering design of fully functional artificial skin, graft materials should adhere with wounded skin and should be porous enough to allow diffusion of gases, water, nutrients, waste and most importantly prevent dehydration of surrounding wounded skin. graft materials should allow migration and relocation of cell components and should be comparable with natural skin in mechanical and electronic properties. finally yet importantly, artificial graft must support regeneration of underlying dermal layer that in turn will support the regeneration of epidermal layer. these advances on one hand will prevent microbial invasion to wound site, on the other hand give an opportunity to fast healing.39 material design for artificial skin graft must fulfill nutrient and growth factor requirement, taking care of immunological aspect to avoid foreign body and prevent rejection of its own. further, they must have inherent ability to integrate artificial tissue with supporting innate vasculature and must be supplemented with cultured skin cells that makes it truly bioactive and helps in establishing connection with the underlying natural tissue.40 moreover, we need to put the basics on designing skin with mechanoreceptors, pressure and tactile receptors with impregnated hair follicles and nerve branching. one fascinating work had reveled construction of nanotransistors tagged with large area, flexible pressure sensor matrix that eventually work as electronic skin for futuristic nanorobots aimed to surgical procedures in vitro.37,41 so for progress made in this area adapted discriminative approaches supplying grafts with cultured epidermal cells in one case, cultured dermal in another case and a supplement of duo in third case. researcher suggested that grafts with dermal layer after regeneration supports a subsequent auto graft and provide best opportunity in burned tissue regeneration.42 basic design of artificial skin must include the vide-infra scope of chemical composition that leads to the fundamental success of the story. studies hypothesizing importance of chemical compositions have given insight that collagenglycosaminoglycan (gag) membranes cross linked with glutaraldehyde (as cross linking agents), used as artificial skin, had shown to have capacity to escape fluid loss and infection over longer period of time (figure 4). most important they prevent graft rejection and contraction of wounds that is of primary importance for cosmetic purposes in facial wounds and functional importance in corneal wounds since contraction in corneal wounds produces astigmatism.43 as an evidence, chemically crosslinked glycosaminoglycan (gag) with hyaluronan (ha) and chondroitin sulfate (cs) as an active ingredients have been shown to perform better wound dressing materials than the traditional one.44 nanobiomaterials have numerous advantages over the traditional one due to their various properties as discussed next. in terms of thermal sensitivity, traditional biomaterials are moderate due to meso-micro scale modifications in comparison to the nanobiomaterials showing higher thermal sensitivity due to nano scale modification.45 the hydrophilicity of nanobiomaterials due to surrounding temperature control46 is more than the traditional biomaterials. the nanobiomaterials have higher surfacevolume ratio,47 which helps in cell attachments and grafting more than the traditional ones, which have the low protein interaction surface energies. due to the biological origin and bio-polymers,48 nanobiomaterials are superior, in terms of figure 4. schematic plan showing hyaluronan-gag-core protein cross-linking strategy to design hydrogel based artificial skin-ecm analogue. fundamental design includes hagags backbone that supports nanoscale protein-carbohydrate monomer buildings blocks pegged meticulously to mimic biostructure (n: repeating units; authors personal communication). [page 38] [veins and lymphatics 2018; 7:7196] no nco mm er cia l u se on ly review biocompatibility and biodegradability, to traditional biomaterials. nanobiomaterials also has preferences in terms of hydro retention due to use of hydrogel-based dressing49 rather than traditional gauze based dressing materials used in traditional biomaterials. also nanobiomaterials are more bioadhesive and antimicrobial due to the impregnated antimicrobial supplement into its nanoporous membrane50 which is supplied from outside in the conventional biomaterials. however, traditional biomaterials have an advantage concerning the tissue abrasion over nanobiomaterials due to foam-based airfluidized.51 with reference to mechanical properties, the usual biomaterials show sufficient strength but less than the nanobiomaterials which have nanopolymer layer.52 designing of biomaterial mimicking ecm using nanoscale tissue engineering ecm defines extra cellular part of cell that often provides structural supports to cell and more precisely defines connective tissue. ecm regulates cell’s dynamic behavior in terms of intercellular communication and deporting a number of growth factors those helps in cell signaling and cell anchorage in various biological phenomenons.53 it becomes an important issue to consider ecm morphology and function when considering design of nanobiomaterials for wound healing and reparative tissue management, as formation of ecm is the fundamental process in morphogenesis, wound healing, growth and fibrosis. deep understanding ecm components such as proteoglycan and non-proteoglycan (gags) that form a matrix by interlocking with the fibrous proteins will help to assemble biological moieties to form artificial ecm membrane for wound healing and burned skin.54 ecm contains cell-binding domains those interact with cell receptors and transmit cellular signals to cell-cell/cellecm adhesion and binding. ecm mediated cell signaling also helps in sequestering various bioactive molecules such as fibrous proteins, gags, growth factors and cytokines which is important steps in tissue remodeling at wound sites.55 in vitro ecm synthetic analogue artificial design must sketch structural and functional relationship between ecm and biomaterials that can sustain and respond pharmacological action at living tissue and engineered interface.56 some studies had shown nanofibre scaffold mimicking ecm designed by tissue engineering.12,57 dynamic interaction among cell components nanobiomaterials must exhibit a dynamic microenvironment at wound site to facilitate cross talk among soluble (growth factors, cytokines, morphogens) and insoluble components (cells, ecm components) under ambient chemical environment (ph, o2)58 to establish a vital connection between the living tissue and nonliving biomaterials.12 tissue regeneration most sought requirement of designing ecm replica should support tissue regeneration at wounded tissue site. this could be achieved by meticulous surface modification of proteins and cell binding domains and incorporation of such ligands (rgd, ikvav) in molecular design. the scaffold must provide a guided mechanical platform for new skin growth.59 active cellular/tissue responses biomaterials design so for give nonspecific responses towards biological system due to inappropriate design of cellular components. this is major challenge to today’s material research to pinpoint the target specific receptor to respond cellular functions viz. adhesion, proliferation and differentiation in artificial design of molecular components. this needs controlled incorporation of cell binding and enzymatic sequences sites in bioactive design. specialized application of soft nanomaterials corneal wound healing corneal wounds repair is of paramount importance as cornea is site of refraction and focusing light in order to make correct vision. non-vascular nature and patterned collagen fibrils provide characteristics transparency to cornea that makes it special tissue for normal vision. corneal wounds are caused due to a number of reasons including corneal ulcer, ocular surgery (intraocular implantations, incisions for cataract surgery, in situ keratomileusis and transplants) and trauma caused by lacerations or perforations. currently, nylon sutures are choice of surgical procedures but they achieved cold reception from clinicians due to some undesired properties. nylon sutures often cause wound constrictions and asymmetrical healing that often leads to astigmatism. moreover, suture and incision during ocular surgery inflicts additional trauma to corneal tissue and thus inflammations and vascularization ending into corneal scar that contribute significantly to astigmatism. more often, sutures need special attention and technical skills by trained ophthalmologists in order to avoid postoperative loosening and corneal trauma during in and out of suture removal.60 therefore, technological skills to design new surgical materials and tools constitute competitive race in this field in order to restore natural vision and patient care in ophthalmic and corneal wounds healing. designing new recipes must consider technical achievements mentioned above. considering above design requirements, we need a polymer adhesive that can seal corneal wound rapidly and accurately restoring correct intra ocular pressure (>80 mmhg) and must comprise sufficient viscosity allowing clinician for precise placement and workability (viscosity <100 cp).61 moreover, polymer adhesive must restore structural integrity of patterned collagen fibrils to provide native corneal transparency to focus the lights accurately and most important elastic modulus of polymer adhesive must be greater than corneal tissue to negate any possibility of astigmatism. solute diffusion properties, biocompatibility, microbial barrier and biosorption of wound exudate are additional designing essentials where beauty meets utility for corneal wound care.62 fundamentals of corneal wound management require repairing lacerations and clear sealing of incisions with securing corneal transplants. closings of lasik flaps are other ophthalmic indicators where nanoadhesives may prove to be landmark success. next age materials such as polymeric dendrimer provide unique solutions to special wound care such as in corneal and ophthalmic injuries. biodendrimers63 made up of polyethylene glycol (peg), succinic acid (sa) and polylactic acid (pla) are unique biocompatible and degradable polymeric dendrimers that shows controlled hydrophilicity and cell attachment/detachment properties.64 further, capability of peptide-ligation based soft cross-linking avoids complex photochemistry and procedural risks that makes this more amenable for clinical procedures. peptide cross-linking provides additional support to physico-mechanical properties (e.g., modulus and plasticity) and fit for clinical response in situ.65 peptide lock and cross links in hydrogel and adhesive used for corneal wound care further give possibility to peptidases based easy cleavage when it comes to integration of nano-domain [veins and lymphatics 2018; 7:7196] [page 39] no nco mm er cia l u se on ly review [page 40] [veins and lymphatics 2018; 7:7196] protein or monomer in multigenerational biodendrimer synthesis66 (figure 5). nanobiomaterials for synthetic bladder wall substitute a large number of populations suffer from cancer and disorders related to bladder. in absence of suitable surgical treatment and chemotherapeutic panic, removal of entire bladder wall is considered best strategy to prevent the recurrence of bladder cancer and disorders. considering essentials of designing new materials, mimicking topographic features of bladder wall with stretchability, mechanical properties and optimal knowledge of cellular and molecular events in vivo, are the main requisite.67 surface features of bladder gives an understanding of designing biological nanostructures, such as nano-dimension extra cellular matrix constituent proteins that should be precisely incorporated and tagged with the biological moieties to give maximal cell response. researchers have designed nano-dimensional poly (latide-co-glycolide) acid (plga) and polyurethane (pu) based artificial structures mimicking bladder topography in 50-100 nm range those exhibit excellent in vitro cytocompatibility and enhanced bladder smooth muscle cell adhesion and proliferation.68 designed materials show parallelism with in vivo functionality of natural bladder wall that opens new avenues for nanobiomaterials for designing tissue engineered artificial structures.69 nanobiomaterials in artificial blood vessel replacement: a special case of intravascular wound healing apart from surface wound, deep vascular tissues often meet intra vascular tissue damage due to ischemia and perfusion such as in myocardial and endothelial injuries which need immediate clinical attention, being part of vital organ.69 more often cardiac procedures are supplement with bypass surgery of affected blood vessels with autologous arteries or veins of less than 6 mm diameter, in order to reduce procedural and invasive risk of heterologous grafts rejection.70 many myocardial infarction patients need an alternative to innate blood vessels in coronary artery bypass graft surgery (cabg) as a replacement to their diseased or sclerosed blood vessels.71 in this regard, the design strategy involving core technology must meet a number of cell construct in vitro that can precisely mimic the vessel architecture and land marks in vivo with respect to biochemical and biomechanical aspect. new age biomaterials and micro to nanoscale technologies provide artistic liberty to meet the precision in this regard by meticulously mounting biochemical building blocks. for example, artificial endothelial layer production needs cross linking of collagen fibers, integrated with growth factors needed for cell communications between different vessel wall layers.72 lately, in vitro studies shown that radial stresses induced by cyclic stimulations give better mechanical strength and histological organizations in which cells get arranged circumferentially throughout the wall thickness like natural blood vessel wall. this mechanical stimulation plays a key role in precise netting and increasing collagen content in artificial structure compared to unstrained controls.72 evidence to mechanical conditioning that stimulates cell mediated construct remodeling is demonstrated by over expression of matrix metalloproteinases (mmps). these are expressed in relation with the production of ecm structural proteins (elastin and collagen) and reinforce the remodeled tissue.73 this is further supported by increased level of collagen and elastin mrna content in mechanically stimulated and cyclically strained cells in vitro.74 another most important factor that paves success of artificial design of blood vessels is cell technologies enabling pinpoint cell manipulation and their controlled functionality.75 these features can be further regulated by creating extracellular environment of embryonic cells (ecs) utilized for making synthetic grafts by encapsulating them in reconstituted collagen matrix, providing functional vaso-activity in biological scaffold.76 by inducing endothelialization in synthetic graft, it is possible to design an artificial blood vessel. this construct should contain an outer adventitia made of fibroblast and collagen, a middle layer (media) made of mesenchymal stroma cells (mscs) and ecs based internal monolayer (intima), when molded in tubular fashion. insight into nanomaterials used for wound healing and tissue repair process nano-hydrogel in tissue repair: soft nanochemistry in new role hydrogels are hydrophilic, insoluble and swallowable materials; made up of natural (alginates/chitosan/agarose/chitosan/fibrin) or synthetic (poly (acrylic acid) and its derivatives;77 poly (ethylene oxide) and its copolymers and polyvinyl pyrrolidine, polypeptides and their derivatives polymers.78 hydrogel derived from biopolymers and designed as bioscaffold precisely mimic ecm in its chemical compositions comprising numerous amino acids, fibrous proteins, growth factors and sugar. designed hydrogels also contribute to ecm functions by bringing cell junction together, recruiting growth factors for cell communications, allowing extracellular metabolite/nutrient transport, and most important controlling cellular architecture in vitro.79 in last few decades, realization of artificial prosthetic organs ranging from dentin, cartilage, ligament, tendon, bone to soft vascular prosthetic implants (arteries, bladder, skin) have been made possible due to generous hydrogel based scaffolds.80 lately, uses of hydrogel for wound healing and tissue repairs process have gain applause in medicine based on capability to design and control their physical properties as per tissue repair requirement and support figure 5. (a) dendrimer with internal cavity, core and branching units with unique interior and surface chemistry to couple the therapeutic pay-load (colored dots show simultaneous loading of different drug molecule delivery at wound site). (b) cartoon showing sequential addition of generations in those has advantages over controlling globular/linear/symmetrical faces of dendrimer to design 3-d architecture. inset showing interaction of ligand-receptor complex at dendrimer surface (yellow line shows peptide spacer linked to ligands; authors personal communication). no nco mm er cia l u se on ly review for tissue remodeling.81 hydrogels have been devised for occlusive dressing, cartilage tissue repair, and injectable cellular scaffold, axonal regeneration in spinal cord injury and tissue sealant in neurosurgery.82-86 yet there are many open prospects those can serve for more advance use of hydrogel as novel nanomaterials for tissue repair. one novel strategy could be design of hydrogel-based bioscaffold comprising fibronectin functional domains (fnfds) and hyaluronan (ha) for tissue repair. since fnfds hydrogel matrix is a tremendous medium for promoting wound healing by binding with the platelet derived growth factors (pdgfs), it assists with the fibroblast migration in situ that is a crucial step for tissue induction for remodeling of injured tissue.86,87 as mentioned above, hydrogel matrices are available in a wide range of designs from nanoporous, fibrous to fine network of embedded proteins. 3-d hydrogel matrices give a unique opportunity for designing artificial ecm pegged with growth factors and therapeutics required for rapid healing as shown in figure 6. such designs, mimicking porous and fibrous ecm will support cell growth and migration by trapping fibroblast and other inflammatory cells required for tissue remodeling.88 more ambitious; 3-d hydrogel architecture housed with the cultured fibroblast with growth factors, acts as smart natural skin to establish aesthetic remodeling of lost skin in burn cases and massive injuries with severe tissue loss.89 electrospun polymers scaffold: tissue repair at the rate of spinning chemistry biomaterial designers have given a new horizon to biomedicine by developing procedure to control nanostructure by introducing biocompatibility, mechanical stiffness, stability and biodegradability. electrospinning, electrostatic and gas blowing technologies had given an edge to design nanowoven fibrous materials from organic/inorganic to biological polymers. simultaneously we have control over porosity and diameter, mesh size, texture and pattern giving larger surface area and high surface to volume ratio (s/v) for biomedical and industrial applications.90 nanofibrous materials have secured their application from medicine, cosmetics, tissue scaffold for implants to industrial purposes depending upon nanofiber shape, alignment and cross section that are exclusive features in selecting the fiber materials for a particular application.91 one of biggest advantage that we can count over use of electro spun scaffolds for wound healing and tissue repair process over native polymers is their physical resemblance with ecm in native tissue, which makes them a promising candidate for regenerative medicine. electrospun ecm substratum camouflage gives an opportunity to assess cellular function in vitro and applications where such scaffolds are used as cell delivery vehicles and viable cell grafts. compare to traditional polymer engineering techniques, electrospun polymer nanofibers involve controlling a vast array of parameters. this characteristic is tremendously important for their application in postoperative surgeries and stimulating tissue regenerations by promoting adhesion, proliferation, and differentiation cellular flora at the wound site.92 further, electrospun materials fall in both i.e. natural and synthetic polymer categories. clinicians have free option to choose best for our tissue repair mechanism that can either support physical (strength/durability) or biological (cell attachment and proliferations) functionalities, or both and indeed researchers had shown is past such subtle advantage while combining the two.93 thus, above findings reveal the potential of electrospun polymer applications one-step ahead to develop the artificial skin and smart ecm grafts for tissue repair in severe clinical crisis such as heavy burn and injuries involving massive muscular damage. recently polymer colloids have attracted much glare in biomedical applications due to their superior properties of design and feasibility to introduce branching and biodegradability.94,95 polymer colloids are 100-400 nm diameters with great soft architectural diversity. their ability to easy encapsulation, modify hydrophilicity/hydrophobicity and sustained release at application site, makes them good candidate for their surgical use in arteries and connective tissue. moreover, new categories of polymer colloids can be designed based on requisite as per biomedical applications. polymer chemistry has given an opportunity to design resorbable colloids those could be used as promising wound dressing materials.96 in addition, resorbable colloids offer great commercial viability for clinical applications such as postoperative anti-adhesion membranes in trauma. another benefit these resorbable colloids offer is that anti-adhesion biofilms that on one hand offers excellent biosorption barrier to prevent postoperative complications; on the other hand, it undergoes self-degradation when tissue remodeling is completed at augmented wound site. recently endothelial progenitor cell (epcs) has been used as smart biomaterial composite for the control of microenvironmental cues since they promote differentiation, angiogenesis and bone marrow-derived endothelial progenitor cell mobility via secreting vegf and vegfr-2 factors. circulating epcs from human fetal aorta with strong self-renewal ability express cd133, cd34, and vegfr2, which play a vital role in cure of diabetic foot in murine models. transplantation of human fetal aorta (hfa)-derived epcs has recently proved to be vital for treating microvascular dysfunction prevalent in diabetic vascular biology, could be useful for innovative therapeutic strategy for managing other vascular diseases. easy availability and rapid expansion of adipose-derived stem cells (ascs) from autologous adipose tissue with antiapoptotic factor, secretion of proangiogenesis, and capacity for multilineage differentiation has been used vascular tissue repair, rescue and vascular growth. apart from aforementioned applications, electrospun polymer scaffold have been used figure 6. image showing immunostained cells growing (left panel) fine network of hydrogel mesh (right panel) housing granulated collagen, growth, network of keratinocyte and chondroitin 6-sulphate as viable skin for wound repair (authors personal work). [veins and lymphatics 2018; 7:7196] [page 41] no nco mm er cia l u se on ly review [page 42] [veins and lymphatics 2018; 7:7196] in many clinical emergencies as artificial implants for tissue repair. electrospun nanofibres have been developed into different tissue scaffold combining cultured cells with natural and biocompatible materials depending upon clinical requirement as stated in table 2.97-107 limitation, progress and prospect development in nanomedicine had offered many opportunities to improve wound healing and tissue repair process due to progress in biomimetic approach to design bioactive nanomaterials with much closer to natural tissue with respect to structure and function. research in this area have responded to long arguments in scientific community by putting forth rational advances to develop artificial skin and ecm analogues which can be an innovative supplant for future clinical emergencies needing commendable tissue repair back up. recent advances in nanotechnology such as electrospinning have given liberty that is more artistic to researcher while designing the materials of clinical as well as aesthetic superiority. present review outlined the principal clinical requirement for wound healing and their subsequent challenges and applauding measures provided by recent developments in nanomedicine and materials science. perspective arduous biomedical challenges and their possible solutions in designing artificial skin and ecm have been reported provided with ambitious progress in materials sciences. we also reported the use of nanobiomaterials in special clinical practices such as corneal wound, bladder wall and vascular biology applications where we need to put maximum precautions while developing new materials. in addition, details regarding state of the art nanobiomaterials such as dendrimer and polymers (electrospun and hydrogel) those have served in tissue repair process are mentioned. artificial 3d cell culture from a modern neurobiology perspective is at infancy but provides a great hope for tomorrow, bringing relevance and meaning to cell based assays for different applications. realizing the fact that cells in tissue operate in a 3d environment, switching to a 3d cell culture system will involve substantial time and cost, in terms of technology, and most importantly in throughput and scalability.108 the current state-of-the-art three dimensional culture and imaging in multiple planes involves detecting a 3d multicellular body most often embedded in a gel type, ecm mimic, or table 2. represents electrospun nanofibers conjugated (using coupling chemistry) with the mammalian cells, natural and synthetic biocompatible materials for various tissue management clinical practices. clinical conditions biomaterials nerve implants neuronal stem cell + poly(l-lactic acid)97 vascular grafts myofibroblasts, arterial smooth muscle cell human coronary artery endothelial cells, pla, collagen type i&ii, elastin98,99 bone implant osteoblast, mesenchymal stem cells + silk/polyethylene oxide/hydroxyapatite / bone morphogenetic protein100 cardiac implants cradiomyocytes and myoblasts + polyaniline and gelatin, polylactide101,102 human ligament implants ligament fibroblast + polyurethane103 cartilage implants chondrocytes + collagen type ii104 skin implants human fibroblast and keratinocytes + collagen type i coated with collagen type i and laminin, poly(lactide-co-glycolide)12,105,106 breast implants human fibroblast and keratinocytes + collagen type i coated with collagen type i and laminin, poly(lactide-co-glycolide)107 table 3. current organs-on-the chip devices with drawbacks in organ blue prints. model cell niches organ blueprint drawbacks blood brain barrier (bbb) astrocyte-endothelia tight junctions and teer no human cell lines tested for barrier functionality retinal blood barrier (rbb) ocular vascular cells epithelial barrier tight junctions vitreous and mechanotransduction mechanism are and corneal epithelial cells not explored mammary gland breast specific endothelial cancer model for metastasis cancer molecular markers expression fibroblast and epithelial cells and tumor invasion is not validated bone-marrow-on-a-chip viable marrow tissue with organ level marrow toxicity interaction between bone components functional hematopoietic responses to radiation and such as lacunae, canaliculi missing niches protective effect of the radiation counter measure drugs gastro-intestinal-tract (git) gut epithelial cells intestinal absorption mechanism model lack mechanical stimuli mimicking screening of molecular markers microvillus in gut kidney glomerular screening of molecular markers glomerular anatomy blueprint missing network (renal tubular epithelial cells) lungs airway epithelial cells demonstration of lung inflammation complex fabrication, live imaging alveolar epithelial cells and extra pulmonary absorption is challenging, hybrid model lacks pulmonary microvascular alveolar capillary interface vascular network endothelial cells liver hepatocytes liver zone and sinusoid formation, model close to regeneration but lack capability as vascular endothelial cells serum protein synthesis independent implantable device fibroblasts no nco mm er cia l u se on ly review [veins and lymphatics 2018; 7:7196] [page 43] hanging in a drop type culture.109 though existing systems continue to be plagued with issues of reproducibility and variability, the bandage pharmaceutical industry is focused on making great strides in this area of research. the challenge of recreating complex cns functions such as cognition in the brain cannot be recapitulated via 3d patterning. this is due to microscale spatial heterogeneity and macroscopic architecture of the spinal cord and brain. it is however possible to reproduce organ-level functions and electro-kinetic responses by copying barrier functions.110 adding complexity and functionality in the third dimension, further poses a hurdle for high-resolution imaging to determine spatiotemporal locations of cell-cell or tissue-tissue interfaces, similar to visualize processes in living organs. in vitro 3d engineered tissue and its ongoing therapeutic applications so far have been vastly carried out on collagen-based scaffolds.111 however, the cns has minimal fibrillary matrix and collagen in ecm compositions, rendering it difficult to extrapolate the results from an in-vivo perspective. nanotemplate material fabrications, bottom-up nanoengineering and physicochemical modulations of the neuronal culture environment provides new opportunities for neuropharmacology.20,24,108,112-119 for example, self-assembled bioactive peptides, derived from laminin when electrospun as nanofiber scaffolds provide long-term survival and differentiation of neural progenitors into neurons and astrocytes. the density of the laminin epitope in the third dimension is crucial for such fast differentiation and could be a neurotherapeutic target.120 nanostructured surfaces integrated with micropatterns give qualitative versus quantitative information for prosthesis design to minimize bacterial growth and promote neuronal like cell growth.30,33,34,121 multipartite microand nanocarrier designs could be used for targeted diagnostics and therapeutics (theranostics) for debilitating diseases like multiple sclerosis or brain tumors.10,20,23-25,122-127 organ-on-chip devices for current therapeutic development for human organs organs-on-chips are microfabricated systems mimicking in vivo organ like features replicated onto pdms or elastic silicone. the devices imitate key functional components of in-vivo organs to reiterate integrated organ-level physiology in vitro with microfluidic channels.128 the microdevices could be the future for absorption, distribution, metabolism, excretion, and toxicity (admet) testing of neurotherapeutic pharmacokinetics. synthetic organ-on-chip systems could be further useful to create in vitro models of human neurodegenerative disorders to understand pathophysiological modulation under drug trials. drug toxicities based on preclinical animal trials often fail to categorize the drug uptake between the human and animal models owing to speciesspecific molecular differences (e.g., membrane transports). in such circumstances, tissues or human cells are necessary to draw definite conclusions. therefore, miniature-human-brain like devices, designed via integrating 3d patterning and microfluidics, may replace the conventional animal models for neuropharmaceutical and neurochemical applications, reducing the cost of drug trials in the future. with advances in microfluidics and microfabrication technology, it is possible to spatially pattern and connect multiple tissue types on single chip, creating functional humanoid model with connected organs like features on chip. the rise of bioengineered neuronal tissue network, it is possible to predict the outcome of drugorgan interactions in humans using organ on chip platform, negating shortcoming of genetic differences of animal models.129 particularly, microengineering recipes for the assembly and operation of the microfluidically lined blood brain barrier-onchip systems have attracted more attention of the neuropharmacology industry. for example, microengineering principles of the silicone industry could be used to design a multilayered microfluidic device, lined with human endothelial cells separated by a thin porous flexible membrane from astrocytes, into two parallel elastomeric microchannel (figure 7). bbb specific cells cultured under physiological flow and apico-basal polarity into these microdevices can be easily adapted to develop bbb-on-chip using facile experimental techniques to quantify bbb specific functionality on chip.110,130 the biohybrid engineered chip lined with selforganizing pluripotent cells, which could eventually segregate into distinct brain regions, further provides a tool for neuropharmacology as a prototype of neurodevelopmental disorders.130,131 in preliminary reports, hydrophobic and hydrophilic drug transport demonstrated on chip across the artificial blood brain barrier corroborates in vivo findings, supports understanding gene-gene interactions and nanoparticle-guided diagnostics.131,132 many in vitro cerebral organoids produced via 3d dynamic culture that resemble miniature brains, faithfully exhibit cns like characteristics.110 however, in vivo neurons surrounded by the extremely complex system of heterogeneous tissues are physiologically different. therefore, bbbon-chip models lined with network of glial cells may put forth a low cost non-animal research initiative to test stress signaling in neurons and neurotransmitter uptake and recycling. in addition, axonal myelination, nourishment, and trophic support of glial cells could be shown as a minimal, synthetic functional unit to recapitulate a part of brain on chip module, refer to table 3. figure 7. concept of all human organ-on-a-chip. advances in biomimetic micro engineering enable different organs features could be replicated on chip and to be integrated into a single micro device. each further connected with each other via microfluidic circulatory system mimicking physiologically relevant functions as an in vitro model with complex, dynamic process into human body. reproduced from ref.131 with free use creative commons attribution 4.0 international license. no nco mm er cia l u se on ly review [page 44] [veins and lymphatics 2018; 7:7196] furthermore, combining the miniature brain on chip with 3d electrode array, intracellular transport, and axonal targeting may yield novel insight about calcium signaling and synaptogenesis.25 in lieu of organ-on-chip development, not only is there a paradigm shift in approach to research in the pharma industry but also public outreach of technology; especially in developing countries. with clinical trials, countless animal lives are lost amidst growing ethical concerns. in some instances, animal models used fail to predict human responses, as they are not physiologically relevant. cutting edge research topics, such as the bbb-on-chip proposed herein could tremendously lower research budget for drug discovery and may boost sustainable development of therapeutics for poor rural populations of developing countries by helping researchers and scientists elucidate how tissues respond to new drug candidates. the bbb-on-chip model probably provide more understanding about bbb neurovascular unit, which will help to prevent current trend of 90% drug failure when switching from clinical trial from animal model to humans due to generic difference between the two. furthermore, the bbb-on-chip could spearhead the development of in vitro therapeutic vaccines and drugs to counter infectious disease like cholera, diarrhea and tuberculosis, which contribute to high infant mortality in the rural parts developing countries. references 1. singh av, gade wn, vats t, lenardi c, milani p. nanomaterials: new generation therapeutics in wound healing and tissue repair. curr nanosci. 2010 ;6:577-86. 2. gupta as. nanomedicine approaches in vascular disease: a review. nanomedicine. 2011;7:763-79. 3. bender dj, fronek h, arkans e. quantified hemodynamics of compression garments. veins and lymphatics. 2013;2:10. 4. jain kk. research and future of nanomedicine. the handbook of nanomedicine 2017 (pp. 621-636). humana press, new york, ny. 5. singh av, jahnke t, kishore v, et al. cancer cells biomineralize ionic gold into nanoparticles-microplates via secreting defense proteins with specific gold-binding peptides. acta biomater. 2018 mar 1. pii: s1742-7061:300939. 6. griffith m, islam mm, edin j, papapavlou g, et al. the quest for antiinflammatory and anti-infective biomaterials in clinical translation. front bioeng biotechnol. 2016;4:71. 7. shi j, kantoff pw, wooster r, farokhzad oc. cancer nanomedicine: progress, challenges and opportunities. nat. rev. cancer 2017;17:20. 8. yu mk, park j, jon s. targeting strategies for multifunctional nano particles in cancer imaging and therapy. theranostics. 2012;2:3. 9. kesselheim as, avorn j. the most transformative drugs of the past 25 years: a survey of physicians. nat rev drug discov. 2013;12:425. 10. singh a. multiple sclerosis takes venous route: ccsvi and liberation therapy. indian j med sci. 2010;64:337. 11. tang l, cheng j. nonporous silica nanoparticles for nanomedicine application. nano today. 2013;8:290312. 12. dwivedi c, pandey i, pandey h, et al. in vivo diabetic wound healing with nanofibrous scaffolds modified with gentamicin and recombinant human epidermal growth factor. j biomed mater res a. 2018;106:641-51. 13. sheykhansari s, kozielski k, bill j, et al. redox metals homeostasis in multiple sclerosis and amyotrophic lateral sclerosis: a review. cell death dis. 2018;9:348. 14. singh av, zamboni p. anomalous venous blood flow and iron deposition in multiple sclerosis. j cereb blood flow metab. 2009;29:1867-78. 15. vikram singh a, gharat t, batuwangala m, et al. threedimensional patterning in biomedicine: importance and applications in neuropharmacology. j biomed mater res b appl biomater. 2017. 16. xie j, owen t, xia k, singh av, et al. zinc inhibits hedgehog autoprocessing linking zinc deficiency with hedgehog activation. j biol chem. 2015;290:11591-600. 17. sadauskas e, danscher g, stoltenberg m, vogel u, et al. protracted elimination of gold nanoparticles from mouse liver. nanomedicine. 2009;5:162-9. 18. jalili na, muscarello m, gaharwar ak. nanoengineered thermoresponsive magnetic hydrogels for biomedical applications. bioeng transl med.2016;1:297-305. 19. berthet m, gauthier y, lacroix c, verrier b, monge c. nanoparticlebased dressing: the future of wound treatment? trends biotechnol.2018;36:119. 20. singh av, khare m, gade wn, zamboni p. theranostic implications of nanotechnology in multiple sclerosis: a future perspective. autoimmune dis. 2012;2012:1630. 21. ratner bd, hoffman as, schoen fj, lemons je. biomaterials science. mrs bull. 2006;31:59. 22. minuth ww, sittinger m, kloth s. tissue engineering: generation of differentiated artificial tissues for biomedical applications. cell tissue res. 1997;291:1-1. 23. singh av, bandgar bm, kasture m, prasad bl, sastry m. synthesis of gold, silver and their alloy nanoparticles using bovine serum albumin as foaming and stabilizing agent. journal of materials chemistry. 2005;15:5115-21. 24. singh av, patil r, kasture mb, gade wn, prasad bl. synthesis of ag–pt alloy nanoparticles in aqueous bovine serum albumin foam and their cytocompatibility against human gingival fibroblasts. colloids surf b biointerfaces. 2009 mar 1;69(2):23945. 25. singh av, mehta kk, worley k, et al. carbon nanotube-induced loss of multicellular chirality on micropatterned substrate is mediated by oxidative stress. acs nano. 2014;8:2196-205. 26. ghanbari h, de mel a, seifalian am. cardiovascular application of polyhedral oligomeric silsesquioxane nanomaterials: a glimpse into prospective horizons. int j nanomedicine.2011;6:775. 27. liu h, webster tj. nanomedicine for implants: a review of studies and necessary experimental tools. biomaterials. 2007;28:354-69. 28. singh sp, rathee n, gupta h, zamboni p, singh av. contactless and hassle free real time heart rate measurement with facial video. j card crit care. 2017;1:024-9. 29. singh av, baylan s, park bw, richter g, sitti m. hydrophobic pinning with copper nanowhiskers leads to bactericidal properties. plos one. 2017;12:e0175428. 30. v singh a, patil r, anand a, milani p, gade wn. biological synthesis of copper oxide nano particles using escherichia coli. curr nanosci. 2010;6:365-9. 31. griffith lg, naughton g. tissue engineering—current challenges and expanding opportunities. science. 2002;295:1009-14. 32. singh av, vyas v, maontani e, cartelli d, et al. investigation of in vitro cytotoxicity of the redox state of ionic no nco mm er cia l u se on ly review [veins and lymphatics 2018; 7:7196] [page 45] iron in neuroblastoma cells. j neurosci rural pract. 2012 ;3:301. 33. singh av, vyas v, patil r, sharma v, et al. quantitative characterization of the influence of the nanoscale morphology of nanostructured surfaces on bacterial adhesion and biofilm formation. plos one. 2011;6:e25029. 34. singh av, vyas v, salve ts, cortelli d, et al. biofilm formation on nanostructured titanium oxide surfaces and a micro/nanofabrication-based preventive strategy using colloidal lithography. biofabrication. 2012;4:025001. 35. singh av, hosseinidoust z, park bw, yasa o, sitti m. microemulsion-based soft bacteria-driven microswimmers for active cargo delivery. acs nano. 2017;11:9759-69. 36. tabas i, glass ck. anti-inflammatory therapy in chronic disease: challenges and opportunities. science. 2013 ;339:166-72. 37. someya t, sekitani t, iba s, kato y, kawaguchi h, et al. a large-area, flexible pressure sensor matrix with organic field-effect transistors for artificial skin applications. proc natl acad sci u s a. 2004;101:9966-70. 38. basheer ia, hajmeer m. artificial neural networks: fundamentals, computing, design, and application. j microbiol methods. 2000 ;4:3-1. 39. hammock ml, chortos a, tee bc, tok jb, bao z. 25th anniversary article: the evolution of electronic skin (eskin): a brief history, design considerations, and recent progress. adv mater. 2013;25: 5997-6038. 40. yannas iv, burke jf. design of an artificial skin. i. basic design principles. j biomed mater res a. 1980 ;14:65-81. 41. singh av, rahman a, kumar ns, aditi as, et al. bio-inspired approaches to design smart fabrics. mater des. 2012; 36:829-39. 42. singer aj, clark ra. cutaneous wound healing. n engl j med. 1999;341:73846. 43. yannas iv, burke jf, gordon pl, huang c, rubenstein rh. design of an artificial skin. ii. control of chemical composition. j biomed mater res a. 1980;14:107-32. 44. kirker kr, luo y, nielson jh, shelby j, prestwich gd. glycosaminoglycan hydrogel films as bio-interactive dressings for wound healing. biomaterials. 2002;23:3661-71. 45. wang ls, chow py, phan tt, lim ij, yang yy. fabrication and characterization of nanostructured and thermosensitive polymer membranes for wound healing and cell grafting. advanced functional materials. 2006;16:1171-8. 46. dal pozzo a, vanini l, fagnoni m, guerrini m, et al. preparation and characterization of poly (ethylene glycol)-crosslinked reacetylated chitosans. carbohydr polym. 2000;42:201-6. 47. collier to, anderson jm. protein and surface effects on monocyte and macrophage adhesion, maturation, and survival. j biomed mater res a. 2002;60:487-96. 48. berscht pc, nies b, liebendörfer a, kreuter j. in vitro evaluation of biocompatibility of different wound dressing materials. j mater sci mater med.. 1995;6:201-5. 49. daniels s, sibbald rg, ennis w, eager ca. evaluation of a new composite dressing for the management of chronic leg ulcer wounds. j wound care. 2002;11:290-4. 50. lin sy, chen ks, run-chu l. design and evaluation of drug-loaded wound dressing having thermoresponsive, adhesive, absorptive and easy peeling properties. biomaterials. 2001;22:29993004. 51. vermeulen h, ubbink dt, goossens a, de vos r, legemate da. systematic review of dressings and topical agents for surgical wounds healing by secondary intention. br j surg. 2005;92:665-72. 52. johnson fa, craig dq, mercer ad, chauhan s. the effects of alginate molecular structure and formulation variables on the physical characteristics of alginate raft systems. int j pharm. 1997;159:35-42. 53. brownlee m. biochemistry and molecular cell biology of diabetic complications. nature. 2001 ;414:813. 54. singh av. biotechnological applications of supersonic cluster beamdeposited nanostructured thin films: bottom-up engineering to optimize cell–protein–surface interactions. j biomed mater res a. 2013;101:29943008. 55. v singh a, k mehta k. top-down versus bottom-up nanoengineering routes to design advanced oropharmacological products. curr pharm des. 2016;22(11):1534-45. 56. singh av, sitti m. bacteria-driven particles:patterned and specific attachment of bacteria on biohybrid bacteria-driven microswimmers. adv healthc mater. 18/2016;5:2325-31. 57. teo we, he w, ramakrishna s. electrospun scaffold tailored for tissuespecific extracellular matrix. biotechnol j. 2006;1:918-29. 58. hosseinidoust z, mostaghaci b, yasa o, et al. bioengineered and biohybrid bacteria-based systems for drug delivery. adv drug deliv rev.2016;106:27-44. 59. cook ad, hrkach js, gao nn, johnson im, et al. characterization and development of rgd-peptide-modified poly (lactic acid-co-lysine) as an interactive, resorbable biomaterial. j biomed mater res a. 1997 ;35:513-23. 60. shahinian l, brown si. postoperative complications with protruding monofilament nylon sutures. am j ophthalmol. 1977;83:546-8. 61. humphrey jd. cardiovascular solid mechanics: cells, tissues, and organs. springer science & business media; 2013 jun 29. 62. grinstaff mw. designing hydrogel adhesives for corneal wound repair. biomaterials. 2007;28:5205-14. 63. grinstaff mw. biodendrimers: new polymeric biomaterials for tissue engineering. grinstaff mw. biodendrimers: new polymeric biomaterials for tissue engineering. chemistry-a european journal. 2002 jul. 2002;8:2838-46. 64. carnahan ma, grinstaff mw. synthesis and characterization of polyether− ester dendrimers from glycerol and lactic acid. j am chem soc. 2001;123:2905-6. 65. wathier m, johnson cs, kim t, grinstaff mw. hydrogels formed by multiple peptide ligation reactions to fasten corneal transplants. bioconjug chem. 2006;17:873-6. 66. zhao f, zhao y, liu y, chang x, chen c, zhao y. cellular uptake, intracellular trafficking, and cytotoxicity of nanomaterials. small. 2011;7:1322-37. 67. kasza ke, rowat ac, liu j, angelini teet al. the cell as a material. curr opin cell biol. 2007;19:101-7. 68. thapa a, miller dc, webster tj, haberstroh km. nano-structured polymers enhance bladder smooth muscle cell function. biomaterials. 2003;24:2915-26. 69. forman mb, puett dw, virmani r. endothelial and myocardial injury during ischemia and reperfusion: pathogenesis and therapeutic implications. j am coll cardiol. 1989;13:450-9. 70. tu jv, pashos cl, naylor cd, chen e, et al. use of cardiac procedures and outcomes in elderly patients with myocardial infarction in the united states and canada. n engl j med. 1997; no nco mm er cia l u se on ly review [page 46] [veins and lymphatics 2018; 7:7196] 336:1500-5. 71. conte ms. the ideal small arterial substitute: a search for the holy grail?. faseb j. 1998;12:43-5. 72. rocko jm, swan kg. biomaterials in peripheral vascular surgery. biomaterials. 1981 jul 1;2(3):177-8. 73. kim bs, nikolovski j, bonadio j, mooney dj. cyclic mechanical strain regulates the development of engineered smooth muscle tissue. nat biotechnol. 1999;17:979. 74. seliktar d, galis zg, nerem rm. in vitro remodeling of cell-seeded collagengel vascular constructs in response to a uniquely defined mechanical environment. 4th int. conf. cell. eng., nara, japan. 75. girling je, rogers pa. recent advances in endometrial angiogenesis research. angiogenesis. 2005;8:89-99. 76. weinberg cb, bell e. a blood vessel model constructed from collagen and cultured vascular cells. science. 1986;231:397-400. 77. pham qp, sharma u, mikos ag. electrospinning of polymeric nanofibers for tissue engineering applications: a review. tissue eng. 2006;12:1197-211. 78. lee ky, mooney dj. hydrogels for tissue engineering. chem rev. 2001 ;101:1869-80. 79. kim bs, mooney dj. development of biocompatible synthetic extracellular matrices for tissue engineering. trends biotechnol. 1998;16:224-30. 80. hoffman as. hydrogels for biomedical applications. adv drug deliv rev. 2012;64:18-23. 81. lambert ma, belch jj. medical management of critical limb ischaemia: where do we stand today?. j intern med. 2013 ;274:295-307. 82. eisenbud d, hunter h, kessler l, zulkowski k. hydrogel wound dressings: where do we stand in 2003?. ostomy wound manage. 2003 ;49:527. 83. kisiday j, jin m, kurz b, hung h, et al. self-assembling peptide hydrogel fosters chondrocyte extracellular matrix production and cell division: implications for cartilage tissue repair. proc natl acad sci u s a. 2002 ;99:9996-10001. 84. eaglstein wh. moist wound healing with occlusive dressings: a clinical focus. dermatol surg.2001 ;27:175-82. 85. cai s, liu y, shu xz, prestwich gd. injectable glycosaminoglycan hydrogels for controlled release of human basic fibroblast growth factor. biomaterials. 2005 ;26:6054-67. 86. preul mc, bichard wd, muench tr, spetzler rf. toward optimal tissue sealants for neurosurgery: use of a novel hydrogel sealant in a canine durotomy repair model. neurosurgery. 2003; 53:1189-99. 87. ghosh k, ren xd, shu xz, prestwich gd, clark ra. fibronectin functional domains coupled to hyaluronan stimulate adult human dermal fibroblast responses critical for wound healing. tissue eng. 2006;12:601-13. 88. luo y, shoichet ms. a photolabile hydrogel for guided three-dimensional cell growth and migration. nat mater. 2004;3:249. 89. schmidt ce, baier jm. acellular vascular tissues: natural biomaterials for tissue repair and tissue engineering. biomaterials. 2000;21:2215-31. 90. huang zm, zhang yz, kotaki m, ramakrishna s. a review on polymer nanofibers by electrospinning and their applications in nanocomposites. compos sci technol. 2003 63:2223-53. 91. burger c, hsiao bs, chu b. nanofibrous materials and their applications. annu. rev. mater. res. 2006 ;36:333-68. 92. matthews ja, wnek ge, simpson dg, bowlin gl. electrospinning of collagen nanofibers. biomacromolecules. 2002 ;3:232-8. 93. chen g, sato t, ushida t, ochiai n, tateishi t. tissue engineering of cartilage using a hybrid scaffold of synthetic polymer and collagen. tissue eng. 2004 ;10:323-30. 94. mura s, nicolas j, couvreur p. stimuliresponsive nanocarriers for drug delivery. nat mater. 2013 ;12:991. 95. rosenthal a, barry jj, sahatjian r, inventors; boston scientific scimed inc, assignee. triggered release hydrogel drug delivery system. united states patent us 7,066,904. 2006 jun 27. 96. finne-wistrand a, albertsson ac. the use of polymer design in resorbable colloids. annu. rev. mater. res. 2006;36:369-95. 97. yang f, xu cy, kotaki m, wang s, ramakrishna s. characterization of neural stem cells on electrospun poly (l-lactic acid) nanofibrous scaffold. j biomater sci polym ed. 2004 ;15:148397. 98. huang l, nagapudi k, p. apkarian r, chaikof el. engineered collagen–peo nanofibers and fabrics. j biomater sci polym ed.2001 ;12:979-93. 99. vaz cm, van tuijl s, bouten cv, baaijens fp. design of scaffolds for blood vessel tissue engineering using a multi-layering electrospinning technique. acta biomater. 2005 ;1:57582. 100.li c, vepari c, jin hj, kim hj, kaplan dl. electrospun silk-bmp-2 scaffolds for bone tissue engineering. biomaterials. 2006 ;27:3115-24. 101.li m, guo y, wei y, macdiarmid ag, lelkes pi. electrospinning polyanilinecontained gelatin nanofibers for tissue engineering applications. biomaterials. 2006 ;27:2705-15. 102.zong x, bien h, chung cy, yin l, fang d, hsiao bs, chu b, entcheva e. electrospun fine-textured scaffolds for heart tissue constructs. biomaterials. 2005 ;26:5330-8. 103.lee ch, shin hj, cho ih, kang ym, kim ia, park kd, shin jw. nanofiber alignment and direction of mechanical strain affect the ecm production of human acl fibroblast. biomaterials. 2005 ;26:1261-70. 104.shields kj, beckman mj, bowlin gl, wayne js. mechanical properties and cellular proliferation of electrospun collagen type ii. tissue eng. 2004;10: 1510-7. 105.min bm, you y, kim jm, lee sj, park wh. formation of nanostructured poly (lactic-co-glycolic acid)/chitin matrix and its cellular response to normal human keratinocytes and fibroblasts. carbohydr polym. 2004 ;57:285-92. 106.rho ks, jeong l, lee g, seo bm, et al. electrospinning of collagen nanofibers: effects on the behavior of normal human keratinocytes and early-stage wound healing. biomaterials. 2006 ;27:1452-61. 107.schindler m, ahmed i, kamal j, nure-kamal a, et al. a synthetic nanofibrillar matrix promotes in vivolike organization and morphogenesis for cells in culture. biomaterials. 2005 ;26:5624-31. 108.singh av, patil r, thombre dk, gade wn. micro-nanopatterning as tool to study the role of physicochemical properties on cell–surface interactions. j biomed mater res a. 2013;101:301932. 109.huh d, hamilton ga, ingber de. from 3d cell culture to organs-on-chips. trends cell biol. 2011 ;21:745-54. 110.gidwani m, singh av. nanoparticle enabled drug delivery across the blood brain barrier: in vivo and in vitro models, opportunities and challenges. curr pharm biotechnol. 2013 ;14:120112. 111.hribar kc, meggs k, liu j, zhu w, et al. three-dimensional direct cell patterning in collagen hydrogels with no nco mm er cia l u se on ly review [veins and lymphatics 2018; 7:7196] [page 47] near-infrared femtosecond laser. sci rep.. 2015 ;5:17203. 112.théry m. micropatterning as a tool to decipher cell morphogenesis and functions. j cell sci. 2010 ;123:420113. 113.singh av, lenardi cr, gailite la, gianfelice an, milani pa. a simple liftoff-based patterning method for micro-and nanostructuring of functional substrates for cell culture. j micromech microeng. 2009 ;19:115028. 114.singh av. biotechnological applications of supersonic cluster beamdeposited nanostructured thin films: bottom-up engineering to optimize cell–protein–surface interactions. j biomed mater res a. 2013 ;101:29943008. 115.lim ck, singh a, heo j, kim d, et al. gadolinium-coordinated elastic nanogels for in vivo tumor targeting and imaging. biomaterials. 2013 ;34:684652. 116.singh av, gailite l, vyas v, lenardi c, et al. rapid prototyping of nano-and micro-patterned substrates for the control of cell neuritogenesis by topographic and chemical cues. mater. sci. eng.: c. 2011 ;31:892-9. 117.singh av, maheshwari s, giovanni d, naikmasur vg, et al. nanoengineering approaches to design advanced dental materials for clinical applications. j. bionanosci. 2010 ;4:53-65. 118.hassan s, singh av. biophysicochemical perspective of nanoparticle compatibility: a critically ignored parameter in nanomedicine. j nanosci nanotechnol. 2014 ;14:402-14. 119.singh av, subhashree l, milani p, gemmati d, zamboni p. interplay of iron metallobiology, metalloproteinases, and fxiii, and role of their gene variants in venous leg ulcer. int j low extrem wounds. 2010;9:166-79. 120.silva ga, czeisler c, niece kl, beniash e, et al. selective differentiation of neural progenitor cells by high-epitope density nanofibers. science. 2004 ;303:1352-5. 121.singh av, galluzzi m, borghi f, indrieri m, et al. interaction of bacterial cells with cluster-assembled nano structured titania surfaces: an atomic force microscopy study. j nanosci nanotechnol. 2013 ;13:77-85. 122.singh av, batuwangala m, mundra r, mehta k, et al. biomineralized anisotropic gold microplate– macrophage interactions reveal frustrated phagocytosis-like pheno menon: a novel paclitaxel drug delivery vehicle. acs appl mater interfaces. 2014 ;6:14679-89. 123.gemmati d, zeri g, orioli e, de gaetano fe, et al. polymorphisms in the genes coding for iron binding and transporting proteins are associated with disability, severity, and early progression in multiple sclerosis. bmc med genet. 2012;13:70. 124.khare m, singh av, zamboni p. prospect of brain machine interface in motor disabilities: the future support for multiple sclerosis patient to improve quality of life. ann med health sci res. 2014;4:305-12. 125.vikram singh a. editorial (thematic issue: recent trends in nanobiotechnology reinforcing contemporary pharmaceutical design). curr pharm des. 2016 ;22:1415-7. 126.v singh a, k mehta k. top-down versus bottom-up nanoengineering routes to design advanced oropharma cological products. curr pharm des. 2016;22:1534-45. 127.vikram singh a, sitti m. targeted drug delivery and imaging using mobile milli/microrobots: a promising future towards theranostic pharmaceutical design. curr pharm des. 2016;22:141828. 128.bhatia sn, ingber de. microfluidic organs-on-chips. nat biotechnol. 2014; 32:760. 129.fine b, vunjak-novakovic g. shortcomings of animal models and the rise of engineered human cardiac tissue. acs biomater sci eng. 2017 ;3:1884-97. 130.lancaster ma, renner m, martin ca, wenzel d, et al. cerebral organoids model human brain development and microcephaly. nature. 2013;501:373. 131.choi jh, lee j, shin w, choi jw, kim hj. priming nanoparticle-guided diagnostics and therapeutics towards human organs-on-chips microph siological system. nano converg. 2016; 3:24. 132. tisato et al. gene-gene interactions among coding genes of ironhomeostasis proteins and apoe-alleles in cognitive impairment diseases. plos one. 2018;13:e0193867. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2017; volume 6:6927 [page 74] [veins and lymphatics 2017; 6:6927] changing interest on saphenofemoral junction in the new century stefano ricci università campus bio medico, roma, italy a review paper entitled the saphenofemoral junction involvement in the treatment of varicose veins disease has been accepted for publication in veins and lymphatics. in that review i tried to analyze objectively (as far as possible) the literature trend concerning the behavior of phlebologists toward the sapheno-femoral junction (sfj) responsibility in causing the chronic venous insufficiency (cvi). in this editorial i try to give a personal commentary. it is astonishing how fast was, in managing cvi, the copernican passage from absolute junction clearance to total no touch method, made by the same generation of surgeons, a kind of very conservative individuals of the human species. in particular they ought to forget their teachers’ recommendations and learn duplex assessment, technical management, local anesthesia activity, outpatient settings and finally, rearrange their ego. this is with great evidence demonstrated by recent international guidelines for the management of varicose veins issued in the uk, us and europe. these guidelines recommend that endovenous thermal ablation (i.e., no direct sfj junction treatment) should be offered before traditional surgery (i.e., sfj high ligation over all) for the treatment of great saphenous vein reflux.1-3 as a phlebologist with a prevalent attitude to surgery, i personally had the opportunity of actively treating patients during nearly 50 years. this period has experienced the most striking changings in the way of approaching this disease and adaptation to these changings has been continuous. at the end of my medicine study (1971) stripping in general anesthesia associated to multiple incisions over varicosities was the right answer at surgery exams at the question: treatment of varices, postoperative bed resting for a week at least being the conclusion for obtaining the higher note. in the real world, stripping was a boring operation, often abundantly bleeding, of limited scientific interest, and for this entrusted to the youngest of the team happy to have the possibility of acquiring manual experience. consequently results were doubtful in hemodynamics, and awful in cosmetics. the operation was the same for every patient as anatomic variations were not foreseen. the alternative treatment, sclerotherapy, gave similar doubtful results apart for few prima donna experiences. the future next generation phlebologist probably will have never seen a groin dissection and a stripping device, never hospitalized a treating patient for longer than few hours; he will be able to draw (and even understand) a hemodynamic map of the varicose network using a color duplex, but it is not sure he will have palpated and inspected the same area of interest. the target being the saphenous stem, after an endovascular procedure he will probably leave the varicosities waiting they disappear spontaneously or treat them secondarily as a cosmetic affair. elastic stockings will be considered useless and will be substituted by plant derivate integrators. bandages will be considered as prehistoric tool, in use by ancestors. between these two extremes we can still find the complete long list of possible treatments, the choice depending only in part from patient’s advantage, but most from advantage of several entities as: i) the same phlebologist (economical interest); ii) the insurance company (trying to limit expenses) or hospital administrators (trying to enhance reimbursement); iii) the industries providing devices and drugs; iv) the industries sponsoring induced activities (hosiery, integrators). new gadgets will continuously be invented, leaving unchanged the gsv closure rate (the same for all methods, near to 95% at 6 months), but maintaining high the costs. as underlined by m. de maeseneer4 requirements for the introduction of a new device are far less stringent than for the introduction of a new drug. moreover, if a new device is similar to ones that have already been approved, companies can use a fast-track system to introduce it into clinical practice, with relatively little evidence of effectiveness. this trend is ligated to the peculiar hemodynamic behavior of the varicose disease that takes benefit from every even minimal reduction of the incompetent network in the immediate ( 6-12 months), so that the treating physician may always be proud of his results, recurrence occurring later on. as a consequence, according to mendoza5 in lots of countries the health professionals’ income depends on their performance. the higher the income for a procedure, the higher the personal financial benefit. in poorer countries foam sclerotherapy is the best option. in high sophisticated places, the more the cost, the better the treatment, the better the income. if this was true, next world congress of phlebology ought to devote one extended session to the revision of the ethics of the present general management. at the opposite, the same peculiar hemodynamic behavior of the vein system cited may be the source of simplifying the treatment, limiting the invasiveness by: i) office setting for the great majority of actions (were possible); ii) local anesthesia (if needed); iii) limited surgery; iv) immediate ambulation; v) sparing the gsv when possible and appropriate; vi) treating the varicosities prevalently; vii) reviewing yearly the state of the limb; viii) repeat limited action when needed (dentist like treatment). in this perspective, and inspiring to zamboni’s editorial,6 varicosities phlebectomy and/or sclerotherapy would be the prevalent required action while gsv stem closure should be re-discussed, giving preference, when needed (i.e., more than 6-7 mm diameter, >1 second reflux, >c3, etc.) to gsv conservative treatments (chiva, asval, isolated crossectomy), or sclerotherapy, that are cheap, do not need technical (expensive) tools, may be office based, may be easily repeated, and finally have even better cosmetic results. in any case, sfj is no more considered as the leading character of varicose veins drama, what is not necessarily a negative event; but the myth disappears under the clouds of technology, that in reality is the new myth. a final comment and a question: development in venous treatment goes towards the invention of new technology, high costs being the moving power (laser, rf, steam, glue, industrial foam, robot?); progress in venous treatment is the search for new ways of doing simpler and cheaper (handmade foam, hook, compression, conservation). between development and progress, what is better for our patients? correspondence: stefano ricci, università campus bio medico, via alvaro del portillo 200, roma, italy. e-mail: varicci@tiscali.it received for publication: 18 july 2017. accepted for publication: 19 july 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright s, ricci, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6927 doi:10.4081/vl.2017.6927 no n c om me rci al us e o nly editorial [veins and lymphatics 2017; 6:6927] [page 75] references 1. national institute for health and care excellence. varicose veins: diagnosis and management. manchester: nice, 2013. available from: www.nice.org.uk/guidance/cg168 2. gloviczki p, gloviczki ml. guidelines for the management of varicose veins. phlebology 2012;27:2-9. 3. wittens c, davies ah, baekgaard n, et al. management of chronic venous disease: clinical practice guidelines of the european society for vascular surgery (esvs). eur j vasc endovasc surg 2015;49:678-737. 4. de maeseneer m. the endovenous revolution br j surg 2011;98:1037-8. 5. mendoza e. primum non nocere. veins and lymphatics 2017;6:6646. 6. zamboni p. 2016: the year of phlebological olympic games. veins and lymphatics 2016;5:6249. no n c om me rci al us e o nly hrev_master veins and lymphatics 2018; volume 7:7233 [page 22] [veins and lymphatics 2018; 7:7233] a renewed interest for surgery of the large veins norman m. rich department of surgery, uniformed services university of the health sciences & the walter reed national military medical center, bethesda, md, usa the editors of the book-text latest frontiers of hemodynamic, imaging, treatment of obstructive venous disease have written a thorough current review of diagnosis and management of challenges associated with and emphasizing the large veins of the body.1 the twenty nine chapters cover a wide variety of subjects and the accompanying references offer the opportunity for further review and study. accompanying graphic illustrations add additional information and clarification to the written material. the chapter titles allow rapid access to specific areas of interest in the venous system. contributors are established physicians and surgeons with extensive experience in managing problems in the venous system including clinical research. that is a most timely contribution with increasing worldwide appreciation of the importance of the venous system in maintaining good health. william harvey, an englishman who had studied in italy at padua university with fabricius where he earned his doctor of medicine in 1602 taught us about circulation in the seventeenth century emphasizing the important role of the venous system. his classic book motu cordis was published in 1628. yet, and particularly in the twentieth century with the many exciting discoveries in treating problems associated with the arterial system, the venous system was ignored in great part as noted in the united states. this has changed in the past twenty five years with multiple new efforts through the american college of phlebology and the american venous forum augmenting and complimenting similar well established activities in similar societies throughout the world.2 the vietnam vascular registry established in 1966 at walter reed general hospital in washington, d. c. provided an early emphasis on the repair of large veins, particularly in the lower extremities, rather than the traditionally accepted ligation. statistics of follow up support the absence of increased thrombophlebitis and of pulmonary embolism with long term patency assured have resulted in increased acceptance of this approach.3,4 a study published in 2017 journal of vascular surgery venous and lymphatic disorders from johns hopkins hospital in baltimore, maryland draws attention to the perceived weakness in venous education in vascular surgery trainees in the united states.5 this book by zamboni, veroux, lee, setacci and giaquinta will contribute immensely to educating the next generation of physicians and surgeons in the evaluation and treatment of venous disorders. norman m. rich, md, facs references 1. giaquinta a, lee bb, setacci c, et al. latest frontiers of hemodynamic, imaging, treatment of obstructive venous disease. torino: minerva medica; 2018. 2. bresadola m. the bassi historical international library of phlebology at the ferrara university hospital. veins and lymphatics 2014;3:4150. 3. rich nm, elster ea, rasmussen te. the vietnam vascular registry at 50 years: an historical perspective and continuing legacy. j trauma acute care surg 2017;83:s4-8. 4. hata kw, propper b, rich n. fifty-year anniversary of the vietnam vascular registry and a historic look at vascular registries. j vasc surg 2017;65:267-70. 5. hicks cw, abularrage c, heller j. the state of venous education in vascular residency programs: a resident questionnaire. j vasc surg venous lymphat disord 2017;5:160-1. correspondence: norman m. rich, department of surgery, uniformed services university of the health sciences & the walter reed national military medical center, bethesda, md, usa. tel.: +1.301.295.3707. e-mail: norman.rich@usuhs.edu this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright n.m. rich, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7233 doi:10.4081/vl.2018.7233 figure 1. the cover of the new book latest frontiers of hemodynamic, imaging, treatment of obstructive venous disease. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2018; volume 7:7627 [page 68] [veins and lymphatics 2018; 7:7627] novel heterogeneous stiffness for dynamic compression reconstruction rong liu institute of textiles and clothing, the hong kong polytechnic university, hum hom, kowloon, hong kong sar abstract compression therapy is the recommended non-pharmaceutical choice for edema and ulcers treatment through delivering static or dynamic pressure dosages to the affected legs. the traditional compression modalities were prone to generate peak or uneven cutaneous pressure around anatomic geometries, leading to ischemia or deficient pressure delivery as well as discomfort or high non-compliance in clinical practice. the aim of this study was to reconstruct compression exertion through novel designed heterogeneous threedimensional knitting structures and stiffness control to avoid sustained peak pressure but enhance muscular pumping action. the new heterogeneous structures integrate yielding and non-yielding elastic design via advanced tension controlled weft-knitting technologies to carter for anatomic morphologies and pressure requirements of the target users. the study indicated that the hybrid ratios of elasticity and their segmental proportions significantly influence cutaneous pressure profile. the new heterogeneous structures can generate hybrid dsi in compression shells with customized figurations. the designed heterogeneous stiffness reconstructed compression around the lower limbs with reduction of cutaneous pressure at anterior tibia bone crest by 2.0%-9.6% (p<0.05) while increased those at posterior gastrocnemius regions by 9.334.6% (p<0.05), resulting in more rationally pressure profiles around lower limb but maintaining degressive gradient from distal to proximal lower limb. the novel compression structures also present positive wearing feedback in our on-going clinical wear trials, which contribute to promote pressure function and user’s compliance in practice. correspondence: rong liu, institute of textiles and clothing, the hong kong polytechnic university, hum hom, kowloon, hong kong sar. e-mail: rong.liu@polyu.edu.hk conference presentation: international compression club (icc) meeting, paris, 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright r. liu, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7627 doi:10.4081/vl.2018.7627 no nco mm er cia l u se on ly 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2018; volume 7:7634 patient compression compliance: winning the battle terri morrison terri morrison consulting, llc, morrison vein institute, scottsdale, az, usa introduction in patients with incompetent great saphenous veins, pelvic veins, accessory veins, refluxing perforators and venous malformations, and leg ulcers, cvi is often associated with debilitating symptoms and complications. chronic venous disease (cvd) and (cvi) chronic venous insufficiency is a major public health issue carrying a high prevalence. despite this, cvd and cvi are largely under-diagnosed and limited choices of efficient, effective, cost effective care is being provided to patients.1-7 anatomic/physiologic consideration anatomic/physiologic consideration sgould include (figure 1): i) ceap class, overall health; ii) improve venous return from the lower extremities with venous stasis; iii) counter effects of ambulatory venous hypertension; iv) help control the progression of venous and lymphatic disease by increased contact of skin and dermal tissues with capillaries. general considerations for winning the battle of patient compliance with compression learn about compression. compression vendors, national and international conferences; use compression yourself; research trials with research grants; smart fabrics, patient monitoring and pressure monitors: embedded and external use. methods educate and explain clear benefit for compression therapy: i) heal or prevent active venous ulceration; ii) prevention of pts after dvt; iii) prevention of te events after surgery when combined with anticoagulant prophylaxis; iv) reduction of edema and inflammation; v) better cosmetic outcome (figure 2). technical tips: i) there are many fabrics, styles and colors available, both in ready-towear and custom-measured garments; ii) two facts become clear at once: nothing fits like skin, and no one fabric, style, brand, or type of compression is perfect for every patient (figure 3). what did we learn after bandaging, velcro inelastic wraps, flat knit compression, elastic stocking compression? adjustable velcro compression devices are more effective than inelastic bandages in reducing venous edema in the initial treatment phase, as described by mosti et al.8 results re-adjustable avcds with a resting pressure of around 40 mmhg are more effective in reducing chronic venous edema than ibs with a resting pressure of around 60 mmhg. avcds are effective and well tolerated, not only during maintenance therapy, and also in the initial decongestive treatment phase of patients with venous leg edema (figure 4). what were the venous reflux or leg ulcer recurrences? grade 1b: strong compression hosiery (30-40 mmhg) is more effective than medium or low compression stockings; grade 1a: 30-40 mmhg compression hosiery prevents recurrence of ulceration after healing. since long-term patient concordance with compression is relatively poor, it may prove more popular, effective and costeffective to provide a single intervention to reduce recurrence, rather than life-long treatment with compression, as described by samuel et al.9 what are the problems and modes of treatment? well-performed compression techniques do not guarantee technical success. more commonly, however, recurrent varicose veins can be from non-saphenous sources such as pelvic insufficiency, saphenous tributary incompetence, previously correspondence: terri morrison, terri morrison consulting, llc, morrison vein institute, scottsdale, az, usa. e-mail: tm@terrimorrisonconsulting.com conference presentation: international compression club (icc) meeting, paris, 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright t. morrison, 2018 licensee pagepress, italy figure 1. the spectrum of venous disease. [page 80] [veins and lymphatics 2018; 7:7634] no nco mm er cia l u se on ly conference presentation [veins and lymphatics 2018; 7:7634] [page 81] unknown abdominal or pelvic obstruction, patient noncompliance or simple disease progression. ‘whatever the cause, it is important to bear in mind that control of lower extremity venous incompetence can be achieved, but permanent cure is an unrealistic goal.’ hugo partsch conclusions no significant, procedure related, adverse events occurred using donning and doffing methods mentioned, nor from the use of velcro devices, circular or round knit stockings, and 4-layer bandaging with inelastic wraps and layered padding options. the battle can be won if compression reduces patient complaints of cramping, restless legs, ankle or leg swelling, heaviness, inflammation, pain, or recurrent leg ulcers and dvt.10-12 compression is not a punishment, if done correctly, with the patient’s involvement and cooperation. references 1. kahn sr, shapiro s, wells pd, et al. compression stockings to prevent postthrombotic syndrome: a randomized placebo-controlled trial. lancet 2014; 383:880-8. 2. moffatt c, kommala d, dourdin n, choe y. factors that affect concordance with compression therapy. j wound care 2004;13:291-4. 3. raju s, hollis k, neglen p. use of compression stockings in cvd: patient compliance and efficacy. ann vasc surg 2007;21:790-5. 4. benigni j-p, cornu-thenard a, uhl j-f. criteria for non-compliance of medical compression stockings. int j angiol 2013;22:23-30. 5. luire f, kistner rl. trends in patients reported outcomes of conservative and surgical treatment of primary chronic venous disease contradict current practices. ann surg 2011;254:363-7. 6. hamel-desnos cm, guias bj, desnos pr, et al foam sclerotherapy of saphenous veins: randomized controlled trial with or without compression. eur j vasc endovasc surg 2010;39:500-7. 7. sell e. compression therapy versus surgery in treatment of patients with varicose veins a rct. j vasc endovasc surg 2014 [epub ahead of print]. 8. mosti g, cavezzi a, partsch h, et al. adjustable velcro compression devices are more effective than inelastic bandages in reducing venous edema in the initial treatment phase: a randomized controlled trial. eur j vasc endovasc surg 2015;1:e7. 9. samuel n, carradice d, wallace t, et al. endovenous thermal ablation for healing venous ulcers and preventing recurrence. cochrane database syst rev 2013;10: cd009494. 10. ad a. hendrickx, wim p. krijnen, robert j. damstra, richard bimmel, cees p. van der schans compression with the juxta reduction kit ® (medi) in patients undergoing a total knee arthroplasty veins and lymphatics 2017; 6:6622 doi:10.4081/vl.2017.6622 11. joseph a. caprini velcro compression devices veins and lymphatics 2017; 6:6624 doi:10.4081/vl.2017.6624 12. patrick carpentier, jean-françois auvert, sophie bensedrine, sophie blaise, chantal elbhar, gilles miserey, monira nou for the compression interface group of the société française de médecine vasculaire compression therapy in everyday life: let the patients have the floor veins and lymphatics 2017; 6:6625 doi:10.4081/vl.2017.6625 figure 2. alternate compression modalities. figure 3. stiff, inelastic, multilayered bandaging. no nco mm er cia l u se on ly 429 too many requests you have sent too many requests in a given amount of time. 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2018; volume 7:7367 [veins and lymphatics 2018; 7:7637] [page 85] how to improve compliance for medical compression stockings thomas stumptner specialist in orthopaedics, phlebology, chirotherapy, nürnberg, germany introduction compression stockings are not an option for therapy. symptoms and venous diseases depend on the function of the venous system. the subfascial main veins manage about 80% of this function.1,2 an insufficiency either of the valves3,4 or of the pumps5,6 both structures on dependency of the fascia7-14 make a reduction of the drainage of the tissue.15 this will be the congestion,16 an extravasal volume overloading of the tissue. the tension of the fascia increases. this pathological tension creates the symtoms.17,18 an elastic compression stocking increases once more this tension by its high resting-pressure.19 it will be painfull. but its working-pressure is not sufficient to reach the region of the subfascial veins in a therapeutical manner. because of this fact it is necessary first, to resolve the problem by a non-elastic compression bandage.20,21 the very high working-pressure guarantees the sufficiency of the valves of the deep veins.22-24 together with walking the congestion will be gone after a short time.25 after this therapy it is necessary to compensate the disposition for the dilatation of the veins by a compression stocking. therefore it is necessary to inform the patient completely about his complaint and enable him by exercising to wear the compression stockings. conclusions first resolving the problem by a nonelastic therapy. then preserving the success by a compression stocking. taking care about the capacity of the patient by enable him in a complete manner like exercises and controls. references 1. harvey w. exercitatio anatomica de motu cordis et sanguinis in animalibus. fankfurt 1628. 2. arnoldi cc. the venous return from the lower leg in health and in chronic venous insufficiency: a synthesis. acta orth scand 1964;35:3-75. 3. lang j, wachsmuth w. praktische anatomie, bein und statik. berlinheidelberg-new york; 1972. 4. staubesand j. zur systemischen, funktionellen und praktischen anatomie der venen des beines. in: schneiderw, walker j. die chronische veneninsuffizienz in theorie und praxis, kompendium der phlebologie. münchen; 1984. 5. schmeller w, schadwinkel m. die beinvenenhämodynamik in abhängigkeit vom bewegungsausmaß im oberen sprunggelenk. phlebol u proktol 1987;16. 6. kügler c, strunk m, rudofsky g. bedeutung einer eingeschränkten gelenkbeweglichkeit für den blutabstrom aus gesunden beinvenen. phlebologie 1999;28. 7. braune w. die oberschenkelvene in anatomischer und klinischer beziehung. veit, leipzig; 1871. 8. schulze w. über die anatomschen bedingungen für die metastasierung bei der allgemeininfektion. dtsch z chir 1933;239:34. 9. schade h, pich h. die pulsationsübertragung von der arterie auf die vene und ihre bedeutung für den blutkreislauf. zschr f kreislauff 1936;28:131-72. 10. lanz vt, kressner a, schwendemann r. der einbau der oberflächlichen und der tiefen venen am bein, morphologisch und konstruktiv betrachtet. zeitschr anat entwicklungsgesch 1936;108:695. 11. lanz vt. über den funktionellen einbau peripherer venen. anat anz 1936/37;83:51. 12. kügelgen va. über den wandbau der großen venen. morph jb 1951;91:447. 13. goerttler k. über den einbau der großen venen des unterschenkels. z anat 1953;116:591-609. 14. stauesand j, li y. begriff und substrat der fasziensklerose bei chronischvenöser insuffizienz. phlebologie 1997;26:72-9. 15. lofferer o, mostbeck a, partsch h. nuklearmedizinische diagnostik von lymphtransportstörungen der unteren extremität. vasa 1972;1:94-102. 16. haid h, lofferer o, mostbeck a, partsch h. die lymphkinetik beim postthrombotischen syndrom unter kompressionsverbänden. med klin 1968;63:754. 17. staubesand j, li y. zum feinbau der fascia cruris mit besonderer berücksichtigung epiund intrafaszialer nerven. manuella med 1996;34:196-200. 18. mosti g. compression treatment in venous insufficiency and arterial disease. phlebologie 2014;3. 19. partsch h. besserung der venösen pumpleistung bei chronischer veneninsuffizienz durch kompression in abhängigkeit von andruck und material. vasa 1984;13. 20. fischer h. eine neue therapie der phlebitis, medizin. klinik 1910;30. 21. lippmann hi. the mechanical basis of supportive therapy in chronic venous insufficiency. zentr phlebologie 1970;9:77-86. 22. haid h. ergebnisse fortlaufender registrierung des andruckes von kompressionsverbänden und gummistrümpfen. in: molen hrv, limborgh jv, boersma w. progres cliniques et therapeutiques dans le domaine de la phlebologie, apeldoorn. 1970;s.857. 23. mostbeck a, partsch h, peschl l. änderungen der blutvolumenverteilung im ganzkörper unter physikalischen und pharmakologischen massnahmen. vasa 1977;6:2. 24. haid-fischer f, haid h. venenerkrankungen, das wichtigste aus anatomie, physiologie, pathophysiologie und orthopädie. stuttgart; 1985. 25. stumptner t. subfascial edema due to venous incompetence demonstrated by mri. icc annual meeting amsterdam 2017. available from: http://www. tagungsmanagement.org/comp/images/ pdf/amsterdam2017_stumptner.pdf correspondence: thomas stumptner, fürther str. 244a (auf aeg), 90429 nürnberg, germany. tel.: +911.23.75.470 fax: +911.23.75.471. e-mail: info@dr-stumptner.de conference presentation: international compression club (icc) meeting, paris, 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright t. stumptner, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7637 doi:10.4081/vl.2018.7637 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2018; volume 7:7630 [veins and lymphatics 2018; 7:7630] [page 73] role of standardized eccentric compression to reduce the varicose vein volume of 70% vincent crébassa clinique du millenaire, montpellier, france abstract the main pitfall of our treatments is the presence of blood in the treated varicose vein. thus, reducing it diameter during and after treatments is a fundamental therapeutic objective. digressive compression don’t alter the diameter of the saphenous veins explaining some doubts about it efficiency. this is why we make eccentric compressions, often artisanal. the main of this study is the reduction of the diameter of the varicose vein under standardized eccentric compression, according to the territory of these varicose vein, their supra-facial situations or in the saphenous compartment situations, according to their depth, their nature: primitive or recurrence, in lying and standing positions. we measured 130 legs from 85 patients. a rectangular window was cut in the device for measuring the diameters and depths of varicose veins. the pressure sensor checked the interface pressure delivered by the compression device. the average patient age was 60 years old. measurements confirmed the existence of a minimum pressure of 50 mm hg. 77% were gsv, 23% were ssm, 95% primary varicose vein and 5% recurrences. 74% of varicose veins had a sub-fascial localization, 26% supra-fascial. in lying position the superficial varicose veins reduce their diameter by 43%, the saphenous veins by 36%. in standing position respectively 36% and 33%. this external tumescence allows a reduction in diameter of at least 43 %, thus, 70% reduction in their volume. this reduction may be even better with an additional 75% stretch. it can be placed on the calf or on the thigh during the treatment but especially after the treatments to reduce side effects (local pains, pigmentations, thrombectomies), complications and promotes harmonious fibrosis. it allows the reduction of the volumes and concentrations injected in the case of foam sclerosis. references 1. jünger m, konschake w, haase h, riebe h. compression stockings with interface pressure fall and rise from the ankle to the mid calf. veins and lymphatics 2017;6:6632. 2. chi y-w. a new compression pressure measuring device. veins and lymphatics 2017;6:6636. 3. chassagne f, badel p, convert r, et al. experimental and numerical approach for the investigation of interface pressure applied by compression bandages. veins and lymphatics 2017;6:6626. correspondence: vincent crébassa, clinique du millenaire, 220 boulevard pénélope, 34000 montpellier, france. e-mail: vcrebassa@club-internet.fr conference presentation: international compression club (icc) meeting, paris, 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright v. crébassa, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7630 doi:10.4081/vl.2018.7630 no nco mm er cia l u se on ly hrev_master veins and lymphatics 2018; volume 7:7745 [veins and lymphatics 2018; 7:7745] [page 109] successful retrograde recanalization of internal jugular vein passing from omolateral external jugular vein tommaso lupattelli,1 paolo onorati,1,2 giovanni bellagamba,1 ginevra toma1,2 1interventional radiology unit, istituto clinico e cardiologico, gvm sanità, roma; 2department of physiology and pharmacology, university of rome la sapienza, roma, italy abstract severe stenosis and/or thrombosis of the internal jugular vein could be managed through a novel technique herein reported. recanalization can be achieved passing through the omolateral external jugular vein. case report we report a case of a 46-year-old female patient who presented to our hospital with severe migraine and recurrent spontaneous attack of dizziness. she underwent clinical examination followed by brain mr. a moderate stenosis of the right left internal jugular vein (ijv) at the vein outlet and an high grade stenosis of the left ijv at j1 were seen at colour doppler ultrasound. following local anesteshia at the left groin, a femoral vein access using a 10 f, 20 cm long introducer sheath (cordis, usa) was obtained. a 5 f, 120 cm long multipurpose catheter (boston scientific, watertown, ma, usa) was then advanced within the left anonimous vein. unfortunately, several attempts at catheterizing the left internal jv in the anterograde fashion by using eithera 0.0035, 180 cm long hydrophilic guidewire (radiofocus, terumo, watertown, ma, usa) and two different highly flexible tipped, 0.014 guidewires (pt graphix, boston scientific, watertown, ma, usa). choice pt, boston sientific, watertown, ma, usa) were unsuccessful. we decided to place the multipurpose catheter in the left external jv with subsequent selective phlebography which showed opacification of the proximal segment of the internal jv from a collateral of an enlarged thiroidal vein (figure 1). further attempts at recanalization of the internal jv were made from the external jv using a 0.0035, 260 cm long, hydrophilic guidewire (radiofocus, terumo, watertown, ma, usa) and a 5 f, 0.035 berenstain catheter (boston scientific, watertown, ma, usa). finally, retrograde crossing of the internal occlusion was obtained (figure 2a) with subsequent snaring of the guidewire tip in the vena cava by means of a 6 f snare catheter (goosneck, ev3, usa) inserted from the right femoral vein (figure 2b). after retrieval of the guidewire tip out of the right femoral introducer sheath (figure 3), 2500 unit of heparin were administered intravenously and a 0.035, 5x40 mm ordinary balloon (evercross, ev3, usa) was inserted over the retrivied guidewire and advanced up to the left internal jv occlusion. vein pre-dilation was then performed for 90 seconds with a pressure rate up to 10 atmosphere followed by stronger and larger dilation using a 0.035, 14x20 mm high pressure balloon (atlas gold, bard, usa) (figure 4). the high-pressure balloon was kept inflated for 60 second reaching a maximum pressure of 26 atmospheres, then progressively deflated and kept in place for further 180 seconds at a pressure of 2 atmospheres only. confirmation phlebography showed complete recanalization of the left ijv with no evidence of ijv contrast extravasation (figure 5). also, evidence of a short clearance time of the contrast dye was noted. procedure time and fluoroscopy time were 50 and 31 minutes, respectively. neither complications nor contrast vein extravasation from the internal jv were observed at the end of the procedure. discussion and conclusions percutaneous transluminal angioplasty (pta) is a well-established method to reopeninternal jugular veins. since zamboni et al. described chronic cerebro-spinal venous insufficiency in 2007, several series have been published in the scientific literature reporting balloon dilatation of these vessels.1-6 particularly, a series of 1202 patients treated in one or both ijv with pta alone was reported by an italian group in 2013, whereas three further studies on feasibility and safety were reported by an american, polish and bulgarian group, respectively. all these studies concluded that ijv pta is safe, provided it is performed by well-trained interventional radiologists or endovascular surgeons. studies on ijv pta have also been published reporting clinical outcome as well as restenosis rate.7-14 the challenges of catheter advancement through an high grade stenosis are legendary and well known. an anterograde approach to such a stenosis may often result extremely difficult and for this reason this kind of lesions are not rarely mistaken for total occlusions or chronic thromboses as well. the catheterguidewire system is moving from a large cylinder through a pinhole and, most of the time, lesion crossing may be tremendously demanding and time consuming. a retrograde approach to the ijv allowed us to advance the guidewire from the upper internal jugular vein up to the innominate vein using a facilitated pathway even though trackability and, most of all, pushability of the whole system resulted much reduced. however the use of a 0.035 hydrophilic wire combined with a 6 f catheter may give the required support to advanced the tip wire up to the stenosis and, finally, cross it out. another possible option in such difficult vein recanalizations was to perform a retrograde puncture of the more distal jugular vein in the neck. however, to the present authors, minimally invasive maneuvers, as we did in the present case, should be ever preferred with the aim to avoid potential unfavourable damage of the target vessel. dealing with tight ijv stenosis may also represent a problem for balloon catheter selection. opposite to carotid arteries, which are normally dilated by using a 5 mm ordinary balloon, internal jugular veins may present with a wide range of calibers, thus requiring careful choice of the balloon size to be employed. from a technical point of view, ordinary balloons are often not capable to completely dilate a highly stenosed jugular vein either for the limited pressure they can reach (14 atmospheres at the most) either for the limited sizes currently availcorrespondence: tommaso lupattelli, interventional radiology unit, istituto clinico cardiologico, via alessandro magno 386, 00124 roma, italy. tel.: +39.06.50173411. e-mail: lupattelli@gmail.com key words: angioplasty; internal jugular vein; recanalization; vein stenosis; ccsvi. received for publication: 7 august 2018. revision received: 29 november 2018. accepted for publication: 4 december 2018. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright t. lupattelli et al., 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7745 doi:10.4081/vl.2018.7745 no nco mm er cia l u se on ly how i do it [page 110] [veins and lymphatics 2018; 7:7745] able in the market. for this reason, ijvs are often treated using high-pressure balloons, which can reach up to 30 atmospheres as well as a diameter of 26 mm. however, in certain cases, like in the one we presently report, a combination of ordinary balloons and high pressure balloons can be strongly suggested. indeed, in our patient we performed a pre-dilation of the occluded ijv using a 5 mm ordinary balloon (with the aim of opening a well defined channel troughout the vein stenosis) in order to allow subsequent advancement of an high pressure balloon up to the target. unfortunately, high pressure balloons, particularly when they are bigger than 10 mm in size, carry limited trackability and crossability, thus preventing them from overcoming, at times, very tight stenoses or occlusions.11 for this reason in such cases, a previous use of a smaller ordinary balloon with better crossing profile is often mandatory. finally, following complete vein reopening, prolonged balloon dilation by using the same high-pressure balloon progressively deflated down to 2 atmospheres is highly reccomended, especially when dealing with very resistent and chronic occlusions. indeed, given that high pressure ptas may easily lead to one or even multiple transient tears in the vessel wall, low-pressure balloon inflation may prevent the occurrance of contrast extravasation from the ijv immediately after dilatation. references 1. zamboni p. the big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. j r soc med 2006;99:589-93. 2. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:392-9. 3 zamboni p, consorti g, galeotti r, et al. venous collateral circulation of the extracranial cerebrospinal outflow routes. curr neurovasc res 2009;6:204-12. 4. bartolomei i, salvi f, galeotti r, et al. hemodynamic pattern of chronic cerebrospinal venous insufficiency in multiple sclerosis. correlation with symptoms at onset and clinical course. int angiol 2010;29:183-8. 5. zamboni p, galeotti r, menegatti e, et al. a prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. j vasc surg 2009;50:1348-58. figure 1. selective phlebography performed with a 5 f multipurpose catheter placed in the external jv (black arrow) shows retrograde filling of the proximal portion of the internal jugular vein (white arrow). figure 3. hydrophilic guidewire tip out the 5 f right introducer sheath. figure 4. ballon angioplasty of the internal jv using a 0.035, 14x20 mm high-pressure balloon. figure 5. confirmation phlebography shows complete recanalization of the left internal jv. figure 2. a) retrograde recanalization of the internal jv using a 260 long, 0.035 hydrophilic guidewire. b) evidence of a snare device (black arrow) and guidewire tip (white arrow) at the level of inferior vena cava following retrograde internal jv recanalization. a b no nco mm er cia l u se on ly how i do it [veins and lymphatics 2018; 7:7745] [page 111] 6. zamboni p, how to objectively assess jugular primary venous obstruction. veins and lymphatics 2014;3:3. 7. lupattelli t, bellagamba g, righi e, et al. feasibility and safety of endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j vasc surg 2013;58:1609-18. 8. ludyga t, kazibudzki m, simka m, et al. endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? phlebology 2010;25:286-95. 9. mandato kd, hegener pf, siskin gp, et al. safety of endovascular treatment of chronic cerebrospinal venous insufficiency: a report of patients with multiple sclerosis. j vasc interv radiol 2012;23:55-9. 10. petrov i, grozdinski l, kaninski g, et al. safety profile ofendovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j endovasc ther 2011;18: 314-23. 11. aftab sa, tay kh, irani fg, et al. randomized clinical trial of cutting balloon angioplasty versus high-pressure balloon angioplasty in hemodialysis arteriovenous fistula stenosis resistant to conventional balloon angioplasty j vasc interv radiol 2014;25:190-8. 12. zamboni p, zivadinov r. extracranial veins in multiple sclerosis: is there a role for vascular surgery? eur j vasc endovasc surg 2018;56:618-21. 13. zamboni p, tesio l, galimberti s, et al. efficacy and safety of extracranial vein angioplasty in multiple sclerosis: a randomized clinical trial. jama neurol 2018;75:35-43. 14. juurlink b, bavera p, sclafani s, et al. brave dreams: an overestimated study, crippled by recruitment failure and misleading conclusions. veins and lymphatics 2018;7:2. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2015; volume 4:4703 [page 34] [veins and lymphatics 2015; 4:4703] associations between flow in paratibial perforating veins and great saphenous vein patterns of reflux carlos alberto engelhorn,1,2 ana luiza dias valiente engelhorn,1,2 sergio xavier salles-cunha,2 nicolle amboni schio,1 giovanna golin guarinello,1 bruna orlandoski erbano1 1university of paraná, pucpr, school of medicine; 2angiolab, inc. non-invasive vascular laboratory, curitiba, pr, brazil abstract perforating veins contribute to chronic venous valvular insufficiency (cvvi, subset of cvi) of lower extremities (le). we investigated the role of medial, proximal calf paratibial perforating veins (ptpv). women with ptpv reflux, diameter ≥3 mm, or tortuosity were selected among 2199 le mappings. duplex ultrasonography (us) was performed standing. reflux >0.5 s was abnormal. ptpv conditions were related to great saphenous vein (gsv) patterns of reflux. us of 442 le of 379 women were analyzed, all being clinicaletiology-anatomy-pathophysiology (ceap) classification c1, c2, and/or having intermittent, conditional swelling. etiology was primary. pathophysiology was reflux, not thrombosis or obstruction. most ptpv drained (n=281, 64% of 442 or 13% of 2199), or were source (n=73, 17%/442, 3%/2199) of gsv reflux; 49 (11%/442, 2%/2199) had reflux not associated with gsv; 39 (9%/442, 2%/2199) did not have reflux. ptpv, when significative for cvvi, primarily drained-gsv reflux. ptpv was linked to reflux in 1 of 5 and was a major source of reflux in 1 of 20 legs. detailed us of ptpv insured over 80% accuracy in cvvi mapping. introduction awareness of chronic venous valvular insufficiency (cvvi, as subset of cvi) is increasing among patients and physicians alike. initial stages of cvvi may differ significantly among patients with telangiectasias/reticular veins, varicose veins, and intermittent swelling versus severe edema, skin changes or ulcers. cvvi abnormalities of great and small saphenous veins (gsv, ssv) and their tributaries have been emphasized. our initial investigations suggested that a primary contribution of perforating veins to cvvi had low frequency.1 sources and drainages of saphenous veins reflux were mostly tributary, not perforating veins. as a quality control project in an international organization for standardization (iso) accredited vascular laboratory, we investigated the role of medial, proximal calf paratibial perforating veins in association with early stages of cvvi. a brief review of international and personal experience follows herein to justify the focus of this laboratory data analysis. publications describing an international consensus emphasized, in their introductory initial sentence, lack of precision in diagnosis.2,3 the union internationale de phlébologie (uip) consensus reports states that duplex ultrasound investigation has become the reference standard in assessing the morphology and hemodynamics of the lower limb veins.4,5 we followed the intended focus of such international perspective and investigated specifically women of a southern brazilian city, mostly of european descent, with early stage of cvvi. we observed that: i) gsv segmental pattern of reflux, from a proximal to a distal tributary vein, was the most common in women with telangiectasias or simple varicose veins;1,6,7 and ii) without treatment, gsv segmental reflux became secondary to multisegmental reflux pattern.8 we hypothesized that cvvi started at the weakest spot of vein degradation plus stress and progressed to the next weakest spot. eventually, perforating veins and the saphenofemoral junction (sfj) become affected. this analysis focused on perforating veins located at the proximal, medial aspect of the calf: the paratibial perforating veins (ptpv), named according to modern consensus that emphasizes an anatomic-based nomen clature.5,9 we investigated four types of ptpv flow conditions: i) drainage of gsv reflux starting proximally; ii) source of gsv reflux in the calf; iii) abnormal reflux without association to gsv reflux; and iv) enlarged vein despite normal flow. the primary research objective was to relate these types of ptpv flow to gsv patterns of reflux. the clinical objective was to enhance awareness of the role of ptpv abnormalities on the development of cvvi. the primary statistical goal was to confirm low incidence of primary contribution of ptpv as reflux source. materials and methods this session describes: i) how the sample population entered in the study was created; ii) the basics of venous duplex ultrasonography (us) employed; iii) descriptive statistics documenting ptpv diameter, leg location, and flow patterns; and iv) the tabulations relating ptpv flow and gsv reflux patterns. all us examinations were performed at the angiolab, inc. non-invasive vascular laboratory of curitiba, state of paraná, brazil, an iso accredited institution. us examinations were performed by physicians who had more than 10 years experience and passed the certification process established by a joint commission of the brazilian societies of angiology/vascular surgery and radiology. a data base has been maintained prospectively. retrospective analysis of gsv and ptsv patterns of reflux was performed. this project was part of protocol number 207-0084-000111 of the national commission on ethics of research and approved by the ethics research correspondence: carlos alberto engelhorn, rua josé casagrande, 1310, bairro vista alegre, curitiba, pr, brazil, cep 80820-590. tel.: +55.41.3362.0133. e-mail: caengelhorn@gmail.com; carlos.engelhorn@pucpr.br; ana.engelhorn@pucpr.br key words: venous valvular insufficiency; duplexdoppler ultrasound; great saphenous vein; paratibial perforating vein. acknowledgments and funding: research supported by angiolab, inc. (curitiba, pr, brazil) performed without external funding. contributions: cae, aldve, primary conception, primary design, data acquisition, data interpretation, data storage, manuscript critical revision, final approval of the version to be published, fully accountable; sxsc, general conception, general design, data analysis, data interpretation, drafting the work, final approval of the version to be published, fully accountable; nas, ggg, boe, medical students: secondary conception, secondary design, data retrieval, manuscript revision, initial approval manuscript, secondary accountability. conflict of interest: ca and aldv engelhorn own the private angiolab, inc. non-invasive vascular laboratory and are medical school faculty; sx salles-cunha is a research, quality assurance consultant for angiolab, inc. conference presentation: oral presentation, society for vascular ultrasound (svu) annual conference, san francisco, ca, usa, may 30thjune 1st, 2013. received for publication: 10 september 2014. revision received: 6 march 2015. accepted for publication: 23 march 2015. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright c.a. engelhorn et al., 2015 licensee pagepress, italy veins and lymphatics 2015; 4:4703 doi:10.4081/vl.2015.4703no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:4703] [page 35] committee of pontificia universidade católica do paraná. sample population a total of 2199 lower extremity venous us examinations of 1129 women were searched for specific report of ptpv data; 1070 were bilateral and 59 were unilateral evaluations. exclusion criteria all us examinations performed in men were excluded even before the search for ptpv started and were not included in the total of examinations searched; women with significant skin changes or ulcers were excluded and their examinations were not evaluated either; prior gsv saphenectomy was the reason to exclude 278 of the 2199 (13%) lower extremities; prior deep or superficial venous thrombosis or phlebitis was the reason to exclude 4 (0.2%) lower extremities; a total of 1475 (67%) lower extremities were excluded for not having a significant ptpv, either undetected or having a diameter of less than 1 mm, or having normal flow and considered not enlarged. inclusion criteria lower extremities with ptpv either; draining gsv reflux; being the source of gsv reflux; refluxing without being major drainage or source of gsv reflux; or estimated to be abnormally enlarged with diameters or approximately 3 mm or more. a total of 442 (20% of 2199) lower extremities of 379 women entered the analysis. bilateral abnormal ptpv were noted in 63 (17%/379) women. clinical-etiology-anatomypathophysiology (ceap) classification was c1telangiectasias/reticular veins, c2-varicose veins ≥3 mm in diameter, and/or c3-mostly intermittent, conditional swelling. etiology was primary. anatomy represented was gsv and ptpv. pathophysiology was reflux and not thrombosis or obstruction. venous ultrasonography the angiolab cvvi us examination has been standardized for over a decade.6-8,10-12 once deep venous thrombosis or obstruction was ruled out, the cvvi examination was performed with the patient standing. intermittent resting and movement minimized ill effects of standing during the testing. siemens®, elegra or antares models, were employed. transducers centered at 7 mhz (4-9 mhz) were used to image superficial veins. flow augmentation, forward or reverse, was forced by hand compression to have versatility, particularly in the study of perforating veins. reflux longer than 0.5 s were considered not normal for the gsv and the ptpv.13 in practice, reflux was longer than 1 s in the vast majority of cases. maps were generated to report the flow findings. figure 1 exemplifies such mapping. the distance between a perforating vein location and the sole of the foot was measured and included in the mapping. specific perforating vein findings included maximum potential diameter, location, flow characteristics and relationship to the gsv or other superficial or deep veins. maximum potential diameter means actual diameter if the perforating vein was perpendicular to the fascia, or, fascial opening if the perforating vein was oblique to the fascia. ptpv flow was classified as: i) gsv reflux drainage; ii) gsv reflux source; or iii) ptpv reflux unrelated to the gsv. figure 2 exemplifies us details commonly found in such exams. in addition, large ptpv were mentioned, usually if its diameter was ≥3 mm. otherwise the ptpv was not mentioned in the report. descriptive statistics prevalence of: i) ptpv draining gsv reflux; ii) ptpv being a source of gsv reflux; iii) refluxing ptpv not associated with the gsv; and iv) anatomically abnormal ptpv despite normal flow were estimated. mean, standard deviation, minimal and maximum values were calculated for ptpv diameters and distances from the sole of the foot. ptpv flow findings were also tabulated as a function of ptpv diameters. comparative statistics comparisons of prevalence were performed using proportions on the chi-square program available with excel. comparison of diameters was performed using t-test, also available with excel. subgroups comparative statistics the 4 types of ptpv flow or diameter abnormalities were cross-tabulated with the following types of gsv reflux patterns: i) segmental: reflux from a tributary or perforating vein distal to the sfj to a tributary or perforating vein proximal to the ankle; ii) distal: reflux from a tributary or perforating vein distal to the sfj including the gsv at the ankle level, draining into distal ankle or foot veins; iii) multi-segmental normal sfj: two or more refluxing segments as defined in i) or ii); iv) proximal: reflux from the sfj to a tributary or perforating vein proximal to the ankle; v) multi-segmental refluxing sfj; similar to iii) but having a iv) type proximal refluxing segment; vi) diffuse: reflux from the sfj to the ankle level; and vii) figure 1. example of a flow mapping diagram at angiolab curitiba. no n c om me rci al us e o nly article [page 36] [veins and lymphatics 2015; 4:4703] non-refluxing gsv. perijunction reflux through the sfj to other veins besides the gsv or through perijunction veins besides the common femoral to the gsv was not included in the analysis because such types were absent, not detected or considered not significant in the sample population studied. results prevalence of ptpv abnormal conditions are listed in table 1. the high-to-low prevalence order was: ptpv as a normal vein, excluded from detailed analysis (n=1475, 67% of 2199 legs, 77% of 1917 legs studied for primary, early stage cvvi); ptpv as drainage point of gsv reflux (n=281, p<0.001); ptpv as source reflux (n=122): i) ptpv as source of gsv reflux (n=73); or ii) ptpv as source of non-gsv reflux (n=49); significantly less than source of gsv reflux (p<0.01); and ptpv perceived as abnormally dilated or tortuous (n=39, p<0.001). chi-square proportion analysis did not demonstrate significant difference between the right and left prevalence of ptpv abnormalities (p>0.26). average distance between the ptpv location and the sole of the foot was 31.7±3.4 (23.041.5) cm. average ptpv diameter was 2.7±0.6 (1.3-7.0) mm. table 2 relates ptpv diameters and patterns of reflux or suspected abnormalities. all 9 veins with diameter <2 mm were draining gsv reflux. veins in the 2 <2.5 mm range were mostly drainage of gsv reflux also (n=96, 76%); otherwise, 90% (28/31) of the abnormal ptpv in this diameter range had reflux. percentage of non refluxing ptpv noted in the 3 <3.5 mm range, 27% was higher than expected. the probability of ptpv reflux as a function of diameters were: 0% for <2 mm, 26% (103/391) for 2.0<3.5 mm, 37% (11/30) for 3.5<4.0 mm and 67% (8/12) for ≥4.0 mm. major source of reflux (n=122, 28%/442, 6%/2199) was more prevalent in ptpv≥2.5 mm in diameter (31%, 94/306) than in smaller veins (21%, 28/136) (p<0.03). average diameters for the two subgroups representing gsv reflux source, 2.9±0.7 (2.07.0) mm, or ptpv reflux independent of the gsv, 2.9±0.7 (2.0-5.0) mm, were similar (p=0.63 by t-test). average diameter of the combination of these two refluxing subgroups, 2.9±0.7 (2.0-7.0) mm, was significantly greater than the diameter of the gsv drainage subgroup, 2.6±0.5 (1.3-4.6) mm (p<0.001). table 3 shows the associations between ptpv flow and gsv reflux patterns. prevalence of gsv reflux patterns were: i) segmental, 227 (51%); ii) multisegmental, 89 (20%); iii) multisegmental with refluxing sfj, 41 (9%); iv) distal, 34 (8%); v) proximal, 28 (6%); vi) diffuse, 15 (3%); and vii) absent, 8 (2%). the sfj had reflux gsv diffuse, multisegmental or proximal in 84 (19%) of the extremities. ptpv were source of segmental (45%, 33/73), multisegmental (33%, 24/73), or distal (22%, 16/73) gsv reflux. chi-square demonstrated that real prevalence of the subgroups was significantly different than expected subgroup prevalence figure 2. ultrasonographic details. a) paratibial perforating vein (ptpv) as drainage of great saphenous vein (gsv) reflux. b) ptpv as source of gsv distal reflux. c) change in diameter showing gsv enlargement distally, suggesting distal reflux. a b c no n c om me rci al us e o nly article [veins and lymphatics 2015; 4:4703] [page 37] (p<0.001) based on general prevalence of gsv patterns of reflux and general prevalence of ptpv subgroups. the altered proportions with pathophysiological significance, having higher prevalence than expected, were: ptpv drainage of gsv reflux (n=281) and gsv segmental reflux, 168 vs 144 or 60% vs 51% (p<0.05); therefore, ptpv as a gsv reflux drainage had a higher association with gsv segmental reflux; ptpv source of gsv reflux (n=73) and gsv distal reflux, 16 vs 6 or 22% vs 8% (p<0.05); therefore ptpv was a significant source of gsv distal reflux; refluxing ptpv without relation to gsv flow (n=49) and gsv diffuse reflux, 8 vs 2 or 16% vs 4% (p<0.05); if ptpv reflux was not associated with gsv reflux, the gsv reflux pattern bypassed the ptpv and was diffuse; enlarged ptpv without reflux (n=39) and i) gvs diffuse reflux, 7 vs 1 or 18% vs 3% (p<0.05); and ii) gsv without reflux, 8 vs 1 or 21% vs 3% (p<0.05). therefore, there was a lack of association between abnormal ptpv despite normal flow and gsv patterns of reflux, being either absent or diffuse. in summary, ptpv was mostly normal in early stages of cvvi in women, ptpv drained gsv reflux, most commonly gsv segmental reflux; as a source of reflux, ptpv was mostly associated to gsv distal reflux to the ankle; and ptpv, either enlarged but not refluxing, or, associated with non-saphenous reflux, showed no relation to gsv patterns of reflux. discussion this investigation focused on a very specific population: women with cvvi at early stages. the sampled population had a high prevalence of gsv segmental pattern of reflux, and a relatively low prevalence of sfj reflux. in particular, a 19% prevalence of sfj was slightly higher than that of 12% described for women with varicose veins.7 it is our impression that perforating veins become abnormal as cvvi progresses, not necessarily at the very early stages. about 4/5 of the extremities examined at this ultrasound laboratory have gsv reflux, but only about 1/5 of the lower extremities evaluated qualified for a study of a proximal, medial calf, ptpv. the ptpv was selected for this specific study based on the perception of specialists accustomed to map superficial veins in patients with cvvi. in addition, paratibial perforating veins are commonly palpated during clinical examinations. quantitative knowledge of common prevalence and an extended, detailed descriptions of less frequent findings were desirable. an specific objective often clarifies doubts more so than extensive data collections of mixed clinical conditions. therefore, our studies are being restricted to women with telangiectasias, varicose veins, and mild swelling, and, in this particular instance, to women with abnormalities of a specific perforating vein. other subgroups demand additional research: men, athletes and patients with special conditions such as recurrence, malformations, past thrombosis, etc. the ptpv diameters described herein provided additional information when compared to diameters previously mentioned in the literature.14 normal diameters of perforators at the medial aspect of the leg averaged 2.2 mm while this study indicated that ptpv draining gsv reflux in women averaged 2.6 mm. draining perforating veins, therefore, may be dilated. also, this study indicated that refluxing ptpv in women averaged 2.9 mm while severely abnormal medial perforators had an average diameter of 3.7 mm.14 possible differentials include: i) refluxing perforators at the distal leg may be larger than refluxing ptpv; ii) reflux was not accessed in ptpv draining gsv reflux; iii) this study included only women; and iv) this population represents subjects with early stage of disease. the most common finding in this study was an uneventful ptpv; previous publications have emphasized the major role of tributaries over perforating veins in early stages of disease.1,11 otherwise, the most commonly abnormal ptpv drained segmental gsv reflux. the next most common finding, also within pathophysiological expectations, was a refluxing ptpv as a source of gsv distal reflux. ptpv abnormalities were not strongly related to gsv diffuse reflux or gsv without reflux. these findings are consistent with early cvvi stages. in summary, contributions of paratibial perforating vein abnormalities to early stages of chronic venous valvular insufficiency were evaluated in women. only about 1 in 5 of more than two thousand extremities evaluated had ptpv abnormalities. the most common, active role of the ptpv was to drain reflux restricted to a segment of the gsv. secondarily, this perforating vein caused reflux at the distal portion of the gsv. exceptionally, ptpv had reflux not associated with the gsv. perforating veins may not be frequently exposed to hydrostatic columns of pressure, but a large ptpv diameter may indicate risk of cvvi progression even in the absence of reflux. specific research may indicate that abnormal perforating veins caustable 1. pathophysiology of proximal, medial leg, paratibial perforating veins in women with early chronic venous valvular insufficiency: prevalence of flow or size abnormalities on ultrasound examinations. condition right leg left leg total p* (n) (n) (n) r vs l gsv reflux drainage 138 (64%) 143 (63%) 281 (64%) 0.70 gsv reflux source 31 (14%) 42 (18%) 73 (17%) 0.27 refluxing perforator° 24 (11%) 25 (11%) 49 (11%) 0.93 non-refluxing perforator# 21 (10%) 18 (8%) 39 (9%) 0.48 total 214 (100%) 228 (100%) 442 (100%) 0.35 ptpv significant reflux 55 (26%) 67 (29%) 122 (28%) 0.39 gsv, great saphenous vein; r, right; l, left; ptpv, paratibial perforating veins. *probability by chi-square proportions between right and left leg prevalence for each condition in relation to the total for each leg; °not major source of gsv reflux; #not major drainage of gsv reflux but considered to have large diameter ≥3 mm and/or unusual anatomy such as length and tortuosity. table 2. proximal, medial leg, paratibial perforating veins in women with early-stage chronic venous valvular insufficiency: relationship between ultrasound measured diameters or fascial aperture representing maximum potential diameter and flow patterns. diameter all gsv reflux gsv reflux refluxing non-refluxing drainage source perforator* perforator° <2.0 mm 9 (2%) 9 (100%) 0 0 0 2.0 <2.5 mm 127 (29%) 96 (76%) 19 (15%) 9 (7%) 3 (2%) 2.5 <3.0 mm 147 (33%) 99 (67%) 25 (17%) 21 (14%) 2 (1%) 3.0 <3.5 mm 117 (26%) 56 (48%) 19 (16%) 10 (9%) 32 (27%) 3.5 <4.0 mm 30 (7%) 18 (60%) 7 (23%) 4 (13%) 1 (3%) ≥4.0 mm 12 (3%) 3 (25%) 3 (25%) 5 (42%) 1 (8%) total 442 (100%) 281 73 49 39 gsv, great saphenous vein. *source of non-gsv reflux; °not major drainage of gsv reflux. no n c om me rci al us e o nly article [page 38] [veins and lymphatics 2015; 4:4703] ing reflux may already represent a more advanced stage of disease than usual, primary venous valvular insufficiency. conclusions detailed evaluation of a major perforating vein in the calves of women with early stages of cvvi confirmed a primary re-entry role draining gsv reflux. ptpv was linked to reflux in about 1 of 5 legs with cvvi. ptpv was an uncommon major source of reflux in about 1 of 20 lower extremities. detailed us of ptpv, however, insured over 80% accuracy in cvvi mapping. references 1. engelhorn c, engelhorn a, casagrande c, salles-cunha sx. sources and drainages of saphenous vein reflux in patients with primary varicose veins. poster, final program of the american venous forum 11th annual meeting of the, dana point, ca, february 18-21, 1999, p 96. 2. allegra c, antignani pl, bergan jj, et al. international union of phlebology working group. the "c" of ceap: suggested definitions and refinements: an international union of phlebology conference of experts. j vasc surg 2003;37:12931. 3. eklöf b, rutherford rb, bergan jj, et al. american venous forum international ad hoc committee for revision of the ceap classification. revision of the ceap classification for chronic venous disorders: consensus statement. j vasc surg 2004;40: 1248-52. 4. coleridge-smith p, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs uip consensus document. part i. basic principles. eur j vasc endovasc surg 2006;31:83-92. 5. cavezzi a, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs uip consensus document. part ii. anatomy. eur j vasc endovasc surg 2006;31:288-99. 6. engelhorn ca, engelhorn al, cassou mf, salles-cunha s. patterns of saphenous venous reflux in women presenting with lower extremity telangiectasias. dermatol surg 2007;33:282-8. 7. engelhorn ca, engelhorn al, cassou mf, salles-cunha sx. patterns of saphenous reflux in women with primary varicose veins. j vasc surg 2005;41:645-51. 8. engelhorn ca, manetti r, baviera mm, et al. progression of reflux patterns in saphenous veins of women with chronic venous valvular insufficiency. phlebology 2012;27:25-32. 9. caggiati a, bergan jj, gloviczki p, et al. nomenclature of the veins of the lower limb: extensions, refinements, and clinical application; international interdisciplinary consensus committee on venous anatomical terminology. j vasc surg 2005;41:719-24. 10. engelhorn c, engelhorn a, salles-cunha s, et al. relationship between reflux and greater saphenous vein diameter. j vasc technol 1997;21:167-72. 11. engelhorn ca, engelhorn al, cassou mf, et al. anatomofunctional classification of saphenous insufficiency by color-flow duplex-doppler ultrasound directed to planning of varicose vein surgery. j vasc bras 2004;3:13-9. 12. engelhorn ca, cassou mf, engelhorn al, salles-cunha sx. does the number of pregnancies affect patterns of great saphenous vein reflux in women with varicose veins? phlebology 2010;25:190-5. 13. labropoulos n, tiongson j, pryor l, et al. definition of venous reflux in lower extremity veins. j vasc surg 2003;38:793-8. 14. sandri jl, barros fs, pontes s, et al. diameter-reflux relationship in perforating veins of patients with varicose veins. j vasc surg 1999;30:867-7. table 3. proximal, medial leg, paratibial perforating veins (ptpv) in women with earlystage chronic venous valvular insufficiency: associations of ptpv flow and great saphenous vein reflux patterns. gsv reflux all gsv reflux gsv reflux refluxing non-refluxing drainage source perforator* perforator° segmental 227 (51%) 168 (60%) 33 (45%) 16 (33%) 10 (26%) multisegmental 89 (20%) 60 (21%) 17 (23%) 10 (20%) 2 (5%) multiseg+sfj 41 (9%) 27 (10%) 7 (10%) 4 (8%) 3 (8%) distal 34 (8%) 0 16 (22%) 10 (20%) 8 (21%) proximal 28 (6%) 26 (9%) 0 1 (2%) 1 (3%) diffuse 15 (3%) 0 0 8 (16%) 7 (18%) sem refluxo 8 (2%) 0 0 0 8 (21%) total 442(100%) 281(100%) 73 (100%) 49(100%) 39(100%) segmental 227 (100%) 168 (74%) 33 (15%) 16 (7%) 10 (4%) multisegmental 89 (100%) 60 (67%) 17 (19%) 10 (11%) 2 (2%) multiseg+sfj 41 (100%) 27 (66%) 7 (17%) 4 (10%) 3 (7%) distal 34 (100%) 0 16 (47%) 10 (29%) 8 (24%) proximal 28 (100%) 26 (93%) 0 1 (4%) 1 (4%) diffuse 15 (100%) 0 0 8 (53%) 7 (47%) sem refluxo 8 (100%) 0 0 0 8 (100%) expected statistical prevalence probability 0.6357 0.1652 0.1109 0.0882 segmental 0.5136 144 37 25 20 multisegmental 0.2014 57 15 10 8 multiseg+sfj 0.0928 26 7 5 4 distal 0.0769 22 6 4 3 proximal 0.0633 18 5 3 2 diffuse 0.0339 10 2 2 1 sem refluxo 0.0181 5 1 1 1 gsv, great saphenous vein; sfj, saphenofemoral junction. *not major source of gsv reflux; °not major drainage of gsv reflux. no n c om me rci al us e o nly hrev_master veins and lymphatics 2014; volume 3:4655 [veins and lymphatics 2014; 3:4655] [page 57] ultrasound guided foam sclerotherapy of recurrent varices of the great and small saphenous vein: 5-year follow up patrizia pavei, maurizio ferrini, giorgio spreafico, attilio nosadini, andrea piccioli, enzo giraldi, ugo baccaglini centro regionale specializzato multidisciplinare per la day surgery, ao padova, italy abstract ultrasound guided foam sclerotherapy (ugfs) proved to be effective in recurrent varices. in this observational study from 2006 and 2012 we treated 142 neovascularization, 155 inguinal recurrence and 28 popliteal recurrent varices. for neovascularization 0.3-0.5% polidocanol (pol) sclerosant foam (sf) was injected for vein having diameter <3 mm and 0.5-1% pol or sodium tetradecylsulphate (sts) sf for higher vein diameters. the patients with residual sapheno-femoral or sapheno-popliteal junctions were treated with 1% sts sf for diameter up to 5 mm, while for larger veins 3% sts was used. from 1 to 3 sessions were necessary in both groups with 4 to 10 ml injected per session. in the group of neovascularization the 3-5years follow up revealed good results in 90.8% of the cases. in the group of popliteal recurrences the 3-5 years follow up showed 60.7% of good results, while in the group of inguinal recurrences we observed 80% of good results at 3-5 years. we did not have major complication. as minor complications we had 0.2% of gastrocnemial vein thrombosis, 0.1% of minor neurological problems, 2.8% of superficial vein thrombosis, 3.9% of pigmentation and light to mild post-treatment pain in 16.5% of the cases. in conclusion our data show that ugfs is a well tolerate technique, preferred by previously operated patients, safe and easily repeatable with good medium-term results both in case of neovascularization and of recurrence from residual femoral or popliteal stump. introduction recurrent varices after surgery are a common, complex and costly problem. the percentage of recurrences varies from 20 to 80% according to the definition of recurrence and to the length of the follow up.1,2 actually, data in literature often lack uniformity and are difficult to compare.2,3 the causes of recurrence are technical or tactical in approximately 29% of the cases, often because of failure to adequately strip a refluxing great saphenous vein or for the presence of a residual saphenous stump, while neovascularization, characterized by fragile, thin walled varices often not easy to treat with surgery and not eligible for endovascular treatments, is responsible for another 29%.4-6 on the other hand, 32% of recurrences are represented by varices in new sites, which can be related to the progression of the disease.2,7,8 another cause of recurrence is an incompetence of the deep venous system that can occur in post-thrombotic syndrome or for congenital reasons (aplasia or valvular agenesis).7 the aim of the treatment of recurrent varices is to control varicose disease and its symptoms and to prevent complications. patients suffering from this condition often belong to class c3 to c6 of the clinical-etiology-anatomy-patho physiology (ceap) classification and they are often reluctant to undergo a new treatment. ultrasound guided foam sclerotherapy (ugfs) proved to be effective in recurrent varices9,10 and in this observational study we report our five-year follow-up results of ugfs in the treatment of varicose recurrence after surgery. materials and methods the prospective cohort study included patients with recurrent varicose veins in the operated site (high ligation + saphenous stripping and phlebectomy). all patients underwent a color duplex ultrasound (cdu) investigation of the operated limb according to the standard;11 residual sapheno-femoral junction (sfj) or sapheno-popliteal junction (spj) diameter was measured 2 cm below the saphenous junction, whereas veins due to neovascularization were measured at their proximal site near to the junction. after cdu examination patients were divided into 2 groups: i) recurrence related to groin/popliteal neovascularization; and ii) recurrence due to new varices emanating from an already operated junction (residual stump of sfj or spj). our study did not include residual veins or recurrences originating from other sites, such as from incompetent perforators. from 2006 to 2012 we treated 142 cases of recurrent varices related to inguinal neovascularization, 155 inguinal recurrences emanating from residual sfj stump and 28 popliteal recurrences related to residual spj (table 1). ugfs was performed as single treatment and tessari method was used to form the sclerosant foam (sf).12 c of the ceap classification of the inguinal recurrences was as follows: 89 c2, 37 c3, 19 c4, 8 c5 and 2 c6. as for popliteal recurrences we had 17 c2, 7 c3, 2 c4, 1 c5 and 1 c6 (table 2). some of the cohort data are summarized in table 3. patients with neovascularization were treated with either polidocanol (pol) (atossisclerol, kreussler pharma, wiesbaden, germany) or sodium tetradecylsulphate (sts) (fibrovein, std pharmaceutical ltd., hereford, uk) in low concentration and low doses. more in detail, 0.3-0.5% pol or sts sf was injected under ultrasound guidance for vein having diameters <3 mm and 0.5-1% pol/sts sclerosant foam was used for higher vein diameters. ceap (c) distribution of the 142 neovascularization cases was: 99 c2, 29 c3, 12 c4 and 2 c5. patients underwent from 1 to 3 sessions [mean 2.2 mm and standard deviation (sd) 0.37], with 4 to 10 ml per session (mean 6.2 and sd 1.58). the patients with residual sfj or spj stump (155 inguinal recurrences and 28 popliteal ones) were treated with 1% sts sf in cases of residual sfj/spj diameter up to 5 mm, while for larger veins 3% sts was used. patients underwent 1 to 3 sessions (mean 2,1 and sd 0.66) with 4 to 10 ml of foam injected per session (mean 7.8 and sd 1.42).the sessions were performed once a week for three consecutive weeks. after each session a short-stretch elastic bandage was applied for 24 h and then patients wore a ii class elastic stocking for other 20 days. no additional sessions were allowed during the follow up period. good clinical results were defined as the absence of clinical evident varices. residual veins were recorded on drawings. correspondence: patrizia pavei, centro regionale multidisciplinare specializzato di day surgery, azienda ospedaliera di padova, via giustiniani 2, 35128 padova, italy. tel.: +39.329.2112367 fax: +39.049.8215672. e-mail: patrizia.pavei@sanita.padova.it key words: recurrent varices, ultrasound foam guided sclerotherapy. received for publication: 4 august 2014. revision received: 8 october 2014. accepted for publication: 10 october 2014. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright p. pavei et al., 2014 licensee pagepress, italy veins and lymphatics 2014; 3:4655 doi:10.4081/vl.2014.4655 no n c om me rci al us e o nly [page 58] [veins and lymphatics 2014; 3:4655] article results in the group of neovascularization the 3-5 years (mean 4 and sd 0.73) follow up revealed good results, defined as the absence of clinical evident varices and/or of any reflux in the injected site(s) at the cdu examination. more in detail 129 patients (90.8%) had no clinical recurrence nor reflux at the groin neovascularization site and 13 patients (9.2%) showed recurrent varicose veins. as to the second group, characterized by the residual stump-based recurrence, a few differences were observed between inguinal and popliteal findings. among the 155 patients with inguinal recurrence, 4 were lost in the follow up, 1 for personal problems, 1 for health problems and 2 were no longer contactable (figure 1). at 1 year follow up (151 patients) cdu showed complete occlusion of the treated veins in 132 patients (87%) and no clinical recurrence was highlighted; at 2 years 98 patients completed the follow up: 83 patients (85.7%) had good clinical results, while cdu showed complete occlusion in 76 patients (77.5%). finally at 3-5 years (mean 4.4 and sd 0.77), 75 patients completed the follow up and the cdu examination showed a 72% occlusion rate (54 patients), while the clinical recurrence was 20% (15 patients). the 28 popliteal recurrences had a 3-5 years (mean 4.3 and sd 0.76) follow up with 60.7% of complete occlusion at cdu (17 patients) and absence of varices. the analysis of patients where cdu highlighted recanalization of the treated stump and network (40% of the total), showed that 13% of patients had recanalization without visible varices and 27% of them showed recanalization with clinical evident varicose veins. the clinical recurrent varices were smaller than the pre-treatment ones in the vast majority of the cases. as for complication we observed: i) gastrocnemial vein thrombosis in 0.2% of the cases; ii) minor neurological problems, namely visual disturbances and migraine, in 0.1%; iii) 2.8% incidence of superficial vein thrombosis; iv) pigmentation in 3.9 % of the patients; and v) light to mild post-treatment pain in 16.5% of the cases (table 4). discussion we divided our patients with recurrent varicose veins into 2 groups: group a with neovascularization at the groin area, and group b with new large varices emanating from a residual stump of the previously operated junction. in fact literature data show that smaller veins have better results with sclerotherapy table 1. type of recurrences. kind of recurrence patients c0, c1 0 >=c2 same site neovascularization 142 inguinal residual stump and varicose network 155 popliteal residual stump and varicose network 28 total 325 table 2. clinical-etiology-anatomy-pathophysiology classification (ceap) classification of the treated patients. ceap class patients % c0 0 0 c1 0 0 c2epasr 89+17+99 c3epasr 37+7+29 c4epasr 19+2+14 c5epas r 8 c5epas+pr 2+1 c6epaspr 3 table 3. cohort data. patients’ characteristics range gender f/m 232/93 mean age 58.63 38-78 years from the first surgery (mean) 11.44 2.35-30.33 figure 1. recruited patients. table 4. complications after ultrasound guided foam sclerotherapy. complications patients (%) gastrocnemius vein thrombosis 0.2% superficial vein thrombosis 2.8% minor neurological complications 0.1% post-treatment pain 16.5% pigmentation 3.9% no n c om me rci al us e o nly article [veins and lymphatics 2014; 3:4655] [page 59] than larger ones.13-15 in particular neovascularization16 is characterized by fragile, thin walled varices, hardly treatable with surgery and not eligible for endovascular treatments.7,8 on the contrary these features make these vessels well suitable for sclerotherapy. our 3-5 years follow-up results confirm this trend with an overall success of 90.8% in 142 patients with neovascularization (group a). conversely ugfs of larger varices emanating from the sapheno-femoral or sapheno-popliteal junction residual stump resulted in a higher recanalization rate at cdu examination and in a slightly higher clinical recurrence rate. literature data show a contrasting evidence as to the best option for treatment of recurrent varices.17-19 in 2008 we published a paper on redo surgery of the sfj in 51 patients who were operated between 1996 and 2004.20 at 5 years follow up 31.4% of them had no clinical recurrence, 29.9% showed new varices; 5.8% residual varices. cdu investigation of these patients showed 23.5% neovascularization rate at the groin and 9.8% patients presented with new large varices coming from the re-operated junction, that is to say 33.3% had a true relapse after redo surgery at the groin. therefore we decided to treat patients with a less invasive technique, namely with ugfs. according to our personal experience and data, recurrent varices may be treated with ugfs in the vast majority of the cases and efficacy and safety of this method has been demonstrated in our and other authors’ clinical series.9-10 recurrence related to neovascularization at the groin or at the popliteal area respond well to ugfs, whereas recurrent varices fed by a residual stump of the sfj or spj shows slightly worse outcomes, especially for spj-based recurrence probably higher concentrations and higher volumes of sclerosant foam may be of help to improve ugfs furthermore in this second group of patients. a strict cdu-based follow up and, if necessary, an early re-treatment should be considered in this second group of patients with residual stump-based recurrence, especially at popliteal fossa. conclusions in conclusion, our data show that ugfs is the treatment of choice in case of neovascularization-based varicose recurrence. similarly in cases of recurrence emanating from the residual stump of the operated junction ugfs may be the first choice treatment. finally in our recent practice we have included phlebectomy of the large varices along the limb, in order to decrease the total volume of injected sclerosant foam and to speed-up the treatment results. ugfs in our patients showed good mid-term results, and furthermore it proved to be a well tolerated technique, largely preferred by previously operated patients, extremely safe, costeffective and easily repeatable. references 1. perrin mr, guex jj, ruckley cv, et al. recurrent varices after surgery (revas), a consensus document. cardiovasc surg 2000;8:233-45. 2. perrin mr, labropoulos n, leon lr. presentation of the patient with recurrent varices after surgery (revas). j vasc surg 2006;43:327-34; discussion 334. 3. perrin m, allaert fa. intraand interobserver reproducibility of the recurrent varicose veins after surgery (revas) classification. eur j vasc endovasc surg 2006;32:326-2. 4. van rji am, jones gt, hill gb, et al. neovascularization and the recurrent varicose veins: more histologic and ultrasound evidence. j vasc surg 2004;40:296-302. 5. jones l, braithwaite bd, selwyn d, et al. neovascularization is the principal cause of varicose vein recurrence: results of a randomized trial of stripping the long saphenous vein. eur j vasc endovasc surg 1996;12:442-5. 6. el wajeh y, giannoukas ad, gulliford cj, et al. saphenofemoral venous channels associated with recurrent varicose veins are not neovascular. eur j vasc endovasc surg 2004;28:509-94. 7. royle jp. recurrent varicose veins. world j surg 1986;10:944-53. 8. labropoulos n, touloupakis e, giannoukas ad, et al. recurrente varicose veins: investigation of the pattern and extent of reflux with color flow duplex scanning. surgery 1996;119:406-9. 9. darvall kal, batev gr, adam dj, et al. duplex ultrasound outcomes following ultrasound guided foam sclerotherapy of symptomatic recurrent saphenous varicose veins. eur j vasc endovasc surg 2011;42:107-14 10. kakkos st, bountouroglou dg, azzam m, et al. effectiveness and safety of ultrasound guided foam sclerotherapy for recurrent varicose veins: immediate results. j endovasc ther 2006;13:357-74. 11. nicolaides an. investigation of chronic venous insufficiency. a consensus statement. circulation 2000;14:1-38. 12. breu fx, guggenbichler s, wollmann jc. 2nd european consensus meeting on foam sclerotherapy, 28-30 april 2006 tegernsee, germany. vasa 2008;37:1-32. 13. myers ka, jolley d, clough a, kirwan j. outcome of ultrasound guided sclerotherapy for varicose veins: medium term results assessed by ultrasound surveillance. eur j vasc endovasc surg 2007;33: 116-21. 14. coleridge-smith p. chronic venous disease treated by ultrasound guided foam sclerotherapy. eur j vasc endovasc surg 2006;32:577-83. 15. cavezzi a, frullini a, ricci s, tessari l. treatment of varicose veins by foam sclerotherapy: two clinical series. phlebology 2002;17:13-8. 16. turton epl, scott dja, richards sp, et al. duplex-derived evidence of reflux after varicose vein surgery: neoreflux or neovascularisation? eur j vasc endovasc surg 1999;17:230-3. 17. société française de phlébologie. les récidives variqueuses après chirurgie. phlébologie 1998;51:387-430. 18. bradbury aw, stonebridbge pa, callam mj, et al. recurrent varicose veins: assessment of the saphenofemoral junction. br j surg 1994;81:373-5. 19. de maeseneer mg, vandenbroeck cp, hendriks jm, et al. accuracy of duplex evaluation one year after varicose vein surgery to predict recurrence at the sapheno-femoral junction after five years. eur j vasc endovasc surg 2005;29:308-12. 20. pavei p, vecchiato m, spreafico g, et al. natural history of recurrent veins undergoing reintervention: a retrospective study. dermatol surg 2008;34:1672-82. no n c om me rci al us e o nly hrev_master veins and lymphatics 2017; volume 6:6814 [veins and lymphatics 2017; 6:6814] [page 51] technique for intraoperatory harvesting of adipose derived stem cells: towards cell treatment of recalcitrant ulcers ilaria zollino,1 maria grazia sibilla,2 sergio gianesini,1,2 erica menegatti,1,2 mirko tessari,1,2 anna maria malagoni2 1department of morphology, surgery and experimental medicine, section of translational of medicine and surgery, university of ferrara; 2sant’anna university hospital, unit of translational surgery and vascular diseases center, ferrara, italy abstract successful wound and ulcer repair remains a major biomedical challenge in the 21st century. innovative and alternative treatment options have been investigated over the last decade and stem cells application has been suggested as a possible novel therapy for regenerative medicine. in particular, stem cells derived from adipose tissue have been attracting a lot of attention in recent years as an alternative to the use of cells derived from bone marrow. this technical note describes the procedure introduced by coleman for intraoperatory harvesting of adipose derived-stem-cells and proposes a rationale for using it in difficult wound healing and recalcitrant ulcers. introduction stem cell technology is increasingly being employed to treat tissue and organs in patients. surgeons are keen to transfer these treatment methods to other applications such as ulcer and wound healing. the use of adipose-derived-stem cells (adscs) appeals to surgeons due to the relative ease of locating sites for harvesting, the harvesting process and the amount of material available for use. adscs also offer several desirable factors including their osteogenic and chondrogenic potential, enhancement of angiogenesis, limitation of apoptosis and immunomodulatory function.1 due to these advantageous characteristics, adscs can be explored as a promising tool to repair recalcitrant ulcers and difficult wounds in those cases where conventional treatments have failed. although numerous promising stem cell approaches are advancing in clinical trials, intraoperative stem cell therapies using adscs offer more immediate benefits, by integrating an autologous cell source with a well-established surgical intervention in a single, safe procedure. coleman’s technique adscs are generally extracted from adipose tissue using a multiple stepwise procedure. coleman’s technique2 is both the first and the most popular method for tissue regeneration:3,4 it provides aspiration, centrifugation and the subsequent re-injection of autologous fat. first, kleine’s solution made up of 250 ml normal saline, 20 ml of 1% carbocaine, 1 ml adrenaline and 2 ml bicarbonate is injected into the fat donor area.5 after diffusion of the solution the harvesting procedure is undertaken, using a two-hole blunt cannula [byron medical (a division of mentor corporation), tucson, az, usa] fitted directly to a 10 ml luer lock syringe (bd syringe luer-lok tip; becton dickinson, franklin lakes, nj, usa), which helps to reduce the pressure generated during the harvesting procedure and preserves the fat parcels.6 following the fat harvesting, the lipoaspirate is processed via centrifugation of the lipoaspirate at 3000 rpm (rotor size: 16 cm; g force: 580) for 3 min in 10 ml syringes. this separates the fat into 3 layers. the upper layer and lower layer are discarded, as they are composed of oil from destroyed fat and blood respectively, leaving the middle layer, which contains a high concentration of stem cells7,8 and the stromal vascular fraction. once the middle layer has been extracted, the micro-fat graft is transferred into 1ml syringes prior to injection into the tissue to be grafted (figure 1). a multilayer technique is used to implant the aliquots of fat, with very small amounts of fatty tissue released into the recipient area in order to optimize the successful implantation of the graft. a blunt coleman microcannula is used to deposit the micro-fat graft via a number of sub dermal and hypodermal tunnels through numerous tissue planes. this technique of minimising the amount of micro-fat graft released with each introduction of the cannula increases the surface area between the grafted fat and the tissue receiving it. in this way there is a reduction in fat damage and adipocyte necrosis, with an improvement in graft vascularization and three-dimensional fat distribution. the recently grafted fat has a readily available blood supply, which facilitates its survival and reduces the possibility of fat necrosis or calcification.9 chronic venous leg ulceration and the potential role of adipose derived-stem-cells chronic venous leg ulceration (cvu) occurs in about 10% of cases of chronic venous disease (cvd).10 although mainly caused due to superficial venous insufficiency, cvu becomes more prevalent when associated with other health issues such as diabetes, malnutrition, rheumatoid arthritis, chronic anaemia or second stage peripheral arterial disease.11,12 cvu can be treated through surgery or through a combination of compression, wound-care and debridement. two randomised control trials have evaluated the healing rate and risk of ulcer recurrence following superficial venous surgery. the long-term randomized study conducted by zamboni et al.13 corroborates the effectiveness of minimally invasive surgical haemodynamic correction of reflux (chiva) for leg ulceration secondary to superficial venous reflux. follow-up after a 3 year period revealed a 100% healing rate at 31 days and a recurrence rate of 9% in those patients who received surgery, compared to the compression only group with a healing rate of 96% after 31 days and a recurrence rate of 38%. the eschar study conducted by correspondence: ilaria zollino, department of morphology, surgery and experimental medicine, section of translational of medicine and surgery, university of ferrara, via aldo moro 8, ferrara, italy. e-mail: zlllri@unife.it key words: coleman’s technique; adipose stem cells; recalcitrant ulcers. contributions: iz, manuscript design, conceiving and preparation; mgs, manuscript design, pictures collection; sg, manuscript design; em, manuscript drafting; mt, manuscript drafting; amm, manuscript drafting and conceiving. conflict of interest: the authors declare no potential conflict of interest. received for publication: 24 may 2017. revision received: 15 june 2017. accepted for publication: 17 june 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright i. zollino et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6814 doi:10.4081/vl.2017.6814 no n c om me rci al us e o nly how i do it barwell et al.14 also advocates simple venous surgery as a benefit to patients with chronic venous ulceration. it assessed the ulcer recurrence rate as significantly reduced in its compression and superficial venous surgery group at 12%, compared to 28% recurrence in the compression alone group. however, a significant proportion of recalcitrant ulcers respond to treatment but do not heal.15-18 in these patients, advanced dressings and skin grafts are generally used to achieve healing21 and new regenerative approaches including the use of adscs have been proposed.19 the positive effect of adscs is due to an increase in vascularization, which is fundamental to the healing process.20,21 adscs are able to release angiogenic factors, and have shown increased angiogenesis in wound healing when injected or delivered via a scaffold.22 treatment is customised for each patient and requires a clean and healthy wound bed with no devitalised tissue and carefully managed protease levels.23 debridement and application of adipose derived-stem-cells in the wound bed there are few reports about the treatment of venous leg ulcers (vlus) using adscs. however, adscs have shown a positive impact on wounds healing in preclinical and clinical studies. recent adscs applications in vitro and in vivo have demonstrated that they are attracted to the wound site and affect regeneration processes by means of paracrine mechanisms in addition to fusion and differentiation, for instance, into keratinocytes or dermal fibrobasts.24-27 promising applications in wounds and ulcers healing have been reported, although thus far these are small studies with a total of only 98 patients.28-32 bartsich and morrison33 discussed the longterm treatment of chronic sickle cell ulcers and the possible use of a skin graft and fat grafting to achieve healing. current treatment using skin grafting and local wound care is often unsuccessful long-term, as wounds that have healed break down again. so, treatment involving permanent alteration of the wound bed, with recruitment of a new cell population and subsequent fat grafting, was applied. our group was attracted by first reports on application of cell therapy in unhealed ulcers, and performed preliminary application in selected cases. in our procedure, we first perform a detailed wound bed preparation following this sequence. prior to the figure 1. coleman’s technique for harvesting adipose derived-stem-cells (adscs). in this particular case the harvesting is performed in the periumbilical area after tumescent local anaesthesia infiltration (a); the adipose tissue is centrifuged in order to separate the different components (b); the samples are separated into: an upper layer of yellow oil, a middle layer composed of adipose tissue with high concentration of stem cells and a bottom layer of blood (c); after oil (d) and blood (e) elimination the adscs are aspirated by luer-lock syringe technique (f). [page 52] [veins and lymphatics 2017; 6:6814] no n c om me rci al us e o nly how i do it procedure, the wound area is sanitized using chlorexidine, then debridement of ulcers is performed by the means of versajet device (versajet™, versajet hydrosurgery system, smith and nephew, hull, uk), a debridement tool able to cut and remove necrotic tissue and fibrin based on a high pressure jet of water which produces the venturi effect.34 we emphasize here that wound bed preparation needs to be meticulous before implantation: the microenvironment for wound regeneration mainly depends on interactions between stem cell progenitors and their niche, and it provides proliferation and differentiation of the cells.35 after this stringent preparation of the wound bed, it is possible to apply coleman’s technique, as described above. the suspension of adscs is injected into the wound bed and the wound margins; a scaffold of commercial hyaluronic acid is positioned on the wound bed in order to cover the implanted cells. finally, advanced foam dressing protects the healing area before the application of compression. centrifugation according to coleman’s procedure creates a graded density of fat with varying characteristics that influence lipoaspirate persistence, properties, and quality.36 compared with other fat-non processing methods, centrifugation clears the fat from most blood remnants and shows the highest concentration of mesenchymal stem cells.37 it is safe and feasible, does not impair cell viability and can augment adscs content.38 the inoculation of these non manipulated cells present in the lower centrifuged high-density layer (hdl) could accelerate the healing of recalcitrant venous and mixed leg ulcers and could be used for the regeneration of large defects: the hdl displays the highest expression of mesenchymal stem cells and endothelial markers, such as vascular endothelial growth factor a (vegfa), indicating the larger vascular potential of the cells in this layer (figures 2 and 3).36 moreover, in presence of specific growth factors, stem cells present in the hdl can differentiate into several lineages, including osteogenic, adipogenic, condrogenic, neuronal, glial, and endothelial lineages. conclusions as a treatment which is based on a widely recognised, safe procedure, intraoperative adscs therapy using coleman’s technique provides a new alternative and potentially regenerative approach to the clinical challenges of recalcitrant ulcers and difficult wound healing. this surfigure 2. pre-operative martorell’s ulcer (a); intraoperative injection of adipose derivedstem-cells (b) post-operative leg ulcer after 4 weeks of treatment (c) and after 8 weeks of treatment (d). figure 3. pre-operative venous leg ulcer over the medial malleolus (a) and over the lateral malleolus (b); post-operative leg ulcer after 14 weeks of treatment (c-d). [veins and lymphatics 2017; 6:6814] [page 53] a b c d no n c om me rci al us e o nly how i do it [page 54] [veins and lymphatics 2017; 6:6814] gical intervention in one single, safe procedure could become an alternative treatment in selected patients, with promising results and future potential. however, at present, there are neither standardised protocols for the clinical application of adscs in vlus nor a consensus on the number of cells (present in the hdl) necessary for different therapeutic options. therefore, standardised protocols and larger randomised controlled trials are indispensable to ensure the safety and effectiveness of adscs in vlus application. references 1. griffin m, kalaskar dm, butler pe, seifalian am. the use of adipose stem cells in cranial facial surgery. stem cell rev 2014;10:671-85. 2. pu ll, coleman sr, cui x, et al. autologous fat grafts harvested and refined by the coleman technique: a comparative study. plast reconstr surg 2008;122:932-7. 3. coleman sr. facial recontouring with lipostructure. clin plast surg 1997;24:347-67. 4. philips bj, marra kg, rubin jp. healing of grafted adipose tissue: current clinical applications of adiposederived stem cells for breast and face reconstruction. wound repair regen 2014;1:11-3. 5. wang g, cao wg, li sl. safe extensive tumescent liposuction with segmental infiltration of lower concentration lidocaine under monitored anesthesia care. ann plast surg 2015;74:6-11. 6. mojallal a, auxenfans c, lequeux c, et al. influence of negative pressure when harvesting adipose tissue on cell yield of the stromal-vascular fraction. biomed mater eng 2008;18:193-7. 7. clauser l, ferroni l, gardin c, et al. selective augmentation of stem cell populations in structural fat grafts for maxillofacial surgery. plos one 2014;9:e110796. 8. gardin c, bressan e, ferroni l, et al. in vitro concurrent endothelial and osteogenic commitment of adiposederived stem cells and their genomical analyses through comparative genomic hybridization array: novel strategies to increase the successful engraftment of tissue-engineered bone grafts. stem cells and dev 2012;21:767-77. 9. clauser lc, consorti g, tieghi r et al. three-dimensional volumetric restoration by structural fat grafting. craniomaxillofac trauma reconstr 2014;7:63-70. 10. kelechi tj, johnson jj, yates s. chronic venous disease and venous leg ulcers: an evidence-based update. j vasc nurs 2015;33:36-46. 11. nüllen h, noppeney t. [diagnosis and treatment of varicose veins. part 1: definition, epidemiology, etiology, classification, clinical aspects, diagnostic and indications]. chirurg 2010;81:1035-44. 12. gemmati d, federici f, catozzi l, et al. dna-array of gene variants in venous leg ulcers: detection of prognostic indicators. j vasc surg 2009;50:1444-51. 13. zamboni p, cisno c, marchetti f, et al. minimally invasive surgical management of primary venous ulcers vs. compression treatment: a long-term randomized study. eur j vasc endovasc surg 2003;25:313-8. 14. barwell jr, davies ce, deacon j, et al. comparison of surgery and compression with compression alone in chronic venous ulceration (eschar study): randomised controlled trial. lancet 2004;363:1854-9. 15. thomas ca, holdstock jm, harrison cc, et al. healing rates following venous surgery for chronic venous leg ulcers in an independent specialist vein unit. phlebology 2013;28:132-9. 16. marston wa, crowner j, kouri a, et al. incidence of venous leg ulcer healing and recurrence after treatment with endovenous laser ablation. j vasc surg may 2017 [epub ahead of print]. 17. van gent wb, hop wc, van praag mc, et al. conservative versus surgical treatment of venous leg ulcers: a prospective, randomized, multicenter trial. j vasc surg 2006;44:563-71. 18. mauck kf, asi n, undavalli c, et al. systematic review and meta-analysis of surgical interventions versus conservative therapy for venous ulcers. j vasc surg 2014;60:60s-70s.e1-2. 19. valle mf, maruthur nm, wilson lm, et al. comparative effectiveness of advanced wound dressings for patients with chronic venous leg ulcers: a systematic review. wound repair regen 2014;22:193-204. 20. yolanda mm, maria av, amaia fg, et al. adult stem cell therapy in chronic wound healing. j stem cell res ther 2014;4:162. 21. fraser jk, wulur i, alfonso z, hedrick mh. fat tissue: an underappreciated source of stem cells for biotechnology. trends biotechnol 2006;24:150-4. 22. king a, balaji s, keswani sg, crombleholme tm. the role of stem cells in wound angiogenesis. adv wound care (new rochelle) 2014;3:614-25. 23. senet p. [cellular therapy and leg ulcers: future approaches]. ann dermatol venereol 2015;142:519-22. 24. nambu m, kishimoto s, nakamura s, et al. accelerated wound healing in healing-impaired db/db mice by autologous adipose tissue-derived stromal cells combined with atelocollagen matrix. ann plast surg 2009;62:317-21. 25. ebrahimian tg, pouzoulet f, squiban c, et al. cell therapy based on adipose tissue-derived stromal cells promotes physiological and pathological wound healing. arterioscler thromb vasc biol 2009;29:503-10. 26. cho hh, kyoung km, seo mj, et al. overexpression of cxcr4 increases migration and proliferation of human adipose tissue stromal cells. stem cells dev 2006;15:853-64. 27. zollino i, zuolo m, gianesini s, et al. autologous adipose-derived stem cells: basic science, technique, and rationale for application in ulcer and wound healing. phlebology 2017;32:160-71. 28. cervelli v, de angelis b, lucarini l, et al. tissue regeneration in loss of substance on the lower limbs through use of platelet-rich plasma, stem cells from adipose tissue, and hyaluronic acid. adv skin wound care 2010;23:262-72. 29. cervelli v, gentile p, de angelis b, et al. application of enhanced stromal vascular fraction and fat grafting mixed with prp in post-traumatic lower extremity ulcers. stem cell research 2011;6:103-11. 30. marino g, moraci m, armenia e, et al. therapy with autologous adiposederived regenerative cells for the care of chronic ulcer of lower limbs in patients with peripheral arterial disease. j surg res 2013;185:36-44. 31. bura a, planat-benard v, bourin p, et al. phase i trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia. cytotherapy 2014;16:245-57. 32. lee hc, an sg, lee hw, et al. safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study. circ j 2012;76:1750-60. 33. bartsich s, morrison n. composite fat and skin grafting for the management of chronic sickle cell ulcers. wounds 2012;24:51-4. 34. fraccalvieri m, serra r, ruka e, et al. surgical debridement with versajet: an analysis of bacteria load of the wound bed preand post-treatment and skin graft taken. a preliminary pilot no n c om me rci al us e o nly how i do it [veins and lymphatics 2017; 6:6814] [page 55] study. int wound j 2011;8:155-61. 35. wong vw, levi b, rajadas j, et al. stem cell niches for skin regeneration. int j biomater 2012:926059. 36. clauser l, ferroni l, gardin c, et al. selective augmentation of stem cell populations in structural fat grafts for maxillofacial surgery. plos one 2014;9:e110796. 37. condé-green a, de amorim ngf, pitanguy i. influence of decantation, washing, and centrifugation of adipocyte and mesenchymal stem cell content of aspirated adipose tissue: a comparative study. j plast reconstr aesthet surg 2010;63:1375-81. 38. ibatici a, caviggioli f, valeriano v, et al. comparison of cell number, viability, phenotypic profile, clonogenic, and proliferative potential of adiposederived stem cell populations between centrifuged and noncentrifuged fat. aesthetic plast surg 2014;38:985-93. no n c om me rci al us e o nly 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2018; volume 7:7621 [page 56] [veins and lymphatics 2018; 7:7621] pressure reconstruction by heterogeneous compression textiles rong liu institute of textiles and clothing, the hong kong polytechnic university, hung hom, kowloon, hong kong abstract the homogeneous elastic structures of traditional compression modalities (e.g. compression stockings) generate uncontrolled cross-sectional pressures around leg geometrics, resulting in highly uneven pressure distributions, which could cause side effects and lowered user’s compliance in compression therapy. a new type of heterogeneous compression sleeves (hcss) has been developed using advanced 3d seamless knitting techniques to proactively reconstruct leg cross-sectional pressures. pressure assessment was conducted in vivo on 20 healthy subjects’ lower limbs applying the designed hcss with hybrid elastic moduli when they were being mounted to the lower limbs under the two testing conditions (i&ii). the results demonstrated that the hcss were capable to reshape compression around lower limbs with reduction of peak pressures at anterior tibia crest and increased pressures at posterior gastrocnemius regions. more even cross-sectional pressure profiles were achieved through reducing the anterior-posterior pressure differences at calf by 41.7-57.1% in condition ii. this study attempts to reform source of pressure in mono-layered compression shell by the design of fabric structure itself rather than additional padding or foam insertions, to promote pressure function and user compliance in practice. introduction chronic venous insufficiency (cvi) is a long-term progressive condition, in which venous pooling reduces venous return, resulting in pain, itching, tiredness, varicose veins and even ulceration in lower limb, which affects approximate 25-40% of women and 10-20% of men globally1. compression therapy has been used in cvi treatment for centuries.2 textile-based compression interventions, as the essential source of pressure, have affected effectiveness of pressure dosage delivery,3,4 in which uniaxial gradient pressure is a core principle of compression textiles used in cvi treatment. through controlling dimensions and densities in continuous fabric segments along the compression shells, a degressive or progressive gradient fashion following certain residual pressure ratios have demonstrated to reduce venous hypertension or increase venous ejection.5-8 however, in clinical practice, high noncompliance resulting from discomfort affected their effectiveness, which was considered much underestimated by previous studies.9-11 homogenous fabric structures were employed in traditional compression modalities (e.g. elastic compression stockings (ecss), which passively generated skin pressures by stretching compression shells onto irregular limbs with larger sizes, as a result, the magnitudes of skin pressure at any angular sites around the limb largely depends upon the geometric structures of the anatomic sites located, causing highly uneven and uncontrollable pressure distributions12 and side effects,13 e.g. ischemia, necrosis and even ulcerations at bony prominence, especially for the elderly with thin and fragile skin.14 to date, few studies have looked at solutions aimed at reforming compression shell itself. aim of this study is to explore a new approach to proactively reshape cross-sectional pressures using hybrid elastic knitting segments in a monolayered compression shell for achieving more even cross-sectional pressure distributions, which integrated with longitudinal gradient pressure as to achieve a new biaxial pressure control for improvement of cvi treatment. materials and methods the hcss specimens were fabricated by using two types of interlaced lycra covered polyamide elastomers, including inlay threads with linear densities of 260 deniers and ground knitting threads with linear densities of 40 deniers. through applying advanced 3d seamless knitting techniques, hybrid elastic segments were formed using specially designed full-knit and laid-in knitting structures. each hcs shell included 8 seamlessly knitted segments. a total of nine types of segments with hybrid ratios of high-low elastic moduli (i.e. shorter or longer stretch) were designed, including: i) hcs-a: 8:0, i.e. all segments were set with low elastic moduli presenting longer stretch property, which was similar with traditional elastic compression stocking); ii) hcss-b, c, d, e, f, g and h: specimens with hybrid elastic moduli. the proportions of segments with low-high elastic moduli were set at 7:1 (b), 6:2(c), 5:3(d), 4:4(e), 3:5 (f), 2:6(g) and 1:7(h), respectively; and iii) hcs-i: 0:8, i.e. all segments were set with high elastic moduli, presenting shorter stretch property, which was similar with rigid or semi-rigid bandage. skin pressures exerted by the developed hcss were tested under the two conditions, including: i) condition i: mounting the short-stretch segments (with higher elastic moduli) at anterior tibia crest, and the long-stretch segments (with lower elastic moduli) at posterior elastic muscular region; and ii) condition ii: mounting the long-stretch segments at the anterior tibia and short-stretch segments (with higher elastic moduli) at posterior elastic muscular calf. a total of 20 healthy subjects aged 24.0±1.6 years old (weight: 59.2±10.4 kg, height: 165.5±10.5 cm and body mass index 21.6 kg/m2) participated in the pressure assessment in vivo. their calves with maximum circumferences were 34.3±2.7 cm. the stretch ratio of hcs fabrics was up to approximate. the skin pressures around the calf cross-sections (anterior p1, medial p2, posterior p3 and lateral p4) were assessed using picopress® testing system (microlab italia, padua, italy) when subjects being worn with hcss. each compression shell was measured by three times and pressure values on average were recorded. results figure 1a presents the skin pressure variations around the calf exerted by the nine designed hcss under the two testing conditions. it can be seen that the increase of correspondence: rong liu, institute of textiles and clothing, the hong kong polytechnic university, hung hom, kowloon, hong kong. e-mail: rong.liu@polyu.edu.hk acknowledgements: we would like to thank the hong kong polytechnic university to support this study through research projects 1ze7k, g-ybuy and itf project its/031/17. conference presentation: international compression club (icc) meeting, paris, 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright r. liu 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7621 doi:10.4081/vl.2018.7621 no nco mm er cia l u se on ly conference presentation shorter stretch segments increased the overall skin pressures for both conditions. in general, the pressure differences around the calf were increased when the shorter stretch segments were placed at anterior rigid tibia crest in condition i. on the contrary, the anterior-posterior pressure differences were obviously reduced by 41.7-57.1% in condition ii, especially for the specimens f (3:5) and g (2:6). figure 1b illustrates the reshaped pressures around the four directions of the calves under both conditions. the hybrid elastic design did not significantly influence skin pressures at medial and lateral lower limb, but did reduce the anterior peak focal pressures and increased posterior muscular pressures at calf. this newly reconstructed pressure profile is promising to avoid side effects caused by excessive pressure and to augment muscular pumping action in dynamic wear. based on this testing results, a new generation of compression stocking with bi-axial pressure profile has been developed (figure 2), which produced degressive gradient pressure from ankle to knee in a sagittal plane and more even crosssectional pressures around lower limbs in a horizontal plane. discussion shorter stretch materials (e.g. static stiffness index ssi >10 mmhg/cm) deliver intermittent high-working but low-resting pressures, which has demonstrated a significant muscular pumping action for promoting venous return in previous clinical studies. however, the sustained uneven pressures by compression shells, and the short functional term (e.g. one-week) by short-stretch fabrics reduced their user compliance and usability in practice. the available studies on heterogeneous properties of compression textiles mainly focused on the four aspects, i) yarn multi-components; ii) anisotropic and nonlinear behaviors of elastic fabrics; iii) integrative elastic or inelastic layers in sub-bandage; and iv) tension variations by inserting or sewing rigid or supportive elements to elastic fabrics. in fact, combining hybrid elastic moduli materials into a continuous compression shell is challenging in fabrication since any protruding seams or overlaps may potentially alter local pressure and chafe the skin in long-term wear. this study integrated high and low elastic moduli segments into mono-layered compression shell by applying seamless laid-in structures and adjusting yarn tension and knitting densities to produce a bi-axial pressure profile along the lower limb. according to laplace’s law,15 the reduced fabric tension may lower figure 1. skin pressure exerted by hcss with nine types of hybrid elastic moduli. a) condition i: segments with higher elastic moduli (shorter stretch) at anterior side, and segments with lower elastic moduli (longer stretch) at posterior region; b) condition ii: segments with lower elastic moduli (longer stretch) at anterior side, and segments with higher elastic moduli (short-stretch) at posterior calf. figure 2. a) cross-sectional pressure variations of calf by hcss under conditions i and ii. a new cross-sectional profile with reduced anterior pressure and increased posterior pressure was demonstrated; b) a new compression stocking with hybrid low-high elastic moduli (2:6) set in condition ii was developed to deliver a controlled bi-axial pressure mode along lower limb. [veins and lymphatics 2018; 7:7621] [page 57] no nco mm er cia l u se on ly conference presentation [page 58] [veins and lymphatics 2018; 7:7621] pressure at a given sized limb. the hybrid elastic moduli segments set at condition ii demonstrated to reduce the anterior tibia pressure but increase posterior muscular pressure. the design of specimen g with low-high elastic moduli panel ratio of 2:6 (i.e. 25%:75%) set in condition ii could be a possible solution to fulfill the findings reported by stolk et al.16 they found that only 35% on average of leg perimeter near the calf expanded at posterior side, whereas 65% including anterior region did not expand at all in kinematic movement. in the designed hcss, the segments with higher elastic moduli set at posterior region against muscular expansion shows the promising capability to augment pumping action during muscular contraction and relaxation in dynamic use. calf muscular pump plays significant role in promotion of venous return; however, the anatomy of the calf puts it at increased risk for side effects induced by uneven pressure delivery. build-up of pressure in anterior bone area cannot decompress to around compartment due to higher tissue stiffness (36.4-44.9 kgf/mm2). the anterior tibia crest with less radius of curvature may cause high peak pressure and be more subjected to skin damage and pressure sore in sustained compression therapy. the skin pressure at posterior muscular region could be deficient due to absorption and dissipation of pressure by surrounding tissues with less stiffness (16.5-25.4 kgf/mm2). the new heterogeneous compression shells provide an optional method to proactively control and reshape crosssectional pressure at calf. conclusions the new hcss demonstrated an important mechanism, that is, heterogeneous compression shells can reconstruct pressure profiles on irregular body to improve pressure function, which is considered to be a promising mode to reduce peak focal pressure at anterior tibia crest but augment muscular pumping action in dynamic wear. based on this results, a new generation of compression stockings with bi-axial pressure function has been developed to deliver both controlled more even cross-sectional pressure horizontally and gradient skin pressure along the lower limb lengthwise. further studies need to be carried out to optimize hybrid elastic moduli for multiple pressure levels for treatment of cvi symptoms. references 1. shammeri oa, aihamdan n, aihothaly b, et al. chronic venous insufficiency: prevalence and effect of compression stockings. int j health sci 2014;8:231-6. 2. hohlbaum gg. zur geschichte der kompressions therapie. i. phlebol proktol 1987;16:241-55. 3. robertson bf, thomson ch, siddiqui h. side effects of compression stockings: a case report. br j gen pract 2014;64:316-7. 4. hooke’s law. in: pautrup b ed.), physics of continuous matter: exotic and everyday phenomena in the macroscopic world. 2nd ed. crf press; 2011. pp.125-138. 5. partsch h. compression therapy: clinical and experimental evidence. ann vasc dis 2012;5:416-22. 6. mosti g, partsch h. duplex scanning to evaluate the effect of compression on venous reflux. int angiol 2010;29:41620. 7. lattimer cr, kalodiki e, kafeza m, et al. quantifying the degree graduated elastic compression stockings enhance venous emptying. eur j vasc endovasc surg 2014;47:75-80. 8. mosti g, partsch h. improvement of venous pumping function by double progressive compression stockings: higher pressure over the calf is more important than a graduated pressure profiles. eur j vasc endovasc surg 2014;47:545-9. 9. tandler sf. challenges faced by healthcare professionals in the provision of compression hosiery to enhance compliance in the prevention of venous leg ulceration. ewma j 2016;16:29-33. 10. kahn sr, shapiro s, wells ps, et al. compression stockings to prevent postthrombotic syndrome: a randomised placebo-controlled trial. lancet 2013. 11. raju s, hollis k, neglen p. use of compression stockings in chronic venous disease: patient compliance and efficacy. ann vasc surg 2007;21:790-5. 12. strölin a, häfner hm, jünger m. biophysical characteristics of medical compression stockings. phlebologie 2007;36:197-204. 13. perrin m. skin necrosis as a complication of compression in the treatment of venous disease and in prevention of venous thromboembolism. phlebolymphology 2008;15:27-30. 14. robertson b, thomson c, siddiqui h. side effects of compression stockings: a case report. br j gen pract 2014;64: 316-7. 15. thomas s. the use of the laplace equation in the calculation of sub-bandage pressure. ewma j 2003;3:21-3. 16. stolk r, wegen van der-franken cpm, neumann ham. a method for measuring the dynamic behaviour of medical compression hosiery during walking. dermatol surg 2004;30:729-36.no nco mm er cia l u se on ly hrev_master veins and lymphatics 2018; volume 7:7633 [page 78] [veins and lymphatics 2018; 7:7633] keys to enhance patients’adherence to compression therapy joseph n. harfouche thoracic, cardiac and vascular surgery centre, chirec, delta hospital, brussels, belgium introduction many studies have demonstrated the effectiveness of compression therapy (ct) in the treatment of veno-lymphatic insufficiency.1-4 in daily practice, therapists are often faced with a lack of patients’ adherence to treatment and especially regarding ct.5 the causes are multiple and it is up to the therapist to understand them, to provide personalised solutions for their patient, and thus boost the wearing of the compression depending on the stage of the illness, in addition to other aspects of treatment. materials and methods this preliminary study was conducted over 16 months on patients with venous and/or lymphatic insufficiency whose treatment consisted, among other things, in the wearing of a compression garment. the 17 subjects matching the criteria of inclusions were patients: i) admitted to the hospital for venous or lymphatic insufficiencies; ii) suffering from their pathology for at least 3 years; iii) reluctant to ct (decided to stop it or never accepted it). the observations resulting from the methodology chosen for this analysis are of a more qualitative than quantitative nature, since its objective is to understand the mechanisms of non-adherence to the wearing of the compression, in order to find appropriate responses and thus optimise the ct. the next phase of this study will consist in quantifying and classifying the results with tests that are currently under development. it will also include a decisional tree to support the therapist in the choice of the most appropriate compression garment according to the patient’s profile. results it appears that the primary causes of non-adherence with the ct are: i) the lack of understanding by the patient concerning the importance and therapeutic value of the ct, because of the lack of explanation by the therapists; ii) the high pressures applied by the compression garment; iii) the discomfort associated to compression garment; iv) the irritation of the skin; v) the wrong size of the garment because of erroneous circumferential measurements; vi) the difficulty to put on and take off the garments; vii) the psychosocial reasons that often discourage the patient from following the recommended treatment play an important role. after analysing the reasons of nonadherence to ct, corrective actions were put in place in order to enhance the compliance and by consequence the therapeutic benefits of the treatment. after accepting to follow the procedure, 13 patients complied with the ct. discussion this preliminary study has shown that most of the non-adherent patients are sceptical because of the lack of understanding and trust in the ct therefore, to avoid isolation of the patient it is essential to establish the confidence. the most effective and fastest way to win the trust of the patient is to demonstrate the effectiveness of the therapeutic means put in place. manual lymphatic drainage (mld) if done by experts is part of the holistic treatment of veno-lymphatic insufficiency. when the patient with oedema, at the end of the mld session, notes a visible volume reduction as well as a shape enhancement, he will be convinced of the usefulness of the treatment put in place. this will positively impact his acceptance of other aspects of treatment, including the ct. to solve the inconvenience and discomfort experienced by the patient that are related to the high pressures applied by the compression garment, we found that these high pressure prescribed were not necessary for all the patients, especially when the whole treatment is respected (mld, exercises, hygiene/lifestyle tips, …). less pressure is much better than no pressure. decreasing the pressure of the compression garment will help solve at the same time the discomfort that patients experienced and will facilitate the putting on and taking off of the garment. if the non-adherence is due to skin irritation (e.g. in case of urticaria factitia), the physician after assessment can prescribe anti histaminic. when the non-adherence comes from erroneous circumferential measurements. the solution, in this case, was the use of the perkit a reproducible e and accurate technic6 and give the measurement the importance it deserves in treatment, not only in order to bring the patient a garment, perfectly adapted to their morphology and measurements but also to follow-up the changes in the limb volume and thus to encourage the patient with convincing results and to adjust the treatment according to the results obtained. when the psychosocial reasons are responsible of the non-adherence, the costeffectiveness must be systematically highlighted by the therapist in order to propose to the patient the most appropriate treatment, taking into account the therapeutic objective, the duration of the treatment, the financial means, etc. an effort is done by some companies to enhance the aesthetic of the current garments. compression bandages are preferred in the phase of decongestion, because they are effective7 and economical due to their ability to adjust. so bandages or adjustable garments must be privileged in this phase. because a premature choice of a made-tomeasure compression garment, while the limb volume is still reducible, will lead to inefficiency of the treatment and at the same time it will be of high cost for the patient. when the therapist estimates that the limb volume is stabilized, the choice of a compression garment will be preferred to promote comfort and autonomy and selfmanagement of the patient. correspondence: joseph n. harfouche, thoracic, cardiac and vascular surgery centre, chirec, delta hospital, brussels, belgium e-mail: joseph.harfouche@yahoo.com conference presentation: international compression club (icc) meeting, paris, 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright j.n. harfouche, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7633 doi:10.4081/vl.2018.7633 no nco mm er cia l u se on ly conference presentation [veins and lymphatics 2018; 7:7633] [page 79] conclusions the therapist is responsible for choosing the most appropriate treatment for the patient but also for ensuring the patient’s self-adherence to the therapeutic means put in place. a personalised and multidisciplinary approach makes it possible to involve all the therapeutic team to optimise the results of the treatment. a crucial point is that the patient must understand that he is not a spectator, but he is one of the active members of his therapeutic team. applying this protocol means: saving patients’ money and giving him a better result within an optimal time. these observations, when validated by an upcoming study, might allow a different approach to current standards by combining treatment efficacy and patient compliance. references 1. motykie gd, caprini ja, arcelus ji, et al. evaluation of therapeutic compression stockings in the treatment of chronic venous insufficiency. dermatol surg 1999;25:116-20. 2. mauck kf, asi n, elraiyah ta, et al. comparative systematic review and meta-analysis of compression modalities for the promotion of venous ulcer healing and reducing ulcer recurrence. j vasc surg 2014;60:71s-90s. 3. blair sd, wright dd, backhouse cm, et al. sustained compression and healing of chronic venous ulcers. bmj 1988;297:1159-61. 4. partsch h, menzinger g, mostbeck a. inelastic leg compression is more effective to reduce deep venous refluxes than elastic bandages. dermatol surg 1999;25:695-700. 5. brownjc, chevilleal, tchou jc, et al. prescription and adherence to lymphedema self-care modalities among women with breast cancer-related lymphedema. support care cancer 2015 jan 1. 6. harfouche, joseph. the perikit: an innovative connected portable device with high level of accuracy and reliability in taking circumferential limb measurements. veins and lymphatics, [s.l.], mar. 2017. issn 2279-7483. 7. king m, deveaux a, white h, et al. compression garments versus compression bandaging in decongestive lymphatic therapy for breast cancer-related lymphedema: a randomized controlled trial. support care cancer 2012;20: 1031-6. no nco mm er cia l u se on ly 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2018; volume 7:7636 [veins and lymphatics 2018; 7:7636] [page 83] compression stockings after deep vein thrombosis: where is the evidence? jan schuren retired from 3m health care, neuss, germany introduction in 2014, the results were published of a randomised placebo-controlled trial to evaluate the effects of compression stockings after deep venous thrombosis (dvt to prevent a post thrombotic syndrome (pts). 806 patients were randomly assigned. treatment allocation was masked from patients, health-care providers, study personnel and study statisticians. the outcome was clearly defined and the surveillance was active and of clinically appropriate duration. the authors conclude that the findings of this study do not support routine wearing of elastic compression stockings after deep venous thrombosis. this study is generally referred to as the sox-trial.1 shortly after its publication, this study was analysed and, on behalf of the german society of phlebology, the authors state that wearing compression stockings after deep venous thrombosis of the leg is still advisable.2 an expert opinion, based on many years of experience and the result of two systematic reviews and meta-analyses, states that the long term use of compression stockings may reduce the incidence and severity of a post-thrombotic syndrome.3 this article reviews the literature and tries to answer the question: where is the evidence? compression stockings after dvt to prevent pts: guidelines in 2012 a paper was published in chest, the journal of the american college of chest physicians, in which evidence-based clinical practice guidelines on antithrombotic therapy and the prevention of thrombosis are provided.4 the authors suggest the use of compression stockings in patients with acute symptomatic dvt of the leg. in addition, it is suggested that compression stockings should be worn for two years and beyond that if patients have developed pts and find the stockings helpful. also in 2012, the uk national institute for health and care excellence (nice) published guidelines on venous thromboembolic diseases (vte).5 it is recommended to offer belowknee graduated compression stockings with an ankle pressure greater than 23 mmhg to patients with proximal dvt a week after diagnosis or when swelling is reduced sufficiently and if there are no contraindications. patients should be advised to continue wearing the stockings for at least two years. in 2015 the nice guidelines are updated and now it is recommended that elastic graduated compression stockings should not be offered to prevent post-thrombotic syndrome or vte recurrence after a proximal dvt.6 shortly after that, also the 2012 us-guidelines are updated.7 for patients with acute dvt of the leg, it is now suggested that compression stockings to prevent pts should not be routinely used. in other countries, like australia, new zealand, germany, france and the netherlands, guidelines still recommend the use of graduated compression stockings after dvt to prevent pts.8-11 compression stockings after dvt to prevent pts: systematic reviews and meta-analyses after the publication of the sox-trial, five systematic reviews with meta-analyses were published in which the sox-trial was included.12-16 this high number of reviews not only illustrates the increasing recognition of pts as a long-term complication of dvt, it also demonstrates a clear need for evidence-based information on the best treatment. in addition, the number of reviews demonstrates the confusion among clinicians on this complication with a significant impact on quality of life and major health economic implications. baldwin et al. state that up to half of the patients with proximal dvt will develop pts despite optimal anticoagulant therapy.17 although much has been published to date, the reviews of the recent literature are very uniform in their conclusions. they can best be summarised with some of them, which are listed below: i) the findings should be interpreted with caution and hence more largescale and well-designed rct’s are still warranted;12 ii) the evidence is too weak to draw a reliable conclusion and further randomised, double-blind, placebo-controlled multicentre trials with larger sample size are needed;13 iii) use of elastic compression stockings does not significantly reduce the development of post thrombotic syndrome, but more study is needed;14 iv) low-quality evidence suggests that elastic compression stockings may reduce the occurrence of pts after dvt but large rct’s are needed to confirm these findings because of current lack of high quality evidence and considerable heterogeneity.16 burgstaller et al. summarise their findings with the statement that there is evidence favouring compression stockings, but that there is also evidence showing no benefit of compression stockings.15 discussion the conclusions of the presented reviews are obvious; more research on compression to prevent pts is needed. however, after the sox-trial with over 800 patients included, it can be questioned how realistic the expectation is that in the near future a similar large double-blinded randomised controlled trial will be executed that fulfils all needs. in a journal editorial in the issue in which one of the mentioned reviews was published,15 ten cate-hoek states that, besides compression therapy, more therapeutic options are needed for prevention and treatment of pts. she suggests to take action and to assess the possibilities ahead of us, instead of trying to solve the current conundrum around elastic compression therapy.18 for the time-being, the only reasonable and unfortunately not evidence-based direction lies in a quote from the christian author elisabeth elliothoward (1926-2015): don’t dig up in doubt what you planted in faith. references 1. kahn sr, shapiro s, wells ps, et al. for the sox trial investigators. correspondence: jan schuren, grotestraat 34, 6067 br linne, the netherlands. e-mail: jan.schuren@gmail.com conflicts of interest: js is a retired 3m employee and invented and co-developed the 3m coban 2 layer compression systems and holds a master’s degree in evidence-based health care from the university of oxford. conference presentation: international compression club (icc) meeting, paris, 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright j. schuren, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7636 doi:10.4081/vl.2018.7636 conference presentation [page 84] [veins and lymphatics 2018; 7:7636] compression stockings to prevent postthrombotic syndrome: a randomized placebo-controlled trial. lancet 2014;379:31-8. 2. schwahn-schreiber c, marshall m, wienert v, et al. wearing compression stockings after deep venous thrombosis of the leg is still advisable: analysis of a publication in the lancet, december 2013. phlebologie 2014;43:144-7. 3. partsch h. compression and deep vein thrombosis. veins and lymphatics 2016;5:22-3. 4. kearon c, akl ea, comerota aj, et al. antithrombotic therapy for vte disease. chest 2012;141:e419s-94s. 5. national institute for health and care excellence (nice). venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. clinical guideline [cg144]: published june 2012. 6. national institute for health and care excellence (nice). venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. clinical guideline [cg144]: published june 2012, updated november 2015. 7. kearon c, akl ea, ornelas j, et al. antithrombotic therapy for vte disease: chest guidelines and expert panel report. chest 2016;149:315-52. 8. australian and new zealand society for vasular surgery. guidelines deep venous thrombosis; 2015. available from: www.anzsvs.org.au 9. awmf, arbeitsgemeinschaft der wissenschaftlichen medizinischen fachgesellschaften e.v. s2-leitlinie: diagnostik und therapie der venenthrombose und der lungenembolie. awmf leitlinienregister nr. 065/002; 2015. 10. haute autorité de santé (has). la compression médicale dans le traitement de la maladie thrombo-embolique veineuse; décembre 2010. 11. nhg-werkgroep diepe veneuze trombose en longembolie. nhg standaard: diepe veneuze trombose en longembolie. huisarts wet 2015;58:26-35. 12. tie ht, luo mz, luo mj, et al. compression therapy in the prevention of postthrombotic syndrome: a systematic review and meta-analysis. medicine 2015;94:1-8. 13. jin yw, ye h, li fy, et al. compression stockings for prevention of postthrombotic syndrome: a systematic review and meta-analysis. vasc endovasc surg 2016;50:328-34. 14. subbiah r, aggarwal v, zhao h, et al. effect of compression stockings on post-thrombotic syndrome in patients with deep vein thrombosis: a metaanalysis of randomised controlled trials. lancet haematol 2016;3:293-300. 15. burgstaller jm, steurer j, held u, amann-vesti b. efficacy of compression stockings in preventing postthrombotic syndrome in patients with deep venous thrombosis: a systematic review and metaanalysis. vasa 2016;45:141-7. 16. appelen d, van loo e, prins mh, et al. compression therapy for prevention of post-thrombotic syndrome. cochrane database syst rev 2017;9:cd004174. 17. baldwin mj, moore hm, rudarakanchana n, et al. post-thrombotic syndrome: a clinical review. j thromb haemost 2013;11:795-805. 18. ten cate-hoek a. efficacy of compression for the prevention of post-thrombotic syndrome: an unsolved clinical conundrum. vasa 2016;45:85-6. hocaoglu c. clozapine-induced rabbit syndrome: a case report comment to: pre-operative determination of anatomic variations of the small saphenous vein for varicose vein surgery by three-dimensional computed tomography venography by kim sy, park ea, shin yc, min si, lee w, ha j, kim sj, min sk. phlebology 2012;27:235-41. stefano ricci abstract short saphenous vein (ssv) surgery is more challenging due to higher recurrence and complication rates than great saphenous vein (gsv) surgery. the main reason for that is the presence of many anatomic variations in ssv anatomy and the close proximity of the vein with adjacent nerves in the somewhat crowded popliteal fossa. accurate anatomic knowledge about the varicose veins (vv) and neural topography is necessary to prevent nerve damage during surgery. duplex ultrasound (dus) imaging is the gold standard investigation for vv, but has limitations such as operator-dependent variable results, a time-consuming procedure, possible omission of perforators in unusual locations and a difficulty in the evaluation of pelvic vessels. three-dimensional computed tomography venography (3d-ctv) cannot replace dus, but can provide additional powerful 3d images. the exact anatomy of the individual patient can be evaluated before surgery, so that the surgery can be performed with full knowledge of the patient specific anatomy and hemodynamic. this may contribute to minimizing complications and recurrence after vv surgery with ssv reflux. from january 2005 until december 2007 a total of 120 limbs in 103 patients with ssv insufficiency confirmed by duplex underwent conventional operations of high ligation, segmental stripping and varicosectomy. on the basis of the classification of venous disease (ceap), clinical grades were c2 in 106 cases (88.3%), c3 in 13 (10.8%) and c4 in 1 (0.9%). duplex ultrasound and 3d-ctv were performed pre-operatively mostly on the same day and were analyzed retrospectively for this study by two expert radiologists. saphenous veins and perforators larger than 1 mm were detected and marked on computed tomography (ct) volume-rendering images. the presence of reflux in axial veins and the marked perforators was evaluated by duplex. surgeons reviewed this information pre-operatively and ct volume-rendering images were used as road maps during the operation. short saphenous vein terminated to popliteal vein (pv) in 115 limbs (95.8%) with saphenopopliteal junction (spj) in the popliteal fossa, to the veins above the popliteal fossa without spj in 5 limbs (4.2%) – including femoral vein in 2, great saphenous vein in 2 and deep femoral vein in 1. thigh extension (te) of ssv was encountered in 74 limbs (64.4%), ssv and gastrocnemial vein (gnv) drained to pv separately (100 limbs, 87%), as a common channel which drained to pv (15 limbs, 13%). the neural topographic situation of the ssv was analyzed at the level of the gastrocnemius muscle origin. routine post-operative dus performed 4–6 weeks after surgery found no residual reflux. during six months of follow-up, two transient sural nerve neuralgia resolved spontaneously. sural nerve location could not be evaluated by ctv because of the small diameter of the nerve and many variations of the nerve division. possible disadvantages of ctv, such as renal dysfunction, allergic reaction to radio contrast, radiation injury and additional cost can be a problem. however, a careful patient selection and a meticulous protocol can minimize these complications. comment by stefano ricci three-dimensional computed tomography venography offers exiting images of vv anatomy. however, the question is when this tool should be used. dus may provide the same type of information (ssv termination, ssv morphology, the relationship between ssv and gnv, and that between ssv and adjacent nerves) as ct. yet, it also provides functional aspects that are not retrievable with ct. furthermore, dus is performed on standing subjects, to whom static (compression/release, valsalva) and dynamic maneuvers (oscillation, parana) may be applied to study the hemodynamic behaviour of flow. on the contrary, ct is done on laying subjects. patently enough, dus examination needs certain (although basic) training, even though such training is currently requested to all who want to deal with vv treatments. conversely, ct – apart from yielding nice images – has plenty of drawbacks, as described by the same authors. these images may surely be useful in some limited cases (malformations, recurrences, anatomical complicated variations), but are not necessary in more than 95% of them. moreover, a patient selection is suggest by the authors, but no criteria for such selection is given. finally, concerning sural nerve location, while ctv is not able to evaluate these nerves, dus with adequate probes is able to show the nervous structures.1 reply by the author this comment was sent to the author but we have not yet received a reply. references 1. ricci s, moro l, antonelli incalzi r. ultrasound imaging of the sural nerve: ultrasound anatomy and rationale for investigation. eur j vasc endovasc surg 2010;39:636-41.[crossref][pubmed]   [top] mirko tessari reparing veins and saving lives, while giving birth to modern venous surgery: lesson from the icon inside and outside the operating room sergio gianesini vascular diseases center, university of ferrara, italy. correspondence: sergio gianesini, vascular diseases center, university of ferrara, italy, e-mail: sergiogianesini@gmail.com in san diego, last october 24, the american college of surgeons recognized dr. norman rich as icon in surgery, in honor of his outstanding contributions to the field of surgery. considering the legendary resume of this pioneer of modern vascular surgery, rarely such recognition has been assigned more properly. dr. norman rich in vietnam in 1965 (from ‘the pulse’, https://usupulse.blogspot.it/2017/11/dr-norman-rich-named-icon-in-surgery.html) indeed norman rich, md, now a retired general of the united states of america army and founding chair of the uniformed services university of the health science department of surgery, served as chief of surgery at the 2nd mobile army surgical hospital (mash) unit during the vietnam war in 1965. even if just recently specialized, at that time dr. rich was able to significantly innovate war surgery, focusing on vascular trauma restoration. the expertise and technical advancement he developed saved a countless number of soldiers from amputation and created the fundamentals for modern vascular surgery. history teaches us that often medicine, and in particular surgery, before a war is significantly different from the one practiced after the conflict ends.1 indeed, as tragic as a war can be, by representing an epidemic of trauma it provides the need to move forward in the management of severe injuries. the expertise gained from world war ii led to the creation of those mobile army surgical hospitals where dr. rich served during the vietnam war. dr. norman rich is now recognized as the man who brought the expertise gathered by the colleagues during the korean conflict to a new age in vascular injury management, with a particular focus on venous reconstruction. in those years the introduction of helicopters significantly changed the fate of limbs previously easily addressed toward amputation. dr. norman rich. the reduction in transportation time surely facilitated the rapid intervention of an experienced equipe operating in a proper setting rather than on the battlefield. at the same time the evolution of the weaponery created such devastating lesions to increase extremities injuries by 300% versus world war ii.2 the expertise gathered on the field is so significant that, in 1966, it led the same dr. rich to start the famous vietnam vascular registry, a still ongoing precious database reporting more than 10,000 cases treated by surgeons involved in war vascular trauma. if we look back at the historical battles we understand how the last 50 years determined such an advancement in vascular trauma management. indeed, for more than 2000 years, the focus has been just hemorrhage control by packing and bandaging. yet the same galen already stressed the importance of identifying an arterial rather than venous bleeding.3 although the expertise gathered during the following centuries was translated into several techniques to repair vessels, up to world war ii ligation was the preferred management of whatever bleeding. during the korean conflict, huge pioneers like huges, spencer and few others demonstrated the possibility of predicting successful outcome in vascular repair near the battlefield in less than ideal settings. dr. rich took this heritage, expanded it and donated it to all the vascular world and to both the military and civilian patients who have benefitted from such expertise of this new vascular surgery age. last but not least, as usually said, a surgeon value is measured by the words of his/her disciples and today literally an army of top quality surgeons, from the norman rich department of surgery of the usuhs university in bethesda to all the rest of the world, recognizes dr. rich as the living legend who has taken such an active part in modern surgery birth and education. references barr j. evolution of surgical repair of the arteries in war and peace, 1880-1960. new haven, ct: yale university; 2014. available from: http://www.proquest.com/products-services/dissertations/ accessed: april 20, 2015. burkhalter w. surgery in vietnam: orthopaedic surgery. washington, dc: otsg department of the army; 1994. rich nm, rhee p. an historical tour of vascular injury management: from its inception to the new millenium. surg clin north am 2001;81:1199-215. [top] 429 too many requests you have sent too many requests in a given amount of time. hrev_master veins and lymphatics 2017; volume 6:6822 [veins and lymphatics 2017; 6:6822] [page 65] the sapheno femoral junction involvement in the treatment of varicose veins disease stefano ricci università campus bio medico, roma, italy abstract sapheno femoral junction (sfj) incompetence has been considered the most important cause of chronic venous insufficiency in a high percent of cases since the beginning of history varicose veins treatment. as a consequence sfj dissection, ligation and section has been practiced all along the last century, generally associated to great saphenous vein stripping, with the porpoise of stopping the effect of hydrostatic pressure considered the origin of varicose veins. recurrence prevalence at the site of sfj, even in correctly performed dissection suggests that this attitude may not be the ideal one. moreover, with the introduction of catheter-based systems of endovenous heating of the great saphenous vein with radiofrequency or endovenous laser ablation, it was shown that venous ablation could be achieved without high ligation of the sfj. also foam sclerotherapy demonstrated good results, even if less effective, always leaving the sfj untouched. following this trend several methods have been suggested that spare the sfj, so that this site have lost its strategical importance. in this review history of the sfj involvement in the varicose vein strategy is analyzed with particular attention to the new generation methods, technology assisted, launched on the market. introduction sapheno femoral junction (sfj) as origin of the varicose veins disease has been the center of the attention from the beginning of the history of varicose veins treatment, however its responsibility has been weighted differently in the course of the last 100 years in parallel to technological innovations (us, endovascular methods), clinical evolution (conservative surgery, follow up experience), new materials (nitinol, cyanoacrylate) and physical preparations (foam). at the beginning of 1900, very rapidly sfj surgical ablation become a truism for any ideal treatment and on this basis the phlebologists proceeded without any doubts for a century; but how history teaches, cyclic changes of ideas are the rule and not the exception, so that now the sfj, still important, is a supporting actor of the screenplay, needing a lesser if no attention at all. it would not be strange if in the following cycle things would turn back again, however, this review is centered mandatorily on the first present revolution and its reasons and causes. trendelemburg era in 1890 friedrich trendelemburg1 published a fundamental paper entitled: ligation of the greater saphenous vein in varicose veins of the leg. the author describes the phenomenon of downward filling of the varicose bed through the incompetent saphenous trunk: a very simple experiment will prove the correctness of this view. one lays the patient flat again, raises the leg to perpendicular, lets all the blood flow out of the saphenous field and compresses the trunk of the saphenous with a finger at a spot where it is definitely recognizable. now one lets the patient come down from the cot cautiously, without removing the compressing finger from the saphenous. we see that the whole saphenous vein now remains empty at first on standing. not until the lapse of a quarter to a half minute does one see the varicosities in the leg gradually begin to fill with blood again. the fullness, however, is not nearly so tense as it previous was, as long as pressure on the trunk persists. only when removes the compressing finger, does a larger amount of blood rush down from above into the saphenous and the old picture of the tensely distended varicosities returns. this is the birth of what will be called the trendelemburg test. as a consequence, quoting trendelemburg: in thus the simple fact that the varicose branches of the saphenous are separated from the vena cava by no valve closure as the result of the simultaneous dilatation of the trunk causes a large part of difficulties and dangers to which the sufferers from varicosities of the legs are subject, then the next thought is to prevent the back flow of blood from the vena cava through the saphenous into the varices operatively, by a permanent closure of the saphenous at one place, and to the same time to relieve the veins at the lower leg and foot from the abdominal pressure which burdens them. such a permanent closure can be produced easily and without danger by double ligation and section of the vein between the ligatures, and as i have used the operation since the year 1880 in a large series of cases with the best results, i can recommend it for all cases of lower leg varicosities with simultaneous dilatation of the saphenous. this publication starts the modern treatment of varices: no more direct actions on varices (only), but attempt to eliminate the cause (saphenous reflux). although the discovery of saphenous vein incontinence has many previous fathers (home, rima, brodie)2 trendelemburg had the merit of a large scientific diffusion ligated to his reputation, but also times were ready to a better solution of varicose disease thanks to surgical art evolution in the second half of the century ( antisepsis and anaesthesia overall). trendelemburg operation spread and had great success; results were reported as very satisfying3 but recurrences were already registered (22%, considered optimistic rose4) as frequent for collateral veins canalization and perthes, trendelemburg’s pupil, already suggested to ligate gsv the higher possible for eliminating bypass possibilities: when the ligation is made high up on the trunk there will be fewer side branches above the point of ligation and it will be less likely that one of them will reopen the area of varicose veins to the pathological blood pressure.3 he had a recurrence rate of 18%.4 junction conquest the sapheno femoral junction, initially correspondence: stefano ricci, università campus bio medico, via alvaro del portillo 200, roma, italy. e-mail: varicci@tiscali.it key words: sapheno femoral junction; high ligation; conservative surgery; history of varicose veins treatment. conflict of interest: the author declares no conflict of interest. received for publication: 28 may 2017. revision received: 18 july 2017. accepted for publication: 18 july 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright s. ricci, 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6822 doi:10.4081/vl.2017.6822 no n c om me rci al us e o nly review [page 66] [veins and lymphatics 2017; 6:6822] not considered, was involved or at least nearly attained already in thelwell thomas paper of 1896:5 to avoid new varicose vein formed along the branches which entered the saphena above the site selected by trendelemburg…since 1893 i resolved to tie and cut the internal saphena immediately below the saphenous opening, and have operated upon fifteen cases in this manner with perfect results. moore,6 in 1896, has the same suggestion: an incision one and a half to two inches long is then made parallel to the fold of the groin, and about two inches below poupart’s ligament. in 1916 john homans7 admirably describes the state of the art of varicose veins disease of its age, and in particular: the radical removal of the surface veins is perhaps most satisfactorily performed upon the following plan: a transverse incision several inches long is made in the groin about one inch below poupart’s ligament: through this incision the great saphenous vein is divided at the saphenous opening. at the same time any other veins which parallel it or enter from above are found and divided in order to do away with any vessel capable of reestablishing a large, single, collateral trunk. the internal saphenous is then dissected out with the mayo stripper or other appropriate means to the region just below the knee. parallel to the groin dissection of the gsv, at the beginning of the century it appears evident that gsv interruption alone is not sufficient to control the disease, but also that the dilated gsv system should be eliminated for reducing recurrences. for this porpoise between 1905 and 1907, in the turning of only 3 years, 3 american surgeons (keller,8 mayo,9 babcock10) conceived the 3 basic stripping methods today still in use (respectively invagination, external, internal stripping), in the attempt of finding less aggressive methods than those in use at that time (madelung: long incisions over the varices, schede: circular incisions, rindfleisch: spiral incisions).11 interestingly, none of the 3 surgeons suggested junction ligation at their time. babcock10 describes the inguinal time of his operation as: about 2, inches below poupart’s ligament a transverse incision, one inch in length, is made through the skin and subcutaneous fat down to the muscular sheath. the index finger is then inserted to the bottom of the wound, slid backwards for a short distance close to the muscular sheath and then hooked inward and forward away from the muscle, when it at once catches the thik resistant cord of the saphenous vein., which is lifted into the wound and at once clamped above by a hemostat. still it is not matter of high ligation, homans’ rules came later. in northern america stripping becomes a new tool in surgeons’ hands obtaining progressive (but not so fast) agreement, till the general consensus at the half of the century,11,12 finally popularized by myers’11 experience (1954) with the use of flexible strippers, also in europe. sclerotherapy (r)evolution frightened by the cruelty of surgical procedures, physicians develop in parallel injection method starting from the archaic roots of the pravaz syringe invention and of the first coagulating substances (ferric perchlorure and iodotannin solution). originally considered a too dangerous method (congress of surgery lion 1894), injection treatment progressively evolved through the search of new less toxic substances like phenic acid (tavel 1904), potassium iodio-iodure (schiassi 1906), sublimate 0.5% (linser 1916), sodium carbonate and finally salicylate (sicard 1920).13salicylate revolution, finally a nontoxic agent, fixed the beginning of sclerotherapy renaissance at least in europe. sclerotherapy begun a very busy affair in europe, enhanced by the creation of the first society of phlebology (societé francaise de phlebologie) in 1947. a deep dualism between sclerotherapy and surgery took place that partly is present still nowadays. according to marmasse14 starting with 30 years of advantage over sclertherapy 1890-1920 varices surgery fell to sleep during the following 30 years 1920-1950. at present very effective and safe agents are in use (polidocanol, tetradecilsulfate) and, finally, a new way of administration (foam) that appears more efficient, however direct sfj treatment is not really expected with this method as shown by, butie,15 biegelsen.16 some attempts have been made in the past to treat directly the junction.17-19 preferably by injections few centimeters below the groin to avoid pudendal artery injection and femoral vein thrombosis, but the wash out of the tributaries seems to avoid closure of the terminal part of the gsv, how demonstrated in duplex era assessment.20,21 surgery/sclerotherapy (liquid) combination tavel (1904),22 from berne, published the first an experience in injection treatment after subcutaneous gsv ligation, if spontaneous post ligation saphenous thrombosis was lacking. however, schiassi (1907)23 suggested what is considered a milestone in treatment of varices: simultaneous ligation (by local anesthesia) and injection (iodide solution) of varices. according to foote,11 he was much in advance of his time, as the combination of the two methods became firmly established in 1925 and for quarter of century high resection of the gsv in combination with retrograde injection of sclerosant has been employed all over the world.4,24-27 interestingly, nobili (1921), schiassi pupil, had the merit of suggesting the injection higher in the groin, allowing the sclerosant to be eliminated through a second distal incision; unger (1927) suggested to use a catheter for injecting the distal gsv through the groin dissection; moszkowics (1927) employed dextrose injections; mairano (1949) made thigh stripping and salycilate injection in the crural gsv.28 rose4 tells us, in one historical talk, that: the operation i performed in 1941 was high ligation of sfj, tributaries ligation and retrograde passage of a ureteric catheter down the cut end of the vein until it would go no further (unger technique editor’s note.). about 6 to 8 ml of 5% to 10% of sodium morrhuate was injected down the catheter as it was slowly withdrawn. the entire procedure was carried out with the patient under local anesthesia and done in an outpatient basis. the result was an immediate massive reaction along the line of the saphenous vein from ankle to groin. a chemical thrombophlebitis was produced that required heavy bandaging and caused considerable disability. the patients were painfully incapacitated during the 2 to 4 weeks it took for the condition to solve. the ultimate fate of the thrombosed vein was recanalization, which took place sooner than expected…. use of ureteric catheter was discontinued in 1945, and the practice of simultaneous sclerotherapy was ended in 1946. in the french survey (1962),29,30 over 147 participants, 24 still practiced the method, 20 of them reporting thromboembolic accidents or even death. more recently lofgren,31 jakobsen,32 sladen,33 neglen,34 racek35 still practiced this method with good but not stable results, in any case inferior to stripping methods. whatever method was used to treat the distal varices, high ligation become highly recommended for avoiding groin recanalization while sclerosing injection were preferably practiced in limited extension and successively. no n c om me rci al us e o nly review [veins and lymphatics 2017; 6:6822] [page 67] stripping prevalence after the ii word war the american way took place.4,11,12,28,36,37 high ligation and gsv stripping became the gold standard although with plenty of variations and “inventions” as: long or short stripping, below-upward or above downwards stripping, pleating or inversion by string or mesh, redon drainage, association to perforator ligation or varicectomy or sclerotherapy, by general, spinal, local anesthesia, with a choice of plenty of strippers in commerce. in 1962 the french enquete sur la crossectomie et le stripping29 based on a questionnaire to whom participated more than 147 phlebologists (69)/surgeons (77) experts of france (93) and europe (53) reveals that high ligation/stripping is largely prevalent over sclerotherapy alone, but evidence appeared that neither surgery alone, or sclerotherapy alone (apart carl sigg opinion), could satisfy the request of the ideal treatment of varices, a wise combination being the best solution: (e. maesbelgique): that phlebologist that operates on varices excluding sclerosant injections is like a piano player playing only on white keys leaving out the black ones.29 the myth while things constantly change in varicose treatment history, one single concept becomes a myth: spheno-femoral junction should be full dissected and all junction collaterals should be ligated/divided possibly till their secondary division. this act would stop the pressure from above, primary cause of varicose disease. every single junction collateral vein left could be the origin of recurrence. dissection should be even extended to the common femoral vein, to possibly exclude branches joining separately to the deep system.30 according to foote,11 the only way to ensure a satisfactory clearance is to divide everything entering the sapheno-femoral trunk, however small it may be. it is essential to seek out the circumflex iliac branch for a little distance laterally to ensure that it has no descending branch… the rule is, therefore, any adjacent descending branch must be ligated however small it may be. according to geier:38 although never proven by a randomized study, long-lasting experience with varicose vein surgery has led to the postulate that resection of the sfj should be done as close to the femoral vein as possible, without leaving a long residual stump. the rationale behind this technique is the assumption that such a long residual stump will be affected by refluxing blood from the femoral vein, which with time will cause further dilatation and incompetence of the stump and its branches, resulting in recurrent varicose veins. recurrences no other disease, maybe except dental pathology, has so great tendency to recurrence than varicose veins. as soon as a scientific method of treatment has been undertaken (trendelemburg, perthes), the first cases of recurrence were recorded (22, 18% respectively). already in 1940 stalker26 writes: with all types of treatment there have been a large percentage of recurrences in spite of the fact that immediate results have been encouraging. no type of therapy for the relief of varicose veins of the lower extremities is new. all have been tried, have been discarded, and have reappeared at one time or another. due to the benign nature of varices, that are not life threatening and respond positively to any treatment in the immediate, usually phlebologists consider their results very positively unless their patients are assessed after at least 5 years (but often even 2 years are critical). furthermore recurrence are generally due to others’ management. a more scientific approach (hobbs39) and us facilities (fisher40) showed a different and more realistic situation in outcomes that is going to originate a new research movement, still going on today. hobbs,39 in 1974 by clinical analysis comparing “enthusiastic sclerotherapy with enthusiastic surgery” observed, after one year 82% of unselected patients were cured (no symptoms or signs and no varicose veins ) by injection, but after six years the cure rate was only 7%. at the opposite after surgery, at one year 40% were cured versus 20% at six years. according to fisher,40 in 2001, 125 limbs (77 patients) that underwent operation between 1960 and 1967, were evaluated clinically and with duplex sonography for possible superficial-to-deep vein reconnections and clinical recurrence of thigh varicosities at a mean follow-up of 34 years. clinical examination suggested sapheno femoral recurrence in 59 limbs (47%)while duplex ultrasonography demonstrated sapheno femoral reflux in 75 limbs (60%). interestingly, all the patients were considered receiving a correct terminal high ligation. more than 50% of recurrences are localized at the sfj: a phenomenon that is linked to gsv trunk recanalization, a pelvic leaking point involvement and/or a neovascularization.41-44 the recurrent varicose veins after surgery study (revas)41 reported the outcomes from a large cohort of patients treated with ligation and stripping at a number of international centers and demonstrated that 20% of these recurrences originated from sapheno femoral neovascularization, 19% from incorrect junctional ligation, and 55% from perforator reflux. evidence based results and ultrasound assessment of outcome outlined that the phlebologists’ optimism had to be reviewed. while groin recurrence has been universally related to insufficient quality of surgical procedure (technical failure), evidence exists that junction recanalization occurs in proper groin dissection too.45 this phenomenon of formation of new venous channels between the saphenous stump on the common femoral vein (cfv) and the residual gsv or its tributaries is called neovascularization.46 the potential pathophysiological mechanisms of reference are many: angiogenic stimulation in the free endothelium of the ligated stump, trans-nodal lymphovenous connection, dilation of small adventitial vessels in the vasa vasorum of the femoral vein, disturbed venous drainage of the ligated tributaries of the sfj. a significantly higher risk of sfj recurrence was reported44 in cases of iliac femoral valve incompetence (ifv) with an odd ratio of 4.8. in the 45 cases of recurrence over 381 cases analyzed at 5 years follow up, 27% of recurrences were associated to ifv incompetence, versus 7% in non-recurrence patients. paradoxically, when the sfj has been missed and a portion of the gsv has been left attached to the cfv, the postoperative hemodynamic situation (reflux) remains unchanged, with minimal or missing impetus for postoperative neovascularization. on the contrary, after correct ligation, the hemodynamic situation at the sfj changes completely, activating possible pathophysiologic mechanisms.47 complete resection of the gsv stump48 and inversion suturing of the common femoral vein did not seem to decrease neovascularization.49 results on the use of barrier materials are conflicting and these techniques have also not yet been introduced into common clinical practice.50,51 re-do surgery in symptomatic patients with varices recurrence and hemodynamic anomalies treatment is indicated. there is no consenno n c om me rci al us e o nly review [page 68] [veins and lymphatics 2017; 6:6822] sus on preferring sclerotherapy versus surgery as evidence is very poor.52 surgery is considered the best option when a major reflux may be identified due to a large stump. a lateral approach first visualizing the femoral artery has been the most employed technique,53 while a medial indirect approach may be used in alternative.54 however this type of surgery, easy in skilled hands, but rarely analyzed in the literature is anecdotally considered technically challenging, time consuming, at risk of complication, reported to fail in 30 to 80% of cases,44 inducing to refrain from aggressive surgery.55,56 as an alternative, sclerotherapy alone57,58 or associated to surgery59 may give good results. the duplex advent the development of duplex ultrasound has been like the invention of the microscope or telescope in biology or physics, allowing us to see better in real time the venous network, to monitor venous disease noninvasively in clinical and research uses. ultrasound is now used preoperatively, intraoperatively, and postoperatively.60 duplex evaluation of varicose veins was first reported in 1986,61-63 however routine use of duplex scanning prior to varicose vein surgery has not become an established practice till the end of the century. in the mid-1990s, it was found that in the united states, 18% of noninvasive vascular laboratories did not use duplex ultrasound for vein mapping and another 37% did so only occasionally.64 some investigators advocated using color coded duplex sonography only for investigation of the popliteal fossa65,66 or recurrences. phlebology practice of 2000 is strongly ligated to duplex /color assessment due to the large diffusion of modern, simple and relatively cheap equipment allowing the single phlebologist to display its own assessment. this induced a progressive enormous advancement in anatomic and functional knowledge of venous pathology67-68 and, as a consequence, an evolution of treatment methods. already in 1989 sclerotherapy through ultrasonic guidance of injection into the superficial venous system was first published.69 the initial aim of this technique was more to reduce the risks inherent in injection of hidden (non visible and palpable) veins than to improve results.70 in 1990s foam appeared and rapidly became popular and diffused for its efficacy and us visibility.71-73 furthermore, also postoperative analysis changed its perspective as clinical aspects could be verified by duplex revealing a much higher recurrence rate.74 in particular, it became clear that gsv reflux is not always associated to sfj incompetence;75 in fact terminal valve may be competent in a very high number of cases (33% abu-own;76 40% pieri;77 55% cappelli;78 56% somjen79). in this instance junction dissection and high ligation is useless80 and even harmful, the source of reflux coming from a perforator or tributaries. terminal and pre-terminal valves function,77 prevalence of aasv incompetence,81 possible influence of common femoral valve on sv hemodynamics,44-78 peri junctional veno-lymphatic network,82 gsv hypoplasia83 are all aspects revealed by us observation, influencing treatment strategy and tactic, and often rising recurrences. a new perspective given by us studies was started already in 1988 (maybe too much early over an unprepared audience) by franceschi84 who conceived a method (chiva) that allowed conservation of the gsv stem and venous network even incompetent for possible bypass use, with simple limited surgical actions (ligatures), but after a deep analysis of the single patient’s venous hemodynamic. again sfj is the chief character but in a new conservative perspective, to be adapted to single patients hemodynamic. chiva crossotomy in ideal chiva treatment cases, the junction is high ligated without interruption of the junction tributaries which are drained through the incompetent saphenous stem in counter current through the distal perforator(s) centered on the same saphenous stem; the incompetent tributaries are de-connected from the saphenous stem but are not removed. the final result is a normalization of the venous hypertension without removal of any venous tract. the junction phase is called crossotomy (section of the crosse, the french name for junction), in opposition to what is conventionally called crossectomy (removal of the crosse). unfortunately, scientific evidence of crossotomy results is lacking and single chiva authors mostly report anecdotic experience. junction dissection without tributaries interruption may be a challenging operation due to the great anatomical variations of tributary arrangement when they merge proximal to the femoral vein . once the junction dissected, interruption may be obtained by placing a clip flush to the femoral vein plus a second clip in proximity placed in opposite direction. traditional ligation by non-resorbable threads seems at risk of ice effect recanalization. section of ligated saphenous stump is the best option for a de-connection but may be difficult if a limited space remain between the femoral wall and the tributaries. in some instances the more proximal tributary(s) can be sacrificed.85 del frate86 compared surgical division crossotomy to two different triple superimposed flush ligations (n. 2 nonabsorbable braided coated suture versus n. 0 polypropylenene ligation) without division. the incidence rates of neovascularization was 4.9%, 6.1% and 37.5% respectively. according to zamboni,87 recurrence rate at 3-10 years is 2.9% for crossotomy versus 5.5% for crossectomy (stripping). valvuloplasty another way of sparing incompetent gsv opposite to ablation is the reconstitution of competence of the junction when valvular incompetence is due to diameter dilatation while the valves are still efficient. the basic idea has inspired different methods of obtaining the goal: banding of the junction area with fascia lata,88 with prosthetic material (dacron or politetrafluoretilene ptfe),89 fenestrated for tributary sparing,85 with the venocuff stapler (dacron/silicon banding with automatic caliber fixation),90 with the evs (gore external valve support), a dacron device nitinol reinforced,91 with oses™ (oval shaped external support): acting traction onto the inter-commissural diameter of an incompetent valve (assut europe spa, italy)92 perivenous injection of viscose fluids like jaluronic acid has also been attempted for the same porpoise.93 generally good results are reported even at long term considering symptoms and function, however usually studied population is limited in numbers and specifically selected. belcaro94 reported his 15 years clinical experience of external valvuloplasty with evs in 101 patients. this author completed a four-year follow-up of a total of 47 patients without infections, thrombosis, foreign body reactions or other prosthesis-related complications, with 4% of sfj reflux recurrence. jin-hyun joh95 re-examined thirty-one limbs from 27 patients at mean of 92.6 months registering persistent reflux in 19 (61%). the true advantage is the conservation of gsv integrity opposite to ablation, and particularly the maintenance of centripetal flow in the same gsv. the present loss of compulsory need of absolute suppression of no n c om me rci al us e o nly review [veins and lymphatics 2017; 6:6822] [page 69] junction reflux can explain the loss of interest in these techniques. surgery with junction respect in 1993 dortu96 suggested the possible over the fascia junction interruption: this author currently practiced muller phlebectomy on varicosities and, in selected cases, pushed the vein avulsion to the saphenous stem arriving till the groin: through a micro incision of 2-3 mm, 2 to 3 cm below the skin projection of the junction he hooked the saphenous stem out, ligated the tributaries and finally double ligated the saphenous stump, that remained 6-10 mm long. over 276 limbs controlled after at least 3 years (mean 5.6 years) 271 had good outcome, two cases having recurrence on posterior accessory and 2 on anterior accessory and one as typical neogenesys. rapidly other authors followed this revolutionary trend.97,98 this atypical and heretical surgical application, corresponding to a stripping with an uncomplete high ligation (and to eva techniques result) has been successively re-evaluated by several authors for its very satisfying outcomes: pittaluga99 with only 2.7% recurrence at 27.3 months; casoni100 with 8% recurrence at two years; this same author, in a randomized trial (stripping alone versus stripping high ligation) found at 8 years 9.8% versus 29% of clinical recurrences and 11.4 versus 32.2 of us reflux recurrence respectively.101 mariani in 2015102 reported an experience of selective high ligation (sparing veins coming from the abdominal wall, as the superior epigastric vein or the superior iliac circumflex vein), on 360 limbs with follow up from 5 to 12 years, recording only 1.9% (7 cases) of groin recurrences. recently ricci103 described gsv pre terminal ligation/transection by a simplified surgical approach made easy by us assistance: gsv is hooked 3 cm from the junction through a micro incision under direct visualization of the vein. the distal saphenous stem then can be treated in the preferred way or left for conservation. tributary avulsion without gsv reflux treatment the evidence of varicose veins development not associated to sfj and gsv incompetence (labropulos, coleridge) suggested a possible ascending mechanism of progression of varicose disease, for which the terminal/junctional valve represents the last stage of a venous reflux that advances from lower levels, challenging the traditionally accepted retrograde theory descending directly from trendelemburg’s observations. venous wall weakening is the initiating factor of primary reflux that, therefore, might not develop in a retrograde manner beginning from the terminal valve but, more likely, following a reverse, upward directed, pattern.104 according to this hypothesis, pittaluga in 2005 suggested the ablation selective of varices in anesthesia in local (asval). following the author’s words:105 progression of the disease starts in the supra fascial tributaries, which are the most superficial, the most exposed veins outside the saphenous compartment and whose walls are the thinnest. venous dilatation begins on the supra fascial tributaries distally, where the hydrostatic pressure is higher, creating a dilated and refluxing venous network called varicose reservoir (vr) within the supra fascial space.106 when this refluxing network becomes large enough, it can create a filling effect in the saphenous vein, leading to decompensation of the saphenous vein wall, reaching progressively the sfj or spj. the goal of the asval method is to decrease or eliminate the saphenous vein reflux by minimizing vr using ambulatory phlebectomy described by robert muller107 or sclerotherapy. preoperative ultrasound assessment has enhanced the precision for phlebectomy. although isolated treatment of varices leaving an incompetent gsv was not new,107-109 asval had the merit of giving a scientific dignity to an empiric method. endovascular generation endovenous laser treatment of saphenous veins developed during the 1990s, only from 2000 were published the first relevant papers about endovenous treatments of the great saphenous vein. at the beginning of the new century, minimally invasive endovenous laser ablation (evla)105 and radiofrequency (rf) ablation106 have emerged as effective outpatient treatment approaches both delivering electromagnetic energy to destroy by heating the vein wall.107 initially, reports of successful ablation of the gsv using either radiofrequency or laser energy without ligation or stripping were treated with great skepticism. in fact all the endovascular approach methods are applied for closing the gsv stem, leaving untouched the last 2-3 cm of gsv, i.e. the sfj. this technical aspect assures the junction tributaries drainage and avoids the nearer common femoral vein involvement (ehit: endovenous heat-induced thrombus) 108 similarly to what occurs to sclerotherapy, where the washout of the same tributaries maintain the junction patent. however, the absence of neovascularization appeared so striking that many skeptics have begun to believe that former emphasis on a clean groin dissection may have been in error.30 in fact, the majority of cases of recurrence occurred due to recanalization of a segment of a previously treated vein with recurrent reflux or new reflux in an accessory or alternate truncal pathway as shown by some 5 years outcome randomized studies.109-113 gradman, in a survey of members of the american venous forum and american college of phlebology, concluded that regardless of the method of saphenous vein ablation (rf, laser, or foam sclerotherapy), concomitant ligation of the sapheno femoral junction offered no advantage in outcome no matter the size of the proximal great saphenous vein.114 in the same time sclerotherapy begun its renaissance through foam formula of the two detergent agents (polydocanol, tetradecilsulfate). foam ultrasound guided sclerotherapy rapidly showing a better efficacy compared to liquid sclerotherapy became a valid alternative to eva as endovenous chemical ablation. although offering a lower occlusion rate as primary treatment, but with a good secondary success, it has the advantage of a low cost and a simple administration so that it can be easily repeated.115 based on the new concept that sfj dissection is not necessary while gsv stem still needs to be eliminated, several methods are constantly and progressively conceived to satisfy the following requests, the order of importance of the factors being variable: i) outpatient setting; ii) ease to perform; iii) efficacy; iv) industrial business. in 2007 milleret116 started to study an endovascular heat ablation employing steam. at the tip of the catheter, steam is emitted at 120°c achieving results similar to the other heating methods. in 2011 a new mechano chemical device (clariveinw, madison, ct, usa), was developed to minimize the negative aspects of both endothermal ablation and ultrasound-guided sclerotherapy (ugs), while incorporating the benefits of each.117 the method has the advantage of not needing tumescent anesthesia that thermal ablations do. in 2013 almeida118 begun to study feano n c om me rci al us e o nly review [page 70] [veins and lymphatics 2017; 6:6822] sibility of gsv occlusion by a special glue, having the advantage of not requiring peri venous tumescence and post treatment compression. post ablation thrombus extension (paste) through the sfj, seen infrequently following thermal or foam saphenous ablation, was seen in 8/38 (21%) patients in the first human study; this problem appears to have been resolved by moving the 1st injection to 5 cms below the sfj.119,120 in 2013 frullini121 published preliminary results of a technique combining a particular attenuated laser action, that shrinks the vein wall, to foam sclerotherapy. in 2013 thermal segmentary ablation has been suggested by gianesini122 and contemporarily by passariello123 with the purpose of using endovascular techniques for high gsv occlusion (below the junction, for a length of few centimeters only) sparing the more distal part of the saphenous stem. recently mendoza124 employed this technique on 104 patients with results comparable to surgical crossectomy. followed: i) a vessel occluder that can be placed percutaneously, in initial study phase;125 ii) a mechanical closure using a spiral shaped device;126 iii) a coil closure combined to foam injection us assisted127 or by image intensifier (and conscious sedation).128 to be continued… references 1. trendelemburg f. ueber die unterbindung der vena saphena magna bei unterschenkelvaricen). beitrage zur klinischen chirurgie 1890;7:195. 2. ricci s. who discovered saphenous vein incontinence? acta phlebol 2003;395-100. 3. perthes. ueber die operation der unterschenkelvvaricen nach trendelemburg. deutsche medinische wochenschrift 1895;16:235. 4. rose ss. historical development of varicose veins surgery. in: bergan jj, goldman m, ed. varicose veins and telangectasias. st. louis, mo: qmp; 1993. 5. thelwell t. operative treatment of varicose veins of the lower extremity by ligature and division of the internal saphena vein at the dsaphenous opening. liverpool med chir j 1896;16:278. 6. moore w. the operative treatment of varicose veins, with special reference to a modification of trendelemburg’s operation. intercolon med j austral 1896;1:393. 7. homans j. the operative treatment of varicose veins and ulcers based upon a classification of these lesions. surg gynecol obstet 1916;22:143. 8. keller wl. a new method of extirpation the internal saphenous and similar veins in varicose conditions: a preliminary report. ny med j 1905;82:385. 9. mayo ch. treatment of varicose veins. surg gynecol obstet 1906;2:385. 10. babcock ww. a new operation for extirpation of varicose veins of the leg. new york med j 1907;86:153. 11. foote rr. historical landmarks in treatment. chapter 2. in: foote rr, ed. varicose veins. london: butterworth; 1954. 12. myers tt, cooley jc. varicose vein surgery in the management of the postphlebitic limb. surg gynecol obstet 1954;99:733-44. 13. tournay r. historique. in: tournay r, ed. la sclerose des varices. paris: expansion scientifique; 1972. 14. marmasse j. avant propos. in: tournay r, ed. la sclerose des varices. paris: expansion scientifique; 1972. 15. butie a. experience with injection at the saphenofemoral junction in the united states. in: davy a, stemmer r, eds. phlebologie ‘89. montrouge: john libbey eurotext; 1989. 16. biegeleisen k, nielsen rd. failure of angioscopically guided sclerotherapy to permanently obliterate grater saphenous varicosity. phlebology 1994;9:21. 17. marmasse j. les injections sclerosantes dans la crosse des veines saphènes. exploration, injection, critique. phlébologie 1961;14:85-102. 18. wallois p. suppresion des reflux sapheniens par sclerotherapie. technique et résultats. phlébologie 1986;3:15-23. 19. raymond-martinbeau p. two different techniques for sclerosing the incompetent saphenofemoral junction: a comparative study. j dermatol surg oncol 1990;16:626. 20. thibaud p. 5 years follow-up of grater saphenous vein incompetence treated by ultrasound guided sclerotherapy. aust n z j phlebol 2003;7:5. 21. de maeseneer m, pichot o, cavezzi a, et al. duplex ultrasound investigation of the veins of the lower limbs after treatment for varicose veins e uip consensus document. eur j vasc endovasc surg 2011;42:89-102. 22. tavel e. behandlung der varicen für durch ligature und die künstliche thrombose. corrispondenz-blatt für schveizer aerzte 1904;34:617. 23. schiassi b. the treatment of varicose veins of the lower limb by intravenous injections of iodine. med press 1909;april 14:377. 24. de takats g, quilling l ligation of the saphenous vein a report on two hundred ambulatory operations. arch surg 19332;6:72-88. 25. ochsner a, mahorner hr. the modern treatment of varicose veins. surgery 1937;2:889. 26. stalker lk, heyerdale ww. factors in recurrence of varicosities following treatment. surg gynecol obstet 1940;71:723. 27. nobili u. contributo alla cura delle varici dell’arto inferiore con speciale rigurdo almetodo schiassi. il policlinico 1921;28:134. 28. bassi g. terapia. chapter v. in: bassi g, ed. le varici degli arti inferiori. torino: minerva medica; 1962. 29. natali j, marmasse j. enquete sur la crossectomie et le stripping. phlebologie 1962;15:231. 30. bergan j. overview: treatment of venous insufficiency. chapter 17. in: bergan j, ed. the vein book. elseiver academic press; 2007. 31. lofgren ka. management of varicose veins: mayo clinic experience. in: bergan jj, yao js, eds. venous problems. chicago, il: year book; 1978. pp 71-83. 32. jakobsen b. the value of different forms of treatment of varicose veins. br j surg 1979;66:182-4. 33. sladen jg. flush ligation and compression sclerotherapy for saphenous vein insufficiency. am j surg 1986;152:535-8. 34. neglen p, einarson e, eklof b. high tie with sclerotherapy for saphenous vein insufficiency. phlebologie 1986;1:10511. 35. recek c. saphenofemoral junction ligation supplemented by postoperative sclerotherapy: a review of long-term clinical and hemodynamic results. vasc endovasc surg 2004;38:533-40. 36. agrifoglio g, edwards ea. results of surgical treatment of varicose veins. one-to fourteen-year follow-up study of 416 patients. jama 1961;178:90611. 37. browse nl, burnard kg, thomas ml. varicose veins: natural course and treatment. chapter 7. in: browse, burnard, thomas, eds. diseases of the veins – pathology, diagnosis and treatment. london: arnold; 1988. 38. geier b, stucker m, hummel t, et al. residual stumps associated with inguinal varicose vein recurrences: a multicenter study. eur j vasc endovasc no n c om me rci al us e o nly review [veins and lymphatics 2017; 6:6822] [page 71] surg 2008;36:207-10. 39. hobbs jt. surgery and sclerotherapy in the treatment of varicose veins. a random trial. arch surg 1974;109:793-6. 40. fischer r, linde n, duff c, et al. late recurrent sapheno femoral junction reflux after ligation and stripping of the greater saphenous vein. j vasc surg 2001;34:236-40. 41. perrin mr, labropoulos n, leon lr jr. presentation of the patient with recurrent varices after surgery (revas). j vasc surg 2006;43:32734. 42. fischer r, chandler jg, de maeseneer mg, et al. the unresolved problem of recurrent saphenofemoral reflux. j am coll surg 2002;195:80-94. 43. de maeseneer mg, cavezzi a. etiology and pathophysiology of varicose vein recurrence at the saphenofemoral or saphenopopliteal junction: an update. veins and lymphatics 2012;1:10-4, e4. 44. gianesini s, occhionorelli s, menegatti e, et al. femoral vein valve incompetence as a risk factor for junctional recurrence. phlebology 2007. [epub ahead of print]. 45. de maeseneer m. neovascularization: an adverse response to proper groin dissection. chapter 26. in: bergan jj, ed. the vein book. elsevier academic press; 2007. 46. glass gm. neovascularization in recurrence of the varicose great saphenous vein following transection. phlebology 1987;2:81-91. 47. stücker m, netz k, breuckmann f, et al. histomorphologic classification of recurrent saphenofemoral reflux. j vasc surg 2004;39:816-21. 48. winterborn rj, foyb c, heather bp, earnshaw jj. randomised trial of flush saphenofemoral ligation for primary great saphenous varicose veins. eur j vasc endovasc surg 2008;36:477-84. 49. heim d, negri m, schlegel u, de maeseneer m. resecting the great saphenous stump with endothelial inversion decreases neither neovascularization nor thigh varicosity recurrence. j vasc surg 2008;47:1028-32. 50. de maeseneer mg, vandenbroeck cp, van schil pe. silicone patch saphenoplasty to prevent repeat recurrence after surgery to treat recurrent saphenofemoral incompetence: long-term follow-up study. j vasc surg 2004;40:98-105. 51. winterborn rj, earnshaw jj. randomised trial of polytetrafluoroethylene patch insertion for recurrent great saphenous varicose veins. eur j vasc endovasc surg 2007;34:367-73. 52. perrin m. classification and treatment of recurrent varicose veins. chapter 33. in: bergan j, ed. the vein book. elseiver academic press; 2007. 53. li akc. a technique for re-exploration of the saphenofemoral junction for recurrent varicose veins. br j surg 1975;62:745-6. 54. nelzén o. a medial approach for open redo groin surgery for varicose vein recurrence. safe and effective. phlebologie 2013;42:247-52. 55. de maeseneer m. surgery for recurrent varicose veins: towards a less-invasive approach. perspect vasc endovasc ther 2011;23:244-9. 56. pittaluga p, chastanet s, locret t, rousset o. retrospective evaluation of the need of a redo surgery at the groin for the surgical treatment of varicose vein. j vasc surg 2010;51:1442-50. 57. pavei p, ferrini m, spreafico g, et al. ultrasound guided foam sclerotherapy of recurrent varices of the great and small saphenous vein: 5 years follow up. veins and lymphatics 2014;3:4655. 58. darvall kal, batev gr, adam dj, et al. duplex ultrasound outcomes following ultrasound guided foam sclerotherapy of symptomatic recurrent saphenous varicose veins. eur j vasc endovasc surg 2011;42:107-14. 59. creton d. place de la chirurgie d’exérèse à ciel ouvert dans le traitement des récidives variqueuses. phlébologie 2008;61:281-7. 60. mowatt-larssen e, shortell ck. treatment of primary varicose veins has changed with the introduction of new techniques. semin vasc surg 2012;25:18-24. 61. franceschi c, franco g, luizy f, tanitte m. precis d’echotomographie vasculaire paris: ed.vigo; 1986. 62. szendro g, nicolaides an, zukowski aj, et al. duplex scanning in the assessment of deep venous incompetence. j vasc surg 1986;4:237-42. 63. luizy f, franceschi c, franco g. a method of venous study by real time ultrasonography associated with directional and continuous doppler ultrasonography. ann med interne 1986;137:484-7. 64. leers sa, blackburn dr, burnham sj, et al. vascular technology in evolution: results 0f the 1994 ardms task survey. j vasc tech 1995;19:127-45. 65. darke sg. preoperative duplex imaging is required before all operations for primary varicose veins. br j surg 1998;85:1495-7. 66. meyer fj, taylor pr, burnard kg. preoperative duplex imaging is required before all operations for primary varicose veins. br j surg 1999;86:569. 67. coleridge-smith p, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs uip consensus document. part i. basic principles. eur j vasc endovasc surg 2006;31:83-92. 68. cavezzi a, labropoulos n, partsch h, et al. duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs uip consensus document. part ii. anatomy. eur j vasc endovasc surg 2006;31:288-99. 69. knight rm, vin f, zygmunt ja. ultrasonic guidance of injections into the superfi cial venous system. in: davy a, stemmer r, eds. phlebologie ‘89. montrouge: john libbey eurotext; 1989. 70. shadeck m. duplex phlebology. napoli: gnocchi ed.; 1908. 71. cabrera j, cabrera garcia olmedo jr. nuevo método de esclerosis en las varices tronculares. patol vasc 1995;4:55-73. 72. monfreux a. traitement sclérosant des troncs saphéniens et leurs collatérales de gros calibre par la méthode mus. phlébologie 1997;50:351-3. 73. tessari l. nouvelle technique d’obtention de la sclero-mousse. phlebologie 1997;53:129. 74. de maeseneer m, pichot o, cavezzi a, et al. duplex ultrasound investigation of the veins of the lower limbs after treatment for varicose veins uip consensus document. eur j vasc endovasc surg 2011;42:89-102. 75. cavezzi a, carigi v, campana f, et al. terminal valve of sapheno-femoral junction: a comparative assessment between pre-operative color-duplex ultrasound and intra-operative evaluation. veins and lymphatics 2012;1:3742. 76. abu-own a, scurr jh, coleridge smith pd. saphenous vein reflux without incompetence at the saphenofemoral junction. br j surg 1994;81:1452-4. 77. pieri a, vannuzzi a, duranti a, et al. role central de la valvule pre-ostiale de la veine sapheene interne dans la genese des varices tronculaires des membres inferieurs. phlebologie 1995;48:227-9. 78. cappelli m, molino lova r, ermini s, zamboni p. hemodynamics of the sapheno-femoral junction. patterns of no n c om me rci al us e o nly review [page 72] [veins and lymphatics 2017; 6:6822] reflux and their clinical implications. int angiol 2004;23:25-8. 79. somjen gm, donlan j, hurse j, et al. venous reflux at the sapheno-femoral junction. phlebology 1995;10:132-5. 80. zamboni p, gianesini s, menegatti e, et al. great saphenous varicose vein surgery without saphenofemoral junction disconnection. br j surg 2010;97:820-5. 81. ricci s, georgiev m, cappelli m. définition de la veine saphène accessoire antérieureet de son rôle dans la maladie veriqueuse. phlébologie 2004;57:135-40. 82. lemasle p, lefebvre-vilardebo m, uhl jf, et al. récidive variqueuse post operatoire: et si la vascularization inguinale post chirurgicale n’étaot que le développemet d’un réseau préexistent? phlebologie 2009;62:42-8. 83. ricci s, caggiati a. echoanatomical patterns of the long saphenous vein in patients with primary varices and in healthy subjects. phlebology 1999;14:54. 84. franceschi c. théorie et pratique de la cure conservatrice et hémodynamique de l’insuffisance veineuse en ambulatoire. précy-sousthil: armançon; 1988. 85. zamboni p. la chirurgia conservativa del sistema venoso superficiale. faenza: gruppo editoriale faenza editrice; 1996. 86. delfrate r, bricchi m, franceschi c, goldoni m. multiple ligation of the proximal greater saphenous vein in the chiva treatment of primary varicose veins. veins and lymphatics 2013;3:1919. 87. zamboni p. the chiva results. chapter 11. in: franceschi c, zamboni p, eds. principles of venous hemodynamics. new york: nova science publishers; 2009. 88. mancini s, mariani f. external plastic surgery of pre ostial valve in saphenofemoral junction insufficiency:experimental studies and clinical cases. phlébologie 1991;44:763-9. 89. corcos l, anna dd, zamboni p, et al. reparative surgery of valves in the treatment of superficial venous insufficiency. j mal vasc 1997;22:128-36. 90. jessup g, lane rj. repair of incompetent venous valves: a new technique. j vasc surg 1988;8:569-75. 91. incandela l, belcaro g, nicolaides an, et al. superficial vein valve repair with a new external valve support (evs). the imes (international multicenter evs study). angiology 2000;51:s39-52. 92. camilli d, camilli s. the external stretching valvuloplasty: a new technique for venous valve repair. j vasc endovasc surg 2012;19:37-40. 93. jc ragg. a new modality to shape enlarged veins and restore valves by perivenous injection of viscous fluids. j am coll cardiol interv 2014 [epub ahead of print]. 94. belcaro g, nicolaides an, errichi bm, et al. expanded polytetrafluoroethylene in external valvuloplasty for superficial or deep vein incompetence. angiology 2000;51:s27-32. 95. joh j-h, lee k-b, yun w-s, et al. external banding valvuloplasty for incompetence of the great saphenous vein: 10-year results. int j angiol 2009;18:25-8. 96. dortu j. la crossectomie sus-fasciale au cours de le phlebectomy ambulatoire du complex saphénien interne à la cuisse. phlébologie 1993;46:123-36. 97. fays-bouchon n, fays j. une technique d’endo-eveinage de la saphéne interne en ambulatoire par micro-incisions. phlébologie 1995;48:353-8. 98. horakova ma, horakova e. influence de la phlébectomie ambulatoire du tronc pathologique de la grande saphène sans crossectomie sur la jonction saphèno-fémorale ; phlébologie 2002;55:299-305. 99. pittaluga p, chastanet s, guex jj. great saphenous vein stripping with preservation of sapheno-femoral confluence: hemodynamic and clinical results. j vasc surg 2008;47:1300-4. 100.casoni p, lefebvre-vilardebo m. la chirurgie variqueuse hier, aujourd’hui et demain. phlébologie 2007;60:24951. 101.casoni p, lefebvre-vilardebo m, villa f, corona p. great saphenous vein surgery without high ligation of the saphenofemoral junction. j vasc surg 2013;58:173-8. 102.mariani f, mancini s, bucalossi m, allegra c. selective high ligation of the sapheno-femoral junction decreases the neovascularization and the recurrent varicose veins in the operated groin. int angiol 2015;34:250-6. 103.ricci s, moro l, antonelli incalzi r. ultrasound assisted great saphenous vein ligation and division: an office procedure. veins and lymphatics 2014;3:4428. 104.bernardini e, de rango p, piccioli r, et al. development of primary superficial venous insufficiency: the ascending theory. observational and hemodynamic data from a 9-year experience. ann vasc surg 2010;24:709-20. 105.navarro l, min r, boné c. endovenous laser: a new minimally invasive method of treatment of varicose veins preliminary observations using an 810 nm diode laser. dermatol surg 2001;27:117-22. 106.chandler jg, pichot o, sessa c, et al. treatment of primary venous insufficiency by endovenous saphenous vein obliteration. vasc surg 2000;34:20114. 107.kabnick l. effects of different laser wavelengths on treatment of varices. in: bergan j, ed. the vein book. elseiver academic press; 2007. 108.genut e, marston wa, kouri ae. significance of patent saphenous vein stump length after endothermal ablation. j vasc surg venous lymph disord 2014;2:105. 109. rasmussen l, lawaetz m, bjoern l, et al. randomized clinical trial comparing endovenous laser ablation and stripping of the great saphenous vein with clinical and duplex outcome after 5 years. j vasc surg 2013;58:421-6. 110.winokur rs, khilnani nm, min rj. recurrence patterns after endovenous laser treatment of saphenous vein reflux. phlebology 2015 [epub ahead of print]. 111.rass k, frings n, glowacki p, et al. same site recurrence is more frequent after endovenous laser ablation compared with high ligation and stripping of the great saphenous vein: 5 year results of a randomized clinical trial (relacs study). eur j vasc endovasc surg 2015;50:648-56. 112.o’donnell tf, balk em, dermody m, et al. recurrence of varicose veins after endovenous ablation of the great saphenous vein in randomized trials. j vasc surg venous lymphat disord 2016;4:97-105. 113.disselhoff bcvm, der kinderen dj, kelderc jc, moll fl. five-year results of a randomised clinical trial of endovenous laser ablation of the great saphenous vein with and without ligation of the saphenofemoral junction. eur j vasc endovasc surg 2011;41:685-90. 114.gradman ws. adjunctive proximal vein ligation with endovenous obliteration of great saphenous vein reflux: does it have clinical value?. ann vasc surg 2007;21:155-8. 115.myers ka, jolley d, clough a, kirwan j. outcome of ultrasound guided sclerotherapy for varicose veins: medium-term results assessed by ultrasound surveillance. eur j vasc endovasc surg 2007;33:116e21. no n c om me rci al us e o nly review [veins and lymphatics 2017; 6:6822] [page 73] 116.van den bos rr, milleret r, neumann m, nijsten t. proof-of-principle study of steam ablation as novel thermal therapy for saphenous varicose veins. j vasc surg 2011;53:181-6. 117.elias s, raines jk. mechanochemical tumescentless endovenous ablation: final results of the initial clinical trial. phlebology 2012;27:67-72. 118.almeida ji, javier jj, mackay e, et al. first human use of cyanoacrylate adhesive for treatment of saphenous vein incompetence. j vasc surg venous lymphat disord 2013;1:174-80. 119.morrison n. cyanoacrylate glue for saphenous ablation. veins and lymphatics readers’ forum innovation circle 2012. available f r o m : https://doi.org/10.4081/innovatcircle. 2012.1 120.morrison n, gibson k, mcenroe s, et al. randomized trial comparing cyanoacrylate embolization and radiofrequency ablation for incompetent great saphenous veins (veclose). j vasc surg 2015;61:985-94. 121.frullini a, fortuna d. laser assisted foam sclerotherapy (lafos): anew approach totye treatment of incompetent saphenous veins. phlébologie 2013;66:51-4. 122. gianesini s, menegatti e, zuolo m, et al. laser-assisted strategy for reflux abolition in a modified chiva approach. veins and lymphatics 2013;4:53-7. 123.passariello f, ermini s, cappelli m, et al. the office based chiva. j vasc diagn int 2013;1:13-20. 124.mendoza e. chiva performed with endoluminal heat technique: laser versus vnus cross treatment of the great saphenous vein. phlebologie 2017;46:5-12. 125.miller a, lilach n, miller r, kabnick l. ny society for vascular surgery. a preclinical animal study of a novel, simple, and secure percutaneous vessel occluder for the treatment of varicose veins. j vasc surg venous lymph disord 2016;5:114-20. 126.boersma d, j de borst g, moll fl. a proof-of-concept study of the veinscrew: a new percutaneous venous closure device. vascular onlinefirst 2016 [epub ahead of print]. 127.viani mp, viani gm, sergenti j. oneshot scleroembolization: a new technique for the treatment of varicose veins disease of lower extremities. preliminary results. phlebology 2013 [epub ahead of print]. 128. kayssi a, oreopoulos g, tan kt, jaskolka j. combined coil embolization and foam sclerotherapy for the management of varicose veins. ann vasc surg 2017;38:293-7. no n c om me rci al us e o nly hrev_master veins and lymphatics 2017; volume 6:6976 [veins and lymphatics 2017; 6:6976] [page 91] global and regional brain atrophy is associated with low or retrograde facial vein flow in multiple sclerosis dejan jakimovski,1 karen marr,1 marcello mancini,2 maria grazia caprio,2 sirin gandhi,1 niels bergsland,1 ivo paunkoski,1 jesper hagemeier,1 avinash chandra,1 bianca weinstock-guttman,3 robert zivadinov1,4 1buffalo neuroimaging analysis center, department of neurology, jacobs school of medicine and biomedical sciences, university of buffalo, state university of new york, ny, usa; 2institute of biostructure and bioimaging, national research council, napoli, italy; 3jacobs multiple sclerosis center, department of neurology, school of medicine and biomedical sciences, university at buffalo, state university of new york, buffalo, ny, usa; 4translational imaging center at clinical translational science institute, university of buffalo, state university of new york, ny, usa abstract increased collateral facial vein (fv) flow may be associated with structural damage in patients with multiple sclerosis (ms). the objective was to assess differences in fv flow and magnetic resonance imaging (mri)-derived outcomes in ms. the study included 136 ms patients who underwent neck and head vascular system examination by echo-color doppler. inflammatory mri markers were assessed on a 3t mri using a semi-automated edge detection and contouring/thresholding technique. mri volumetric outcomes of whole brain (wb), gray matter (gm), white matter (wm), cortex, ventricular cerebrospinal fluid (vcsf), deep gray matter (dgm), thalamus, caudate nucleus (cn), putamen, globus pallidus (gp), and hippocampus were calculated. independent t-test and ancova, adjusted for age, were used to compare groups based on fv flow quartiles. thirty-four ms patients with fv flow ≤327.8 ml/min (lowest quartile) had significantly lower wb (p<0.001), wm (p<0.001), thalamus (p=0.004), cortex (p=0.004), gm (p=0.004), dgm (p=0.008), hippocampus (p=0.005), and gp volumes (p=0.044) compared to 102 patients with fv flow of >327.8 ml/min (higher quartiles). there were no differences in t1-, t2and gadolinium-enhancing lesion volumes between the quartile groups. the lack of an association between fv blood flow and inflammatory mri measures in ms patients, but an association with brain atrophy, suggests that the severity of neurodegenerative process may be related to hemodynamic alterations. ms patients with more advanced global and regional brain atrophy showed low or retrograde fv volume flow. introduction multiple sclerosis (ms) is a chronic autoimmune-mediated demyelinating disorder of the central nervous system (cns). however, a neurodegenerative component is being increasingly recognized as an important contributor to the disease pathophysiology. global and regional brain atrophy in ms has been strongly associated with both physical and cognitive decline.1 an emerging vascular hypothesis has sparked intense research regarding the anatomy and physiology of the vascular system in association with the disease pathophysiology.2 a variety of invasive and non-invasive imaging modalities have been used to describe changes in the venous system.3 despite the advantages and disadvantages of each technique, color doppler ultrasound allows real-time, dynamic examination of both the structural and hemodynamic properties of the venous system and remains a valuable diagnostic test.4 the internal jugular vein (ijv) is the main venous drainage pathway for the brain in the supine position, whereas in the upright position, ijvs collapse and the flow shifts to the vertebral veins (vv) and the vertebral venous plexus.5 additional recruitment of further collateral vessels would alleviate the possible flow disruption within the main drainage pathways. along these lines, several magnetic resonance imaging (mri) studies showed that ms patients have increased collateralization when compared to healthy controls (hc).6-8 from increased frequency of posterior paraspinal collaterals,9 to trends of greater occurrence in non-ijv collaterals,6 ms patients exhibit changes of the extracranial vascular system that are not fully understood. moreover, a recent hemodynamic mri study that enrolled 276 ms patients and 106 hcs demonstrated that the ms subjects had decreased flow within the ijvs and increased flow in paraspinal collateral veins.7 the possible obstruction in flow within the major draining pathways can cause substantial re-direction of flow toward the anterior/external jugular veins, facial vein (fv), thyroid veins and the vertebral system. the fv is formed by union of the anterior fv and the anterior branch of the posterior fv. inferiorly, the fv empties into the ijv and drains the blood from areas that largely correspond to the arterial territory of the external carotid artery. additionally, the cavernous sinus represents an anatomical site of communication between the major venous outflow (ijv) and the fv, and therefore, can facilitate compensatory venous redistribution. furthermore, it was shown that presence of valves in the facial and ophthalmic veins can regulate bidirectional flow opposing gravitational flow.10 the distribution of valves causes the blood flow from the orbital veins to be directed caudally towards the fv and the ijv. confirming these assumptions, an additional anatomy-based lumped parameter model of the venous circulation has also shown that any increase in resistance of the main venous drainage can cause retrograde flow changes within the cavernous, inferior, and superior petrosal sinuses.11 similarly, a recent interventional study showed that by restoring the main drainage pathway, the collateral flow decreased from 70% to 30%.12 more importantly, there was a 13-fold reduction in ventricular size associated with decrease of collateral flow lower than 20%.12 additionally, it was shown that the presence of venous abnormalities is associated with decreased perfusion in the gray matter (gm), the white matter (wm) and changes in cerebrospinal fluid dynamics.13,14 against this background, we hypothecorrespondence: robert zivadinov, center for biomedical imaging at clinical translational science institute, buffalo neuroimaging analysis center, jacobs school of medicine and biomedical sciences, university at buffalo, state university of new york, 100 high street, buffalo, ny 14203, usa. tel.: +1.716.859.7040 fax: +1.716.859.7066. e-mail: rzivadinov@bnac.net key words: facial vein; brain atrophy; multiple sclerosis; doppler sonography. received for publication: 4 august 2017. revision received: 8 september 2017. accepted for publication: 11 september 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright d. jakimovski et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6976 doi:10.4081/vl.2017.6976 no n c om me rci al us e o nly article [page 92] [veins and lymphatics 2017; 6:6976] sized that changes in the venous flow of the extra-cranial neck vessels may be associated with worse clinical and mri-derived measures in patients with ms. the ability to examine associations between collateral venous flow patterns like the fv and brain inflammatory and neurodegenerative mri measures may advance the understanding of the vascular pathology in ms. materials and methods subjects this study utilized data from an ongoing prospective case-control cardiovascular, environmental and genetic (ceg) study.15 the study was approved by the local institutional review board (irb) and all subjects signed a written informed consent. the inclusion criteria for this sub-study were: i) age range of 18-75 years old; ii) mri and doppler examination performed within 30 days of the neurological visit; iii) having an ms diagnosis as defined by the 2010 revised mcdonald criteria.16 based on their disease course, the ms patients were classified as relapsing-remitting ms (rrms) or secondary-progressive ms (spms). exclusion criteria for this study consisted of presence of clinical relapse or steroid treatment within 30 days of the mri scan, or being a nursing mother or pregnant woman. therefore, any differences within the presence of gadolinium-enhancing lesions is not representative and rendered to only asymptomatic appearance. all subjects underwent echo-color doppler, mri and full clinical examination. standard demographic and clinical information was collected, along with assessing expanded disability status scale (edss) by an experienced neurologist. mri acquisition and analysis all brain scans were acquired on a 3t ge signa excite hd 12.0 twin speed 8channel scanner (general electric, milwaukee, wi, usa) using an 8-channel head and neck (hdnv) coil. there were no mri hardware or software changes during the study. acquired mri sequences included axial 3d-spoiled-gradient recalled (spgr) t1 weighted image (wi), dual fast spin-echo (fse) t2/proton density (pd) wi, 2d fluid attenuated inversion recovery (flair) and post contrast spin-echo (se) t1-wi 5 minutes after single 0.1 mmol/kg gadobutrol injection. the slice thickness was 1 mm for 3d sequences and 3 mm for 2d sequences. the mri acquisition protocol was previously described.17 mri-derived inflammatory measures (t1, t2 and gadolinium-enhancing lesion volume) were obtained using a semi-automated edge detection and contouring/ thresholding technique.18 for calculation of whole brain (wb), gm, wm, ventricular cerebrospinal fluid (vcsf), and cortex normalized volumes, sienax cross-sectional software tool was used (version 2.6).19 prior to sienax, lesions were filled to reduce the impact of t1 hypointensities. regional tissue-specific normalized volumes of the thalamus, caudate nucleus (cn), putamen, globus pallidus (gp), hippocampus, and amygdala were derived with fmrib’s integrated registration and segmentation tool (first). doppler sonography assessment echo-color doppler (ecd esaote biosound my lab 25 gold) equipped with 2.5 and 7.5-10 mhz transducers (genoa, italy) was used for extra cranial examination. for the purpose of examining the ijv, the 7.5 mhz linear probe was used. the subjects were instructed not to reveal their disease status during the procedure. additional draping from the neck down was applied in order to further eliminate visual cues of disease. each subject was evaluated by the same blinded technologist (more than 25 years of experience). the blood flow of both ijvs was assessed. section above and below the entry of the fv into ijv and levels were used as measurement points for ijv respectively. the flow was calculated by multiplying the time average velocity (vmt) over 4 seconds time phase and vein manually drawn csa on axial view. the vmt has been carefully calculated using manual correction of the doppler angle, whereas the manually drawn csa was performed on color doppler settings. vmt= σvi*∆t (1) flow=vmt* csa (2) fv flow was calculated as the difference of the ijv flow measured below and above the entrance of fv. figure 1 shows the sites of measurements with the fv into the field of view. the step-wise methodology is shown in figure 2. the final variable used for further analysis was derived by summation of the blood flow measured within both the left and right side and from hereafter mentioned as fv blood flow. if the blood flow measured above the entry of the fv was higher than the flow measured below the entry, the fv blood flow was labeled as retrograde one. statistical analysis statistical analyses were performed using spss 24.0 (ibm, armonk, ny, usa). demographic and clinical characteristics were compared by using χ2 cross tabulation with yates’ correction, mann-whitneywilcoxon test, and student’s t-test, as appropriate. in order to determine the difference in mri-derived inflammatory and neurodegenerative measures between groups, student’s t-test was used. moreover, analysis of covariance (ancova), where fv status was considered a fixed factor, patients’ age was considered a covariance factor, and mri-derived measures the dependent measure, was performed in order to assess the fv status influence on the mri-derived measures, controlling for possible aging-related effects. both kolmogorov-smirnov and shapiro-wilk tests were used to determine normality of all variables used. additionally, q-q plots were used for visual inspection of the possible data skewness. four measures (vcsf, dgm, thalamus and gp) were not normally distributed; therefore, normalization by logarithmic transformation was performed. for all statistical results, p<0.05 based on two-tailed tests was considered significant. figure 1. illustration of the determination of the entrance of the facial vein into the ijv. sites of measurements above and below the entry were consequently selected. fv, facial vein; ijv, internal jugular vein; afv, above facial vein; bfv, below facial vein; cca, common carotid artery. no n c om me rci al us e o nly article [veins and lymphatics 2017; 6:6976] [page 93] results demographic, clinical, and doppler characteristics the demographic, clinical, and doppler characteristics of all ms patients (n=136) are summarized in table 1. the doppler characteristics of the fv blood flow ranged from –339.7 ml/min to 2229.6 ml/min. only 8 ms patients had negative fv blood flow. the mean fv flow was 707.0 ml/min and the quartiles were 327.8 ml/min, 651.9 ml/min and, 985.0 ml/min (25th, 50th, and, 75th, respectively). additionally, the initial ijv doppler measurements used for the calculation (tav, csa, and flow) are also presented in table 1. based on the lowest quartile of fv blood flow (327.8 ml/min), the subjects were grouped into higher quartiles and the lowest quartile of fv blood flow (102 vs 34 ms patients, respectively) and hereafter mention as fv status. the higher quartiles group of ms patients, had a mean age of 52.7 years old, a disease duration of 19.6 years, a median disability level of 3.0 edss score, and 70 of the patients had the rr form of ms. on the other hand, patients with the lowest quartile of fv blood flow were on average 55.5 years old, had a disease duration of 21.8 years, and had a disability median level based on edss scoring of 4.5. the lowest quartile group consisted of proportionally more spms patients than the higher quartile ms counterparts (p=0.05). there were no significant differences in female to male ratio between the groups (p=0.13). no significant differences between the two ms groups were observed for age (p=0.202), disease duration (p=0.306), edss (p=0.066), and the type of disease modifying therapies used (p=0.891). facial vein blood flow and mri-derived outcomes all mri-derived outcome measures and table 1. demographic and clinical characteristics of the multiple sclerosis cohort. demographic and clinical characteristics ms cohort (n=136) higher quartiles (n=102) lowest quartile (n=34) p value female, n (%) 100 (73.5) 72 (70.6) 28 (82.4) 0.13 age in yrs, mean (sd) 53.4 (10.9) 52.7 (10.7) 55.5 (11.5) 0.202 disease duration in yrs, mean (sd) 20.2 (10.6) 19.6 (10.3) 21.8 (11.4) 0.306 disease course 0.050 rr, n (%) 87 (63.9) 70 (68.6) 17 (50.0) sp, n (%) 49 (36.1) 32 (31.4) 17 (50.0) edss, median (iqr) 3.0 (4.0) 3.0 (2.5) 4.5 (4.5) 0.066 treatment status im ifn-beta-1a 30 (22.1) 21 (20.6) 9 (26.5) 0.891 sc ifn-beta-1a 10 (7.6) 7 (6.9) 3 (8.8) natalizumab 5 (3.7) 3 (2.9) 2 (5.9) glatiramer acetate 38 (27.9) 30 (29.4) 8 (23.5) other dmt 24 (17.6) 21 (20.6) 3 (8.8) no dmt 27 (19.9)* 18 (16.7)* 9 (26.5) facial vein blood flow (ml/min) 707.0 (511.8) 909.3 (413.9) 100.2 (203.5) <0.001 afv tav (cm/sec) 20.5 (8.7) 20.5 (8.4) 20.5 (9.5) 0.987 afv csa (mm2) 36.3 (17.6) 35.6 (16.9) 38.4 (19.6) 0.433 afv flow (ml/min) 874.8 (438.4) 849.4 (413.5) 951.2 (505.1) 0.243 bfv tav (cm/sec) 20.1 (7.5) 21.1 (7.3) 17.1 (7.3) 0.006 bfv csa (mm2) 67.6 (29.6) 72.6 (28.3) 52.4 (28.6) <0.001 bfv flow (ml/min) 1581.9 (621.6) 1758.7 (548.9) 1051.4 (521.8) <0.001 ms, multiple sclerosis; sd, standard deviation; rr, relapsing remitting; sp, secondary progressive; edss, expanded disability status scale; afv, above the entry of the facial vein; bfv, below the entry of the facial vein; tav, time-averaged velocity; csa, cross-sectional area; iqr, interquartile range; im, intramuscular; sc, subcutaneous; ifn, interferon; dmt, disease modifying therapy. *0dmt data was missing for 2 patients. χ2 test, student’s t-test and mann-whitney test were used accordingly. alpha level of 0.05 was considered as significant, and is shown in italics. figure 2. illustration of the methodology used to measure the facial vein blood flow. ijv, internal jugular vein; afv, above facial vein; bfv, below facial vein; 1, cross-sectional area measurement for above the facial vein segment of internal jugular vein; 2, cross-sectional area measurement for the below facial vein segment below the facial vein; 3, time-average velocity measurement for above the facial vein segment of internal jugular vein; 4, timeaverage velocity measurement for below the facial vein segment of the internal jugular vein. no n c om me rci al us e o nly article [page 94] [veins and lymphatics 2017; 6:6976] differences between groups are summarized in table 2. additionally, the differences in volumes are graphically represented in figure 3. the lowest quartile of fv blood flow group had significantly lower global and regional brain volumes compared to ms patients within the higher quartiles. in particular, they had significantly lower wb volume (p<0.001), wm volume (p<0.001), gm volume (p=0.004), cortical volume (p=0.004), and a trend for higher vcsf volume (p=0.051). similarly, they had lower total deep gm volume (p=0.008), thalamic (p=0.003), gp (p=0.027), and hippocampal (p=0.005) volumes. all findings were confirmed with ancova analyses controlling for age. even though several deep gray matter structures did not reach statistical significance, their volumes were smaller in the group within the lowest quartile. there were no statistical differences between the lowest and the higher quartiles of fv blood flow regarding inflammatory outcome measures, such as t2 hyperintense lesion, gadolinium-enhancing, or t1hypointense lesion volumes. independently, we conducted a similar statistical analysis on both disease subgroups. the differences in inflammatory and neurodegenerative mri-derived measures within the rrms and spms patients are shown in table 3. although in lesser effect than compared with a whole sample, the differences in brain atrophy still persisted. in both the rrms and spms subgroups, the patients with the lowest quartile of fv blood flow had smaller wbv and wmv (p=0.01, p=0.012 for rrms, and p=0.014, p=0.012 for spms, respectively). table 3. differences based on facial vein status in mri-derived global and regional brain volumes in individually relapsing-remitting and secondary-progressive ms patients. mri characteristics rrms p value ancova spms p value ancova higher lowest age higher lowest age quartiles quartile adjusted quartiles quartile adjusted (n=70) (n=17) (n=32) (n=17) t1-lv 1.65 (3.6) 3.3 (6.7) 0.35 0.003 4.1 (8.9) 3.9 (6.6) 0.921 0.467 t2-lv 11.6 (15.7) 11.1 (14.1) 0.91 0.527 21.1 (20.9) 19.8 (23.1) 0.834 0.732 gd-lv 0.03 (0.2) 0.006 (0.02) 0.694 0.001 0.003 (0.02) 0.0 0.471 0.999 whole brain volume 1488.8 (75.5) 1432.8 (92.8) 0.01 0.065 1407.9 (88.1) 1355.3 (69.9) 0.012 0.892 grey matter volume 757.5 (54.1) 728.0 (62.7) 0.054 0.015 705.9 (55.5) 685.4 (52.9) 0.217 0.832 white matter volume 731.2 (38.3) 704.8 (41.9) 0.014 0.725 702.1 (43.5) 669.9 (36.1) 0.012 0.722 cortical volume 614.4 (43.3) 588.2 (47.9) 0.031 0.009 575.7 (45.5) 558.7 (45.3) 0.217 0.898 ventricular csf volume* 47.7 (24.4) 53.1 (21.5) 0.247 0.378 57.7 (25.5) 67.8 (34.9) 0.316 0.872 deep grey matter volume* 56.7 (5.8) 53.8 (7.6) 0.063 0.032 51.3 (7.1) 48.9 (6.4) 0.286 0.482 thalamus volume* 18.8 (2.1) 17.5 (2.7) 0.020 0.118 16.9 (2.4) 16.1 (2.3) 0.307 0.690 caudate volume 8.4 (1.1) 8.1 (1.2) 0.311 0.119 7.6 (1.3) 7.4 (0.9) 0.669 0.234 putamen volume 12.1 (1.5) 11.9 (1.8) 0.666 0.007 10.9 (1.6) 10.4 (1.6) 0.300 0.757 pallidal volume* 4.1 (0.7) 3.8 (7.6) 0.046 0.407 3.9 (0.9) 3.7 (0.7) 0.474 0.762 hippocampus volume 9.1 (1.3) 8.6 (1.3) 0.139 0.044 8.5 (1.3) 7.7 (1.3) 0.071 0.306 amygdala volume 3.1 (0.4) 2.8 (0.6) 0.015 0.511 2.7 (0.5) 2.9 (0.5) 0.386 0.085 rrms, relapsing-remitting multiple sclerosis; spms, secondary progressive multiple sclerosis; fv, facial vein; csf, cerebrospinal fluid; lv, lesion volume, gd, gadolinium. *logarithmic transformation used. student’s ttest and analysis of covariance (ancova) adjusted for age were used. alpha level of 0.05 was considered as significant, and is shown in italics. the volumes are represented in milliliters (mean ± standard deviation). table 2. mri differences between multiple sclerosis patients with lowest and the higher quartiles of bilateral facial vein blood flow. mri characteristics higher quartiles (n=102) lowest quartile (n=34) p value ancova age-adjusted t1-lv 2.4 (5.9) 3.6 (6.5) 0.343 0.381 t2-lv 14.6 (17.9) 15.4 (19.4) 0.819 0.951 gd-lv 0.023 (0.2) 0.002 (0.02) 0.569 0.720 whole brain volume 1463.4 (87.7) 1394.0 (89.9) <0.001 <0.001 grey matter volume 741.3 (59.3) 706.7 (61.1) 0.004 0.010 white matter volume 722.1 (42.0) 687.3 (42.4) <0.001 <0.001 cortical volume 602.3 (47.4) 573.4 (48.3) 0.004 0.006 ventricular csf volume* 50.8 (25.1) 60.4 (29.5) 0.051 0.103 deep grey matter volume* 54.9 (6.7) 51.3 (7.3) 0.008 0.017 thalamus volume* 18.2 (2.3) 16.8 (2.6) 0.003 0.008 caudate volume 8.2 (1.3) 7.8 (1.1) 0.101 0.191 putamen volume 11.7 (1.6) 11.1 (1.8) 0.096 0.177 pallidal volume* 4.0 (0.8) 3.7 (7.2) 0.027 0.034 hippocampus volume 8.9 (1.3) 8.2 (1.3) 0.005 0.013 amygdala volume 2.9 (0.5) 2.8 (0.5) 0.115 0.180 fv, facial vein; csf, cerebrospinal fluid; lv, lesion volume, gd, gadolinium. *logarithmic transformation used. student’s t-test and analysis of covariance (ancova) adjusted for age were used. alpha level of 0.05 was no n c om me rci al us e o nly article [veins and lymphatics 2017; 6:6976] [page 95] discussion we evaluated the relationship between collateral venous outflow and mri-derived outcome measures in ms patients. this study suggests that ms patients within the lowest quartile of fv blood flow presented with decreased global and regional mriderived brain volumes. additionally, the lowest quartile group was no different in terms of inflammatory mri-derived outcome measures when compared to the higher quartile groups. studies have shown that ms patients have larger measured arterial inflow than venous drainage, also known as a mismatch between the arterial and venous flow, which may indicate that the venous blood is drained through supplementary, non-previously detected smaller veins.20 additionally, in a global mathematical model, the effect of extra cranial obstacles has been calculated to increase the intracranial pressure, consequently causing a flow reduction up to 70% in the primary affected vessel, and flow increase in the collateral pathways.21 one way of explaining the results of our study is that due to possible obstruction within the ijv, a redistribution of the blood flow through the fv has occurred. the cavernous sinus, as an anatomical communication between the major venous outflow (ijv) and the fv, may facilitate this compensatory mechanism. therefore, due to the venous abnormalities, compensatory physiological mechanisms of increased collateralization in ms have been hypothesized. increased ijv flattening in ms patients was associated with development of more non-ijv collaterals.6 similarly, this morphological development of collateral vessels has been confirmed with corresponding hemodynamic analysis. a recent phase-contrast mr study showed that ms patients had increased quantified paraspinal and collateral veins flow, coupled with reduced blood flow in the ijv.7 on the other hand, by using quantitative doppler ultrasound measurements of the venous blood flow, several studies showed global venous hemodynamic differences associated with ms. a contrast-enhanced ultrasonography study showed heterogeneity in the venous outflow system consistent with slow washout dynamic.22 all the aforementioned changes have been previously described as part of chronic cerebrospinal venous insufficiency (ccsvi) condition which is characterized by anomalies of the main extracranial cerebrospinal venous routes that interfere with normal blood outflow.2 higher prevalence of ccsvi has been reported not only in ms patients, but also in parkinson disease,24 and meniere disease.25 other entities like transient global amnesia and chronic migraine have also been associated with jugular reflux and changes in the venous dynamics.26,27 additionally, well-known ms susceptibility factors like cardiovascular, infectious, and inflammatory risks have been associated with increased prevalence of ccsvi.28 the paucity of differences in any of the conventional inflammatory outcome measures may be explained by the recent findings, which suggest that the cortical atrophy, and specifically cortical hemispheric volume loss lateralization, could influence the homeostasis of autonomic nervous system (ans).29 for example, autonomic mechanisms related to cardiovascular control are located in the neuronal circuitry of the insular cortex, dorsal anterior cingulate, prefrontal cortex, and hippocampus.30 it has been reported that dysregulation of the ans is associated with variability of the heart rate, and fluctuations of the blood pressure, all of which can contribute to reaching a critical closing pressure that leads to the collapse of the cerebral venous system.31 therefore, it may be hypothesized that an extensive neurodegenerative pathology within cortical regions associated with ans system function can alter regional venous flow redistribution. the change of the posture and the change of the physical forces acting on the vasculature are creating normal physiological shift from the ijv-driven venous outflow in supine position to more vertebral and paraspinal flow in erect positon. the initial reports of ms patients having increased ijv venous return in the seated position were supported by other independent studies.23 on this basis, a quantitative evaluation study that enrolled patients with rrms and primary-progressive (pp) ms, and healthy controls showed that the postural dependency was pronounced in the more disabled patients. in that study, 52.9% of rrms and 75.9% of ppms versus only 13.4% of hcs showed increased supine ijv flow.32 additionally, this alteration of venous blood outflow was able to discern ms patients against other neurological diseases and versus hcs.33 both concepts of i) lack of differences in inflammatory mri-derived measures; and ii) increased prevalence of hemodynamic changes within more disabled ms patients (rr vs sp), further converge on the neurodegenerative etiology of the hemodynamic flow changes seen in ms. lastly, this study extends the need of more comprehensive vascular analysis. examining the ijvs only, on several predetermined levels of measurement might not be sufficient in order to detect the possible global hemodynamic changes. we figure 3. graphical representation of the differences in brain volumes between groups of lowest quartile and higher quartiles of facial vein blood flow. orange, multiple sclerosis patients with lowest quartile of facial vein blood flow; blue, multiple sclerosis patients with higher quartiles of facial vein blood flow. *both significant at level of <0.05; **correlation significant at level of <0.001. no n c om me rci al us e o nly article [page 96] [veins and lymphatics 2017; 6:6976] showed that flow measured within collateral vessels were able to differentiate patients based on their neurodegenerative phenotype. well-designed, longitudinal studies comprehensively examining the secondary vascular system and its associations with clinical/mri measures may overcome the contradictory results reported in the literature. despite recent improvements of the pulse-wave doppler ultrasound, a number of technical limitations in flow measurements still remain inherent to the technique. conventional ultrasound transducers produce an intensity distribution, which varies continuously across the beam, and conventional pulsed doppler systems are designed to achieve high spatial resolution rather than uniformity of insonification. additionally, the method employed also assumes several factors as i) accurate measurement of the csa, ii) non-turbulent flow, iii) correct angle of insonation, and iv) cylindrically symmetric flow profile. possible use of newly developed 3d/4d probes that acquire multivolume color doppler data might circumvent the previously mentioned limitations. until further standardization of the methods used is achieved, any experimental assessment should serve as a research tool, which might help disentangle the vascular pathology seen in ms patients. a limitation in this study was the indirect measurement of the fv blood outflow. color doppler ultrasound can detect extracranial collateral veins; however, it has limited ability in fully following the complete course of smaller size vessels. additionally, the available ultrasound flowoutflow data has already been acquired, and therefore our hypothesis was tested in a post-hoc manner. with the fv used as an anatomical marker for the ijv flow measurements, the flow difference between the below and above the entrance of facial vein ijv segment can only be attributed to the actual fv blood flow. in order to determine if the increased collateral flow within the fv has primary pathology or it is a byproduct by the associated neurodegeneration, a prospective doppler-mri study is needed. conclusions ms patients within the lowest quartile of fv blood flow showed more advanced global and regional brain atrophy. the fv can be a substantial alternative venous draining pathway for the head and neck structures and should be considered in future comprehensive venous examinations. furthermore, we showed that the ability of the fv to compensate and contribute into the venous drainage is associated with higher global and regional brain volumes. the lack of associations between inflammatory mri measures in ms patients, but an association with brain atrophy, suggests that the severity of neurodegenerative process may be related to hemodynamic alterations. references 1. zivadinov r, havrdova e, bergsland n, et al. thalamic atrophy is associated with development of clinically definite multiple sclerosis. radiology 2013;268:831-41. 2. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:392-9. 3. dolic k, siddiqui ah, karmon y, et al. the role of noninvasive and invasive diagnostic imaging techniques for detection of extra-cranial venous system anomalies and developmental variants. bmc med 2013;11:155. 4. zivadinov r, bastianello s, dake md, et al. recommendations for multimodal noninvasive and invasive screening for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency: a position statement of the international society for neurovascular disease. j vasc interv radiol 2014;25:1785-94. 5. ciuti g, righi d, forzoni l, et al. differences between internal jugular vein and vertebral vein flow examined in real time with the use of multigate ultrasound color doppler. ajnr am j neuroradiol 2013;34:2000-4. 6. mctaggart ra, fischbein nj, elkins cj, et al. extracranial venous drainage patterns in patients with multiple sclerosis and healthy controls. ajnr am j neuroradiol 2012;33:1615-20. 7. sethi sk, daugherty am, gadda g, et al. jugular anomalies in multiple sclerosis are associated with increased collateral venous flow. ajnr am j neuroradiol 2017 [epub ahead of print]. 8. zivadinov r, lopez-soriano a, weinstock-guttman b, et al. use of mr venography for characterization of the extracranial venous system in patients with multiple sclerosis and healthy control subjects. radiology 2011;258:56270. 9. zaharchuk g, fischbein nj, rosenberg j, et al. comparison of mr and contrast venography of the cervical venous system in multiple sclerosis. ajnr am j neuroradiol 2011;32:1482-9. 10. zhang j, stringer md. ophthalmic and facial veins are not valveless. clin exp ophthalmol 2010;38:502-10. 11. marcotti s, marchetti l, cecconi p, et al. an anatomy-based lumped parameter model of cerebrospinal venous circulation: can an extracranial anatomical change impact intracranial hemodynamics? bmc neurol 2015;15:95. 12. zamboni p, menegatti e, cittanti c, et al. fixing the jugular flow reduces ventricle volume and improves brain perfusion. j vasc surg venous lymphat disord 2016;4:434-45. 13. zamboni p, menegatti e, weinstockguttman b, et al. hypoperfusion of brain parenchyma is associated with the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a cross-sectional preliminary report. bmc med 2011;9:22. 14. lagana mm, chaudhary a, balagurunathan d, et al. cerebrospinal fluid flow dynamics in multiple sclerosis patients through phase contrast magnetic resonance imaging. curr neurovasc res 2014;11:349-58. 15. zivadinov r, ramasamy dp, vaneckova m, et al. leptomeningeal contrast enhancement is associated with progression of cortical atrophy in ms: a retrospective, pilot, observational longitudinal study. mult scler 2016:1352458516678083. 16. polman ch, reingold sc, banwell b, et al. diagnostic criteria for multiple sclerosis: 2010 revisions to the mcdonald criteria. ann neurol 2011; 69:292-302. 17. zivadinov r, heininen-brown m, schirda cv, et al. abnormal subcortical deep-gray matter susceptibility-weighted imaging filtered phase measurements in patients with multiple sclerosis: a case-control study. neuroimage 2012;59:331-9. 18. zivadinov r, rudick ra, de masi r, et al. effects of iv methylprednisolone on brain atrophy in relapsing-remitting ms. neurology 2001;57:1239-47. 19. smith sm, zhang y, jenkinson m, et al. accurate, robust, and automated longitudinal and cross-sectional brain change analysis. neuroimage 2002;17:479-89. 20. haacke em, feng w, utriainen d, et al. patients with multiple sclerosis with structural venous abnormalities on mr imaging exhibit an abnormal flow distribution of the internal jugular veins. j vasc interv radiol 2012;23:60-8. no n c om me rci al us e o nly article [veins and lymphatics 2017; 6:6976] [page 97] 21. muller lo, toro ef, haacke em, utriainen d. impact of ccsvi on cerebral haemodynamics: a mathematical study using mri angiographic and flow data. phlebology 2016;31:305-24. 22. mancini m, lanzillo r, liuzzi r, et al. internal jugular vein blood flow in multiple sclerosis patients and matched controls. plos one 2014;9:e92730. 23. monti l, menci e, ulivelli m, et al. quantitative colourdoppler sonography evaluation of cerebral venous outflow: a comparative study between patients with multiple sclerosis and controls. plos one 2011;6:e25012. 24. liu m, xu h, wang y, et al. patterns of chronic venous insufficiency in the dural sinuses and extracranial draining veins and their relationship with white matter hyperintensities for patients with parkinson’s disease. j vasc surg 2015;61:1511-20. 25. filipo r, ciciarello f, attanasio g, et al. chronic cerebrospinal venous insufficiency in patients with meniere’s disease. eur arch otorhinolaryngol 2015;272:77-82. 26. ertl-wagner b, koerte i, kumpfel t, et al. non-specific alterations of craniocervical venous drainage in multiple sclerosis revealed by cardiac-gated phase-contrast mri. mult scler 2012;18:1000-7. 27. chung cp, hsu hy, chao ac, et al. detection of intracranial venous reflux in patients of transient global amnesia. neurology 2006;66:1873-7. 28. dolic k, weinstock-guttman b, marr k, et al. risk factors for chronic cerebrospinal venous insufficiency (ccsvi) in a large cohort of volunteers. plos one 2011;6:e28062. 29. guo cc, sturm ve, zhou j, et al. dominant hemisphere lateralization of cortical parasympathetic control as revealed by frontotemporal dementia. proc natl acad sci u s a 2016;113: e2430-2439. 30. shoemaker jk, norton kn, baker j, luchyshyn t. forebrain organization for autonomic cardiovascular control. auton neurosci 2015;188:5-9. 31. czosnyka m, smielewski p, piechnik s, et al. critical closing pressure in cerebrovascular circulation. j neurol neurosurg psychiatry 1999;66:606-11. 32. marchione p, morreale m, giacomini p, et al. ultrasonographic evaluation of cerebral arterial and venous haemodynamics in multiple sclerosis: a casecontrol study. plos one 2014;9: e111486. 33. monti l, menci e, piu p, et al. a sonographic quantitative cutoff value of cerebral venous outflow in neurologic diseases: a blinded study of 115 subjects. ajnr am j neuroradiol 2014; 35:1381-6. no n c om me rci al us e o nly hrev_master veins and lymphatics 2018; volume 7:7662 [veins and lymphatics 2018; 7:7662] [page 105] the impact of the double blinded randomized control trial brave dreams on the nursing staff clara todini,1 michela zanandrea2 1pediatric nursing, la sapienza university, rome; 2university-hospital of ferrara, updating and training service, nursing degree course, ferrara, italy abstract the objective of this study is a qualitative pilot survey to evaluate the impact of the double-blinded randomized controlled surgical trial brave dreams on the nursery staff. chronic cerebrospinal venous insufficiency (ccsvi) is a condition frequently associated to multiple sclerosis, and characterized by impaired venous drainage of the brain and spinal cord as a result of outflow obstruction in the extracranial venous system. the trial was of paramount importance, because the main objective was to test whether re-establishing a correct venous drainage could have therapeutic implications for multiple sclerosis patients, when the disease was associated to ccsvi. basically, brave dreams assessed the efficacy and safety of percutaneous transluminal angioplasty of extracranial veins. to assess the impact of the trial on the nursery staff, an ad hoc questionnaire was used to test a sample of 8 nurses. the tests investigated 5 macro areas: i) managing of patient assistance; ii) how the research team trained the nursery staff; iii) unmasking efficacy; iv) the overall satisfaction of the nursery staff; v) possible introduction of subjects that explain the methodology of clinical trials during degree nursing education. data analysis showed that assistance in a trial context must be personalized and based on primary nursing principles. it also showed that staff training was extremely satisfying and helpful to the study successful outcome. furthermore, it showed that each patient was convinced to have undergone a percutaneous transluminal angioplasty, and not a sham procedure. moreover, the survey showed a strong synergy between the patients and the nursery staff involved in the study. our conclusions are to examine in depth the notions of professional deontology, ethical behavior and patients’ psychology whenever nurses are called to take part in clinical randomized trials. introduction multiple sclerosis is a chronic degenerative inflammatory disease of the central nervous system, with an unknown etiology1,2 as well as the most common disease that causes disability among young people. chronic cerebrospinal venous insufficiency (ccsvi) is a condition characterized by impaired venous drainage of the brain and spinal cord as a result of outflow obstruction in the extracranial venous system, mainly caused by intraluminal obstacles, defective valves, hypoplasia, and/or compression of the internal jugular veins and/or azygos vein. this condition was first described associated to a group of patients affected by multiple sclerosis (ms).3,4 furthermore, the ccsvi research extended to other neurodegenerative diseases even more complicated the scientific picture. recent studies reveal that ccsvi, initially described by zamboni in multiple sclerosis (ms) patients, is also associated to parkinson, alzheimer, ménière syndrome, and sudden sensorineural hearing loss, and even present in healthy controls.5-8 however, independently from the problem of imaging ccsvi, which prevents to reliably collect solid epidemiologic data, the knowledge about the pathology characterizing the jugular venous wall in ccsvi condition has been recently increased by a number of papers. the challenging hypothesis of brave dreams trial was to open the venous obstruction by the means of percutaneous transluminal angioplasty in patients with ms associated with ccsvi, in order to verify if the improvement of venous drainage could in turn improve the clinical outcomes of the diseases.9 the proposal to add an endovascular treatment to the current therapies for the multiple sclerosis created an important scientific controversy which involves vascular and neurological sciences, respectively.4 hence originated the need of an experimental study in order to evaluate the efficacy and safety of percutaneous transluminal angioplasty of extracranial veins in patients affected by multiple sclerosis. the trial, done in doubleblinded, implied the randomization of patients into two groups; respectively the experimental group who underwent the intervention, and the control group to a simulated intervention.5 the nurses, assisting the patients during the trial, were specialized in surgery and faced for the first time in their lives a double-blinded trial. this is the main reason that inspired the will to investigate the influence of brave dreams on the nursing assistance component of this study. materials and methods there has been done a descriptive qualitative survey on june 2017 addressed to the nursery population in the day surgery care unit of the ferrara university-hospital. survey construction in order to do this, there was used a yesand-no questionnaire, 12 items, overall (table 1). inclusion criteria the inclusion was based on having participated actively in all the phases regarding the intervention day of the study, as follows: reception in the surgical ward, post-operative management and discharge. specifically, the nursing staff arranged the patients in their rooms, explained in detail how the day would take place and clarified any further doubts. then they advised the auxiliary staff dedicated to the transfers into the interventional radiology unit. after about two hours, patients returned to the day surgery ward with mandatory bed restraints. from this moment on, that is the post-operative phase, the nurses scrupucorrespondence: clara todini, pediatric nursing, la sapienza university; and pediatric short-stay emergency observation unit/pediatric emergency department, umberto i hospital, rome, italy. e-mail: clara.todini@libero.it key words: brave dreams trial; randomized control trials; chronic cerebrospinal venous insufficiency; multiple sclerosis; chronic cerebrospinal venous insufficiency; nursing. acknowledgements: we thank the nursing involved personnel of the day surgery care unit of ferrara’s university-hospital, italy, and mrs. ornella antoniolli, nursery staff responsible, for allowing and facilitating this study. conflict of interest: the authors declare no conflict of interests. received for publication: 26 june 2018. revision received: 24 september 2018. accepted for publication: 25 september 2018. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright c. todini and m. zanandrea, 2018 licensee pagepress, italy veins and lymphatics 2018; 7:7662 doi:10.4081/vl.2018.7662 no nco mm er cia l u se on ly article [page 106] [veins and lymphatics 2018; 7:7662] lously noted the vital parameters of each patient, drew blood samples for the analysis of the blood count and coagulation, examinations necessary for the assessment of possible bleeding. during the discharge phase, after having assisted professor zamboni staff during the postoperative echo-colordoppler, the nurses evaluated and lightened the compressive medication of the patients. finally, the nurses dealt with the therapeutic education of the latter, instructing the patients on how to practice self-administration of low molecular weight heparin at home over the next 21 days. data analysis nurses joined in voluntary after being wholly informed on the survey aims. the sample dimension is of 8 nurses, each of who filled in the questionnaire anonymously and autonomously. each question in the questionnaire (table 1) also included a motivation, which could be filled out if any of the interviewed nurses wanted to add something more. from the above reasons, key words have been underlined. subsequently, the questions were grouped by common themes, in accordance with a methodology previously described, which allowed us to identify 5 domains emerged from the post-hoc analysis:6-8 managing and improvement of the assistance; patient and nursing staff training; successful result of masking; satisfaction; nursing degree education program. results the sample was composed entirely of female nurses, aged between 40 and 65 years, with at least 20 years of experience in the surgical area, who for the first time faced a double blinded experimental context. each topic included specific questionnaire questions, as follows: i) managing and improvement of the assistance -do you think that something has changed in the nurses role with regard to a typical day surgery intervention?, 63% replied no, 37% replied yes. -is there anything you would have done in a different way for a better service during the assistance phases?, 75% replied no, 25% replied yes. -in your opinion, does this trial contest show any new needs of assistance?, 38% replied no, 62% replied yes. ii) patient and nursing staff training have the operative instructions the research team gave before the study took place been clear? 100% replied yes. do you think that patients and their relatives were well trained? 100% replied yes. do you think that the preparatory training addressed to all the healthcare staff was satisfying? 100% replied yes. iii) successful result of masking did patients and/or their relatives somehow try to violate the double blind method? 88% replied no, 12% replied yes. have there been any indirect questions to let leak anything related to the trial? 63% replied no, 37% replied yes. did any patient show firmly that they had never undergone percutaneous transluminal angioplasty?, 100% replied no. iv) satisfaction do you think that patients were motivated even if there was the possibility for them not to undergo the intervention? 100 % replied yes. did you find participating such an ambitious clinical study gratifying? 100% replied yes. v) nurse degree education in your opinion, should preparation to the trial context be inserted in the nursing degree course? 100% replied yes. the participants answered all the above questions, yes and no. few nurses did not integrate closed questions with a motivation, but the majority did it. from the latter it has been shown how, each nurse involved in the trial, has provided optimal assistance to these patients, considering them in a holistic way, and having the foresight to give particular attention to what is the emotional and relational dimension, given the fragility of the context. the entire nursing staff also expressed extreme satisfaction at the time of the training prior to the implementation of the study, clearly illustrated by the pi and his research team. it also emerged that the research team has fully exposed the study to patients, testified by the fact that they have never, apart from an isolated case, asked questions or tried to violate the integrity of the experimentation and therefore with the successful masking. therefore, overall satisfaction was expressed by nursing staff, but also by patients, who demonstrated a strong motivation, evidenced moreover by the fact that as many as 97% of them have completed the study, including follow-up9-11 (table 2). discussion and conclusions the results of the present pilot study are below discussed by sub setting the survey per domain. managing and improvement of the assistance it was noticed that in a trial context, the table 1. the complete copy of the 12 items’ questionnaire. questions 1. do you think that something has changed in the nurses’ role with regard to a typical day surgery intervention? 2. is there anything you would have done in a different way for a better service during the assistance phases? 3. in your opinion, does this trial contest show any new needs of assistance? 4. have the operative instructions the research team gave before the study took place been clear? 5. do you think that patients and their relatives were well trained? 6. do you think that the preparatory training addressed to all the healthcare staff was satisfying? 7. did patients and/or their relatives somehow try to violate the double blind method? 8. have there been any indirect questions to let leak anything related to the trial? 9. did any patient show firmly that they had never undergone percutaneous transluminal angioplasty? 10. do you think that patients were motivated even if there was the possibility for them not to undergo the intervention? 11. did you find participating such an ambitious clinical study gratifying? 12. in your opinion, should preparation to the experimental contest be inserted in the nursing degree course? no nco mm er cia l u se on ly article [veins and lymphatics 2018; 7:7662] [page 107] role of nurses did not change but the selfawareness of belonging to an assisting profession did. the majority of nurses assert to have done an excellent assistance, personalized and based on primary nursing principles, aiming to satisfy new assistance needs. there appeared a greater sagacity towards patients due to the delicateness of the route taken, putting the patient in a room with less people than usual and allowing relatives to enter beyond visiting hours; thus, major attention was paid to the psychological and relational aspect. patient and nursing staff training all nurses showed themselves to be totally satisfied with the training they were given formerly by the principal investigator and the other components of the research team, and emphasized its priority and necessity to the positive result of the study i.e. to reach the goal. as far as patients and relatives training is concerned, they were found to be more prepared and educated in study matters and about the rules to be followed. furthermore, nurses state that none of the patients showed doubts or suspects about the activities lead during the hospitalization and that they had no difficulties at all in doing their duty. successful result of masking the most crucial step of a double-blinded study in surgery, i.e. unmasking, was solved in this study. apart from an only case in 70 patients treated in the ferrara university-hospital, none of the patients insisted or put any questions directly or indirectly, to understand which group they were randomized. the study showed that the patients tried to understand what was happening through the nurse behavior instead of putting questions to them. the most important thing is that the nursery staff testimony shows that each of them was convinced of having being randomized to the pta intervention, which is crucial to the successful result of this study. satisfaction guided by a spirit of love and dedication for the sake of the people, all the nurses felt that all the patients had constantly been motivated. the patients who underwent this study strongly believed that, this contribution would help other people with the same problem. they were aware that only through a clinical trial the national health system could recognize the intervention making it accessible to all. according to the nurses, this motivation comes as a result of the hope and serenity of those who face resolutions confidently and not only for their own sake. taking part in a clinical trial not only gives hope to other people facing the same problems as yours, but it also gives a huge contribution to the scientific community. being part of a clinical study so well structured, bearing an important purpose, made nurses feel gratified. they also state to have felt as being an active part of the clinical team. nursing degree education program all the nurses involved were of the opinion that it is mandatory to introduce the role of nursing staff in clinical experimental trial context during the degree course. they also stated that it is crucial a deeper study of all the notions related to the professional deontology, to the ethical behavior as well as to the study of patient’s psychology inserted in a clinical trial. this is crucial to the optimal communication approach, to the management and assistance of patients who are subject to a clinical blinded experimental study. this study results show how active involvement of the nurses in the clinical trial can be crucial to the quality of assistance and to the maintaining of the study integrity as well as to the masking ethic. the result of the present study also shows that preparatory training specific for nursery staff is important for the successfulness of the survey. furthermore, it was found out that the research team clearly showed the study to the patients, testified by the fact that they never asked questions or tried to interfere with the trial process (but one case), hence the unmasking positive result. alternatively, we can deduce that the majority of patients was convinced of having been involved in the angioplasty group, i.e. in the treatment group, or we can deduce that the patients were highly motivated by the ethical need to maintain the unmasking integrity. on the other hand, these patients have shown a strong motivation, testified by the fact that 97% of them finished the study, follow-up included. 5 therefore there has been expressed a total satisfaction by the nursery staff. considering that the purpose of the clinical trial is to allow for scientific knowledge finalized to the prevention, diagnosis and treatment of the diseases, serious and motivating research in a hospital is not to be considered an obstacle to the nursing assistance, but a great opportunity for professional growth. from this point of view results show that the staff enjoyed very much the training session heading this study. the experimenters explained to the staff the purposes and the study modality. staff could discuss criticality and could learn beforehand any possible risk, which could potentially have affected the brave dreams integrity. interviews let us know that, after this preliminary work, the staff felt very much motivated and self-confident table 2. the questionnaire used to conduct this survey, and the percentage of yes and no answers. question yes (%) no (%) 1. do you think that something has changed in the nurses’ role with regard to a typical day surgery intervention? 37% 63% 2. is there anything you would have done in a different way for a better service during the assistance phases? 25% 75% 3. in your opinion, does this trial contest show any new needs of assistance? 62% 38% 4. have the operative instructions the research team gave before the study took place been clear? 100% 0% 5. do you think that patients and their relatives were well trained? 100% 0% 6. do you think that the preparatory training addressed to all the healthcare staff was satisfying? 100% 0% 7. did patients and/or their relatives somehow try to ruin the double blind method? 12% 88% 8. have there been any indirect questions to let leak anything related to the trial? 37% 63% 9. did any patient show firmly that they had never undergone percutaneous transluminal angioplasty? 0% 100% 10. do you think that patients were motivated even if there was the possibility for them not to undergo the intervention? 100% 0% 11. did you find participating such an ambitious clinical study gratifying? 100% 0% 12. in your opinion, should preparation to the experimental contest be inserted in the nursing degree course? 100% 0% no nco mm er cia l u se on ly article [page 108] [veins and lymphatics 2018; 7:7662] in participating to a clinical trial activity of a high level. considering the frequency of clinical trials following the recommendations of the evidence based medicine, we believe that it is important to prepare the nursing staff to these activities that involve them professionally starting from the degree course. references 1. noseworthy jh, lucchinetti c, rodriguez m, et al. multiple sclerosis. n engl j med 2000;343:983-52. 2. frohman em, racke mk, raine cs. multiple sclerosis-the plaque and its pathogenesis. n engl j med 2006;354: 942-55. 3. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:392-9. 4. zivadinov r, bastianello s, dake md, et al. recommendations for multimodal noninvasive and invasive screening for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency: a position statement of the international society of neurovascular disease. j vasc interv radiol 2014;25:1785-94. 5. liu m, xu h, wang y, et al. patterns of chronic venous insufficiency in the dural sinuses and extracranial draining veins and their relationship with white matter hyperintensities for patients with parkinson’s disease. j vasc surg. 2015 jun;61(6):1511-20. 6. chung cp, beggs c, wang pn, et al. jugular venous reflux and white matter abnormalities in alzheimer’s disease: a pilot study. j alzheimers dis 2014;39: 601-9. 7. bruno a, napolitano m, califano l, et al. the prevalence of chronic cerebrospinal venous insufficiency in meniere disease: 24-month follow-up after angioplasty. j vasc interv radiol 2017;28:388-91. 8. tessari m, ciorba a, mueller lo, et al. jugular valve function and petrosal sinuses pressure: a computational model applied to sudden sensorineural hearing loss. veins and lymphatics 2017;6:6707. 9. zamboni p, tesio l, galimberti s, et al. efficacy and safety of extracranial vein angioplasty in multiple sclerosis: a randomized clinical trial. jama neurol 2018;75:35-43. 10. zamboni p, menegatti e, occhionorelli s, salvi f, the controversy on chronic cerebrospinal venous insufficiency veins and lymphatics 2013;2:e14. 11. zamboni p, tesio l, galimberti s, et al. efficacy and safety of extracranial vein angioplasty in multiple sclerosis: a randomized clinical trial. jama neurol 2018;75:35-43. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2013; volume 2:e15 [veins and lymphatics 2013; 2:e15] [page 49] an international survey on the interpretation of pigmentation using the c class of the clinical, etiological, anatomical, pathophysiological classification christopher r. lattimer, evi kalodiki, mustapha azzam, george geroulakos josef pflug vascular unit, ealing hospital & imperial college, london, uk abstract skin changes over the gaiter area like pigmentation, lipodermatosclerosis and eczema are a clinical sign of advanced chronic venous disorder. this is documented as c4 in the clinical, etiological, anatomical, pathophysio logical (ceap) classification. the hypothesis was that there is great variability whether skin changes are recorded as early or advanced disease. the aim was to evaluate different patterns of skin changes by delegates at 3 international venous conferences. seven high-definition, a4-sized, color photographs were taken of untreated legs with skin changes from patients attending a public hospital venous clinic. they all had venous disease confirmed on duplex with deep or superficial vein reflux >0.5 s. the photographs were displayed and a questionnaire was provided. delegates familiar with ceap were asked to choose from 3 c class options for each photograph. the responses were summarized by grouping them into mild (c0-3) and severe (c4-6). a total of 117 delegates completed the questionnaire from 30 countries. a percentage of 60 had practiced phlebology >10 years. the percentages of responders scoring mild (c0-3) and severe disease (c4-6) were: mild/severe=3/96 (photo 1), 65/33 (photo 2), 31/67 (photo 3), 56/34 (photo 4), 74/21 (photo 5), 89/10 (photo 6) and 37/59 (photo 7). the median percentage measure of agreement was 36.8 [95% confidence interval (ci): 24.848.9]. the range was 23.2 (95% ci: 10.5-36.0) to 94.8 (95% ci: 90.7-98.9), p<0.001/image, fisher exact test). this indicates a significant difference of opinion between the appearances of mild and severe clinical disease. clinical decisions using the c class as a sign of advanced disease may be unreliable if used alone for recording severity, grouping patients or rationing treatment. introduction the clinical, etiological, anatomical, pathophysiological (ceap) classification for chronic venous disorders (cvd) was set up following an international ad hoc committee.1,2 it was revised in 2004 when it was stated that revision of ceap is an ongoing process and that recommendations for change in the ceap standard be supported by solid research.3 in 2007, a joint statement of the american venous forum and the society of interventional radiology reported that this revision should be included as a baseline patient characteristic prior to endovenous treatments.4 this would facilitate comparison between the results of different studies and improve the overall quality of research on venous disease. the c component is the most widely used part of the ceap classification and it is based solely on clinical appearance. skin changes secondary to cvd are classified as c4 with c4a representing pigmentation or eczema and c4b representing lipodermatosclerosis (lds) or atrophie blanche. in 2004, a questionnaire study without photographs was sent to 3681 phlebologists around the world. they concluded from 206 responders that future work would be required on discriminating between c1 and c2 varicose vein sizes and which c (c1-3) to assign for corona phlebectatica.5,6 discrepan cies on the c placement of varicose veins of differing sizes were also apparent in an interobserver reproducibility study between 3 clinicians on 54 limbs.7 in that study there was disagreement between c0 and c2 or c1 and c2 in 13 legs (24%) but only in 6 legs (11%) between c2 and c4 or c3 and c4. the above studies5-7 suggest that further clarification should focus on the definitions of c0-3 rather than the later stages. furthermore, it has been commented in an international consensus from experts that patients with more advanced venous disease were most reliably classified.8 the hypothesis in this study is that pigmentation is also difficult to classify and that any discrepancy could have greater clinical significance if it spans several points across the 8point c scale. this is because wide variations in the interpretation of skin changes could inappropriately place a leg into a mild (c0-3) or severe (c4-6) category. the aim was to investigate the definition of c4 by asking dedicated phlebologists to use their judgment and experience to classify 7 color photographs of skin changes using the c of ceap. materials and methods study design this was an international observational study involving experienced phlebologists familiar with the ceap classification. the majority of delegates were vascular surgeons/angiologists with an interest in phlebology. there were no responders whose main practice was dermatology. they were asked to complete a short questionnaire in order to grade 7 photographs on the c of ceap. these photographs were displayed on a table, placed at strategic locations, throughout the duration of 3 international venous conferences: the royal society of medicine venous forum (rsmvf), the european venous forum (evf) and the venous section of the world congress of the international union of angiology (iua). participants were either self-selected when they took an interest in the display table or when known specialists, prominent in the venous world, were invited specifically to complete the questionnaire. patients all 7 photographs were from patients with correspondence: christopher r. lattimer, josef pflug vascular laboratory, 7th floor, ealing hospital, uxbridge road, southall, middlesex, ub1 3hw, united kingdom. tel. +44.7960.502253 fax: +44.20.72627681. e-mail: c.lattimer09@imperial.ac.uk key words: ceap classification, chronic venous disorder, hyperpigmentation, skin changes, varicose veins. acknowledgements: we are grateful to the delegates, presenters and faculty at the rsm venous forum, the evf and the iua world congress who classified the photographs for this study. we also acknowledge joseph eliahoo, statistical consultant, statistical advisory service, imperial college, sw7 2az, for his help in the analysis of the data. contributions: cl, conception and design, article drafting; cl, ek, ma, collection of data; cl, je, statistical analysis; cl, ek, ma, gg, analysis and interpretation of data, manuscript final approval; ek, ma, gg, critical revision; gg, overall responsibility. conflict of interests: the authors declare no potential conflict of interests. conference presentation: oral presentation at the xxii meeting of the mediterranean league of angiology and vascular surgery (mlavs), civitavecchia, italy, october 11-13, 2012. received for publication: 16 november 2012. revision received: 21 february 2013. accepted for publication: 10 june 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright c.r. lattimer et al., 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e15 doi:10.4081/vl.2013.e15 no nco mm er cia l assign for corona phlebectatica. no nco mm er cia l assign for corona phlebectatica. cies on the c placement of varicose veins of no nco mm er cia l cies on the c placement of varicose veins ofdiffering sizes were also apparent in an interno nco mm er cia l differing sizes were also apparent in an interobserver reproducibility study between 3 clinino nco mm er cia l observer reproducibility study between 3 clinicians on 54 limbs. no nco mm er cia l cians on 54 limbs.7 no nco mm er cia l 7 in that study there was disno nco mm er cia l in that study there was disagreement between c no nco mm er cia l agreement between c0 no nco mm er cia l 0 and c no nco mm er cia l and c 13 legs (24%) but only in 6 legs (11%) between no nco mm er cia l 13 legs (24%) but only in 6 legs (11%) between and c no nco mm er cia l and c no nco mm er cia l graph. the responses were summarized by groupno nco mm er cia l graph. the responses were summarized by group). a total no nco mm er cia l ). a total of 117 delegates completed the questionnaire no nco mm er cia l of 117 delegates completed the questionnaire from 30 countries. a percentage of 60 had pracno nco mm er cia l from 30 countries. a percentage of 60 had practiced phlebology >10 years. the percentages of no nco mm er cia l ticed phlebology >10 years. the percentages of ) and severe disease no nco mm er cia l ) and severe disease ) were: mild/severe=3/96 (photo 1), 65/33no nco mm er cia l ) were: mild/severe=3/96 (photo 1), 65/33 (photo 2), 31/67 (photo 3), 56/34 (photo 4), 74/21no nco mm er cia l (photo 2), 31/67 (photo 3), 56/34 (photo 4), 74/21 4 no nco mm er cia l 4 or c no nco mm er cia l or c3 no nco mm er cia l 3 and c no nco mm er cia l and c suggest that further clarification should focus no nco mm er cia l suggest that further clarification should focus on the definitions of c no nco mm er cia l on the definitions of c stages. furthermore, it has been commented no nco mm er cia l stages. furthermore, it has been commented in an international consensus from experts no nco mm er cia l in an international consensus from experts that patients with more advanced venous disno nco mm er cia l that patients with more advanced venous disus e ed from 206 responders that future work would us e ed from 206 responders that future work would be required on discriminating between c us e be required on discriminating between c1 us e 1 and us e andvaricose vein sizes and which c (c us e varicose vein sizes and which c (c1-3 us e 1-3) to us e ) to 5,6 us e 5,6 discrepan -us e discrepan cies on the c placement of varicose veins ofus e cies on the c placement of varicose veins of on ly study without photographs was sent to 3681 on ly study without photographs was sent to 3681 phlebologists around the world. they concludon ly phlebologists around the world. they concludon ly contributions: cl, conception and design, article on ly contributions: cl, conception and design, article drafting; cl, ek, ma, collection of data; cl, je, on ly drafting; cl, ek, ma, collection of data; cl, je, statistical analysis; cl, ek, ma, gg, analysis and on lystatistical analysis; cl, ek, ma, gg, analysis andinterpretation of data, manuscript final approval; on lyinterpretation of data, manuscript final approval; ek, ma, gg, critical revision; gg, overall responon ly ek, ma, gg, critical revision; gg, overall responsibility.on ly sibility. conflict of interests: the authors declare no on ly conflict of interests: the authors declare no article [page 50] [veins and lymphatics 2013; 2:e15] leg symptoms who were attending the varicose vein clinic at a single public hospital. patients were referred in the later stages of their disease because uncomplicated varicose veins do not fill the referral criteria under the current public health rationing system. five patients had duplex evidence of reflux in the saphenous trunks greater than 0.5 s9 without evidence of deep venous reflux. two photographs were taken from the same patient (leg elevated and dependant) who had a previous calf vein thrombosis with significant tibial vein reflux. none of the patients had a healed venous ulcer or had received endovenous intervention for their condition. photographs the photographs were high-resolution, taken at close range and printed in color on high-quality photographic a4 print-paper (figures 1-7). dissimilar backgrounds were chosen to avoid direct comparisons between the pictures. each photograph was cropped to highlight the gaiter and ankle areas. the first photograph of lipodermatosclerosis was used as a quality control to determine the standard of the participants at classifying skin changes and to familiarize them with the task. the remaining 6 were selected to highlight controversial areas in the c-class. although they were considered to be representative of venous disease, it is for the reader to decide on the prevalence of these skin changes in their dayto-day practice. all 7 photographs were displayed simultaneously on a table which enabled each participant to pick them up and view each from different angles in order to make their judgment. conferring was not forbidden and occurred occasionally. a copy of the clinical classification of the revision of ceap summary was also placed on the table for information purposes to remind each person of its precise wording as shown below.3 clinical classification (c class) according to ceap classification, c class is divided as follows: c0: no visible or palpable signs of venous disease; c1: telangiectasies or reticular veins; c2: varicose veins; c3: edema; c4a: pigmentation or eczema; c4b: lipodermatosclerosis or atrophie blanche; c5: healed venous ulcer; c6: active venous ulcer. questionnaire design the questionnaire occupied half a page of a4 paper from which participants were asked to check 9 boxes and state their country of practice (figure 8). this restriction on 10 questions/replies was purposeful to prevent lapses of concentration or questionnaire fatigue thereby ensuring data quality with maximal completion.10 participants were given 3 c-class options for each photograph from which to pick their answer. they also had the option of stating an alternative c-class option or checking the don’t know box for whatever reason, including poor quality of photographs. the question on whether a clinical history would influence their judgement was included because it is uncertain whether clinicians should rely on clinical appearance alone or use supplementary information in deciding the c of ceap. this may be relevant because pigmentation could be the result of treatment. discoloration could also be caused by extensive telangectasiae following a deep venous thrombosis (dvt). the clinical history in both of these situations may encourage an enthusiastic c class score of c4a rather than c0 or c1. data analysis data were transferred manually from the questionnaires onto spreadsheets at the end of the study and then imported into the ibm® spss® statistics software version 19 (ibm corp., armonk, ny, usa) for statistical analysis. the results on the c-class determination from the 7 pictures were reported in a similar way to how the c of ceap is used to stratify patients in clinical trials: percentages in each c-class and/or stratification into mild and severe venous disease. similarly, the results were reported in two ways. firstly, specifically, as the percentage of responders choosing each c class (frequency distribution). secondly, generally, as the percentage choosing mild (c03) or severe (c4-6) venous disease (binary outcome). the percentage agreement between mild versus severe disease was determined using the risk difference value of the fisher exact test. full agreement, where all the raters scored either mild or severe, would be represented as 100%, whereas equivalence would be represented as 0% agreement. results participant characteristics a total of 117 delegates completed the questionnaire out of the 120 that were returned. three were excluded because the answers to the 7 picture questions were incomplete. it was interesting that 2 responders ticked multiple boxes for each question in line with the recommendations of the advanced ceap. in this case the single highest descriptor was used for the clinical classification.3 delegates of 30 different nationalities completed this questionnaire, the top 5 being: uk (17), italy (16), usa (10), figure 1. the control image depicting lipodermatosclerosis. survey result: c4 (16%), c4a (39%), c4b (42%). figure 2. corona phlebectatica paraplantaris with an ankle flare. survey result: c1 (16%), c2 (48%), c4a (28%). figure 3. pigmentation over extensive varicose veins. survey result: c1 (0%), c2 (29%), c4a (66%). no nco mm er cia l summary was also placed on the table for inforno nco mm er cia l summary was also placed on the table for information purposes to remind each person of its no nco mm er cia l mation purposes to remind each person of its clinical classification (c class)no nco mm er cia l clinical classification (c class) according to ceap classification, c class isno nco mm er cia l according to ceap classification, c class is corp., armonk, ny, usa) for statistical analyno nco mm er cia l corp., armonk, ny, usa) for statistical analysis. the results on the c-class determination no nco mm er cia l sis. the results on the c-class determinationfrom the 7 pictures were reported in a similar no nco mm er cia l from the 7 pictures were reported in a similar way to how the c of ceap is used to stratify no nco mm er cia l way to how the c of ceap is used to stratify patients in clinical trials: percentages in each no nco mm er cia l patients in clinical trials: percentages in each c-class and/or stratification into mild and no nco mm er cia l c-class and/or stratification into mild and severe venous disease. similarly, the results no nco mm er cia l severe venous disease. similarly, the results were reported in two ways. firstly, specifically, no nco mm er cia l were reported in two ways. firstly, specifically, as the percentage of responders choosing each no nco mm er cia l as the percentage of responders choosing each c class (frequency distribution). secondly, no nco mm er cia l c class (frequency distribution). secondly, generally, as the percentage choosing mild (c no nco mm er cia l generally, as the percentage choosing mild (c 3 no nco mm er cia l 3) or severe (c no nco mm er cia l ) or severe (c come). the percentage agreement between no nco mm er cia l come). the percentage agreement between mild no nco mm er cia l mild using the risk difference value of the fisher no nco mm er cia l using the risk difference value of the fisher us e questionnaires onto spreadsheets at the end of us e questionnaires onto spreadsheets at the end ofthe study and then imported into the ibm us e the study and then imported into the ibm® us e ®statistics software version 19 (ibm us e statistics software version 19 (ibm corp., armonk, ny, usa) for statistical analy-us e corp., armonk, ny, usa) for statistical analysis. the results on the c-class determinationus e sis. the results on the c-class determinationus e o nlyon lyfigure 1. the control image depicting lipoon lyfigure 1. the control image depicting lipo-dermatosclerosis. survey result: c on lydermatosclerosis. survey result: c on ly c on ly c4a on ly 4a (39%), con ly (39%), c4bon ly 4bon ly on ly article [veins and lymphatics 2013; 2:e15] [page 51] czech republic (8) and france (7). this distribution reflected the location of the conferences: london (rsm-vf: 20/117 responders, 17%), florence (evf: 63/117 responders, 54%) and prague (iua: 34/117 responders, 29%). the experience of the delegate was determined by their number of years in phlebology practice which were: less than 2 (6%), between 2 and 10 (31%), between 10 and 30 (43%), over 30 (17%) and failure to answer (3%). of the 27 original members of the ad hoc committee on the revision of the ceap classification,3 12 (44%) were recognized and invited in person into the study. nine members completed the questionnaire and 3 were unable to take part for whatever reason. a further index of experience was provided by the answers to the quality control picture 1 depicting lipodermatosclerosis. a total of 96% of delegates recognized this correctly as c4/c4a/c4b, with 3% as edema (c3) and 1% checking don’t know for whatever reason. c class response stratification the percentage of participants checking each of the three given choices is displayed in the legends underneath each picture for convenience (figures 1-7). pictures 4, 5 and 7 caused the greatest amount of uncertainty with the percentage of participants checking the don’t know box at 10%, 5% and 4%, respectively. the full spectrum is illustrated in table 1. mild and severe response stratification the percentages of participants scoring mild (c0-3) and severe disease (c4-6) for each photograph from 1 to 7 were: mild/severe=3/96 (photo 1), 65/33 (photo 2), 31/67 (photo 3), 56/34 (photo 4), 74/21 (photo 5), 89/10 (photo 6) and 37/59 (photo 7), respectively. apart from the control picture 1 which was classed as severe according to 96% of participants, there was a significant lack of agreement between mild and severe clinical disease for the remaining legs. the percentage agreement (risk difference) of mild versus severe disease is displayed in the last column of table 1. there was clinical uncertainty in classifying picture 2 (figure 2) with 32% of participants choosing advanced disease. however, when the same leg was elevated in picture 6 (figure 6), this was reduced to 10%. importance of a clinical history in response to the influence a clinical history had to judgment of c class (figure 8) the participants chose yes (67%), no (26%), don’t know (3%) with 4% leaving this question unanswered. the fact that two-thirds of participants stated that they would use a history was surprising because the c of ceap was designed to be judged solely from clinical appearance. discussion the ceap classification remains the gold standard classification of cvd. this was confirmed in a recent review article at which they conducted a medline analysis retrieving 266 publications using ceap.11 this review also discussed the limitations of ceap firstly stating that ceap was not a severity classification and then pointed out the controversial areas as c0-3. the current study has demonstrated that the controversial areas can extend into the higher categories of ceap. the reality is that c of ceap is frequently used to group patients into categories and is also used to discriminate patients with mild and severe disease. the c46 group has been discussed as an individual disease.12 the c stratification has been used in epidemiological studies,13 longitudinal studies14 and as a comparator against symptoms and signs,15 quality of life questionnaires16 and hemodynamic assessments.17 many clinical papers stratify patients’ legs into mild/severe or uncomplicated/complicated based on this division between c0-3 and c4-6.18-24 this stratification is also used for rationing treatment in most public hospitals and in cost calculations.25,26 the ceap and venous clinical severity score (vcss) are different tools and do not measure the same items equally. the existence of similar items with different definitions revised or otherwise should be clear in the mind of the assessor to avoid substitution error. for example, c2 uses a definition of >3 mm for a varicose vein whereas the vcss uses a cut-off point of 4 mm.27 furthermore, pigmentation defined by the vcss is more strict than the ceap because focal pigmentation over varicose veins does not qualify, and a focal low intensity (tan) is not considered by the vcss as indicative of significant skin pigmentation.27 eczema is c4a but not a vcss attribute unless it is synonymous with inflammation. the current research demonstrates that there are substantial discrepancies in the clinical classification of cvd using the c of ceap and the distinction between mild and severe venous disease is also unclear. each photograph is commented upon below in order to focus on the controversial areas. picture 1: this is the control photograph which was correctly identified as c4/c4a/c4b by 96% of participants. a plaque of lds is seen in the gaiter region with deeply situated varicose veins above this area. although lds is confirmed by palpation, this was not possible using photographs, a fact probably realized by 16% of participants who decided on choosing c4 alone. nevertheless, the highest percentage score was c4b (42%) indicative of lds. pictures 2 and 6: this is the same leg figure 4. mild pigmentation with eczema at the gaiter region. survey result: c0 (32%), c2 (21%), c4a (34%). figure 5. mild retro-malleolar pigmentation over a normal vein. survey result: c0 (50%), c2 (16%), c4a (21%). figure 6. the same as shown in figure 2 but the leg is now elevated. survey result: c1 (86%), c4a (8%), c5 (2%). no nco mm er cia l (photo 1), 65/33 (photo 2), 31/67 (photo 3), no nco mm er cia l (photo 1), 65/33 (photo 2), 31/67 (photo 3), 56/34 (photo 4), 74/21 (photo 5), 89/10 (photo no nco mm er cia l 56/34 (photo 4), 74/21 (photo 5), 89/10 (photo 6) and 37/59 (photo 7), respectively. apart from no nco mm er cia l 6) and 37/59 (photo 7), respectively. apart from the control picture 1 which was classed as no nco mm er cia l the control picture 1 which was classed as severe according to 96% of participants, there no nco mm er cia l severe according to 96% of participants, there was a significant lack of agreement between no nco mm er cia l was a significant lack of agreement between mild and severe clinical disease for theno nco mm er cia l mild and severe clinical disease for the remaining legs. the percentage agreementno nco mm er cia l remaining legs. the percentage agreement most public hospitals and in cost calculano nco mm er cia l most public hospitals and in cost calcula-the ceap and venous clinical severity score no nco mm er cia l the ceap and venous clinical severity score (vcss) are different tools and do not measure no nco mm er cia l (vcss) are different tools and do not measure the same items equally. the existence of simino nco mm er cia l the same items equally. the existence of similar items with different definitions revised or no nco mm er cia l lar items with different definitions revised or otherwise should be clear in the mind of the no nco mm er cia l otherwise should be clear in the mind of the assessor to avoid substitution error. for examno nco mm er cia l assessor to avoid substitution error. for example, c no nco mm er cia l ple, c2 no nco mm er cia l 2 uses a definition of >3 mm for a varino nco mm er cia l uses a definition of >3 mm for a varicose vein whereas the vcss uses a cut-off no nco mm er cia l cose vein whereas the vcss uses a cut-off point of 4 mm. no nco mm er cia l point of 4 mm. defined by the vcss is more strict than the no nco mm er cia l defined by the vcss is more strict than the ceap because no nco mm er cia l ceap because us e papers stratify patients’ legs into mild/severe us e papers stratify patients’ legs into mild/severe or uncomplicated/complicated based on this us e or uncomplicated/complicated based on thisthis stratifius e this stratification is also used for rationing treatment inus e cation is also used for rationing treatment in most public hospitals and in cost calcula-us e most public hospitals and in cost calculaon ly many clinical on ly many clinical on lyfigure 4. mild pigmentation with eczema on lyfigure 4. mild pigmentation with eczemaat the gaiter region. survey result: c on lyat the gaiter region. survey result: c on ly (32%), c on ly (32%), c2on ly 2on ly on ly article [page 52] [veins and lymphatics 2013; 2:e15] dependent (figure 2) and elevated (figure 6) in a patient who has deep venous reflux in the calf veins following a dvt. the dependent ankle is discolored with a venous flare/corona phlebectatica and small varicose veins but on elevation pigmentation is not present which confirms the c1-2 status of this leg. the dependent leg was reported as c4a by 28% of participants but this reduced to 8% after elevation. elevation was used here to discriminate apparent pigmentation from venous congestion against true pigmentation from extravasation. although corona phlebectatica is currently c1 there are recommendations by many phlebologists to consider it as c3.6 the lack of a marker scale prohibits the sizing of varicose veins. this may be necessary for establishing if they are >3 mm in diameter, in which case they would belong to c2. however, skin thickness and depth of vein should also be taken into consideration. for example it would be difficult to compare vein size in figure 1 with those in figure 2. picture 3: obvious mid-calf pigmentation over extensive varicose veins was reported by only 66% of participants using c4a in comparison to the 29% who reported c2. this may be because pigmentation in ceap is defined as brownish darkening of the skin and occurs in the ankle region but may extend to leg and foot.3 should pigmentation arising de novo over a mid-calf varicose vein without having extended from the ankle be classed as c4a? these factors may explain the reluctance of choosing c4a as an option. pictures 4 and 5: these legs demonstrate mild (figure 4) and very mild (figure 5) degrees of pigmentation with eczema. this is reflected in the percentage of participants choosing c0 at 32% and 50%, respectively. once again, it has been left for the observer to decide on what constitutes brownish darkening and how much eczema is significant to qualify as c4a. both patients also had a normal looking vein present beneath the medial malleolus which may have prompted the choice of c2 at 21% and 16%, respectively. picture 7: many patients have different baseline skin colors which may cause additional problems in defining increased pigmentation rather than basing a judgment on its presence or absence. this has been highlighted in this picture of gaiter telangectasiae where 56% of participants classified the accompanying hyperpigmentation as c4a. in cases of doubt there are two additional ways to evaluate pigmentation. the first is to make a comparison with the normal other side because this will indicate the natural color of the skin. the second is to elevate the leg to confirm a real pigmentation that does not disappear. a published limitation of ceap is that the patient’s venous history is not taken into account.28 the c class according to the current definition is about clinical appearance, not medical history. it is clear from the current study that 67% of participants would use a clinical history in making their judgment on c. this supports the rationale of this study because the c of ceap is nothing more than clinical appearance and was not intended to co-ordinate historical features. however, in everyday practice the judgment of a c class cannot be devoid of a clinical history. pigmentation in the gaiter region may have other etiological factors like post-inflammatory hyperpigmentation occurring after trauma or a skin infection. similarly, eczema may be caused by an allergic reaction or an insect bite rather than venous insufficiency. a c2 classification assessed by a doctor in the morning may become a c3 in the evening. these may only become apparent from the clinical history. furthermore, the presence of minor reflux within a small caliber vein may not be enough to cause pigmentation. it would be interesting if a group of dermatologists were asked to complete the survey since they have a focused interest in pigmentation disorders. the pictures represent legs seen in common practice, which are difficult to classify because of lack of agreement using the c class. improvements in c stratification could be figure 7. telangectasiae and reticular veins with infra-malleolar pigmentation. survey result: c1 (21%), c2 (15%), c4a (56%). figure 8. the questionnaire which delegates were asked to complete. picture 1 is figure 1 and likewise for the remaining 6 illustrations. table 1. percentage of c classes chosen by 117 participants for each picture. the 3 given choices are highlighted in italics. risk difference represents agreement, from no agreement (0%) to full agreement (100%). picture c0 c1 c2 c3 c4 c4a c4b c5 don’t know mild/severe* p value° risk difference % (ci: 95%) 1 2 16 39 42 1 3/113 <0.0005 94.8 (90.7-98.9) 2 16 48 1 28 2 2 3 76/38 <0.0005 33.3 (21.1-45.6) 3 0 29 1 66 1 3 36/78 <0.0005 36.8 (24.8-48.9) 4 32 21 3 34 10 65/40 0.0009 23.8 (10.7-36.9) 5 50 4 16 4 21 5 87/24 <0.0005 56.8 (45.9-67.6) 6 86 1 1 8 2 1 104/12 <0.0005 79.3 (71.5-87.2) 7 21 15 1 56 3 4 43/69 0.0008 23.2 (10.5-36.0) *ratio in absolute numbers of c0-3/c4-5; °fisher exact test. ci, confidence interval. no nco mm er cia l marker scale prohibits the sizing of varicose no nco mm er cia l marker scale prohibits the sizing of varicoseveins. this may be necessary for establishing no nco mm er cia l veins. this may be necessary for establishing if they are >3 mm in diameter, in which case no nco mm er cia l if they are >3 mm in diameter, in which case they would belong to c no nco mm er cia l they would belong to c2 no nco mm er cia l 2. however, skin thickno nco mm er cia l . however, skin thickness and depth of vein should also be taken no nco mm er cia l ness and depth of vein should also be taken into consideration. for example it would be difno nco mm er cia l into consideration. for example it would be difficult to compare vein size in figure 1 with no nco mm er cia l ficult to compare vein size in figure 1 with those in figure 2. no nco mm er cia l those in figure 2. picture 3: no nco mm er cia l picture 3: obvious mid-calf pigmentation no nco mm er cia l obvious mid-calf pigmentation over extensive varicose veins was reported by no nco mm er cia l over extensive varicose veins was reported by only 66% of participants using c no nco mm er cia l only 66% of participants using c son to the 29% who reported c no nco mm er cia l son to the 29% who reported c because pigmentation in ceap is defined as no nco mm er cia l because pigmentation in ceap is defined as brownish darkening of the skin no nco mm er cia l brownish darkening of the skin no nco mm er cia l figure 7. telangectasiae and reticular veins no nco mm er cia l figure 7. telangectasiae and reticular veins with infra-malleolar pigmentation. survey no nco mm er cia l with infra-malleolar pigmentation. survey no nco mm er cia l (56%). no nco mm er cia l (56%). us e the lack of aus e the lack of a marker scale prohibits the sizing of varicoseus e marker scale prohibits the sizing of varicoseus e o nly 36/78 <0.0005 36.8 (24.8-48.9) on ly 36/78 <0.0005 36.8 (24.8-48.9) on ly on ly10 65/40 0.0009 23.8 (10.7-36.9) on ly10 65/40 0.0009 23.8 (10.7-36.9)87/24 <0.0005 56.8 (45.9-67.6) on ly87/24 <0.0005 56.8 (45.9-67.6) on ly on ly 1 104/12 <0.0005 79.3 (71.5-87.2)on ly 1 104/12 <0.0005 79.3 (71.5-87.2)on ly on ly 43/69 0.0008 23.2 (10.5-36.0)on ly 43/69 0.0008 23.2 (10.5-36.0) article [veins and lymphatics 2013; 2:e15] [page 53] made by defining the controversial areas as this work has demonstrated. a consensus statement from a panel of experts using published photographs may improve the reliability and agreement of ceap. limitations this is an observational study where patients with an indeterminate c class were selected deliberately because they would invoke disagreement between different participants. however, the objective of this study was to highlight controversial areas because recognition of a limitation is an essential step prior to an improvement. although all the patients were photographed within the same week the true prevalence of their leg appearances and the extent to which these patients are representative of a diseased venous cohort should be determined by the readers’ individual clinical practice. however, patients attend the clinic because of their varicose veins rather than hyperpigmentation per se. a further limitation is that photographs are not patients. differences in lighting, background and angles are known to have profound effects on the interpretation of varicose veins. the quality of the photographs appears poor from a professional viewpoint, and this is a factor which may have caused difficulties in participant’s choice. however, an a4 photograph at high resolution is much better than its on screen image. each participant had the option to check the don’t know box, for whatever reason, but this rarely happened. care was taken to ensure that each photograph accurately represented the clinical features of each patient. this may have advantages over questionnaire studies which use descriptors without photographs5 and disadvantages in comparison to studies where patients are examined in a clinical setting.7 however, the use of photographs outside a clinical setting may be beneficial because it standardizes the available information from which judgments are made. clinicians are therefore less likely to have their judgments on the c of ceap influenced by the patients’ medical records, symptoms or duplex findings. conclusions clinical trials using the c class as a means of stratifying legs into mild and severe clinical disease should be interpreted with caution because of the difficulties in weighting the importance of pigmentation based solely on appearance. this information is of value in clinical situations where the c of ceap may be used to ration treatment and in research situations were it is often used as a benchmark or comparator for hemodynamic and quality-oflife validations. the results of this work have also indicated that the c of ceap may be improved by using the same rater throughout clinical studies, unifying the ceap definitions with those of the vcss and by using leg elevation to discriminate between telangectasiae and pigmentation. this work also confirms that the c class should not be used as a severity classification. references 1. porter jm, moneta gl. reporting standards in venous disease: an update. international consensus committee on chronic venous disease. j vasc surg 1995;21:635-45. 2. beebe hg, bergan jj, bergqvist d, et al. classification and grading of chronic venous disease in the lower limbs. a consensus statement. eur j vasc endovasc surg 1996;12:487-91; discussion 91-2. 3. eklof b, rutherford rb, bergan jj, et al. revision of the ceap classification for chronic venous disorders: consensus statement. j vasc surg 2004;40:1248-52. 4. kundu s, lurie f, millward sf, et al. recommended reporting standards for endovenous ablation for the treatment of venous insufficiency: joint statement of the american venous forum and the society of interventional radiology. j vasc surg 2007;46:582-9. 5. antignani pl, cornu-thenard a, allegra c, et al. results of a questionnaire regarding improvement of ‘c’ in the ceap classification. eur j vasc endovasc surg 2004;28: 177-81. 6. uhl jf, cornu-thenard a, carpentier ph, et al. clinical and hemodynamic significance of corona phlebectatica in chronic venous disorders. j vasc surg 2005;42: 1163-8. 7. uhl j-f, cornu-thenard a, carpentier ph, et al. reproducibility of the “c” classes of the ceap classification. j phlebol 2001;1: 39-43. 8. allegra c, antignani pl, bergan jj, et al. the “c” of ceap: suggested definitions and refinements: an international union of phlebology conference of experts. j vasc surg 2003;37:129-31. 9. van bemmelen ps, bedford g, beach k, strandness de. quantitative segmental evaluation of venous valvular reflux with duplex ultrasound scanning. j vasc surg 1989;10:425-31. 10. rathod s, labruna a. questionnaire length and fatigue. esomar panel research conference, budapest, 2005. available from: http://www.esomar. org/web/research_papers/web-panel_ 1092_questionnaire-length-and-fatigue. php accessed: 12 july 2012. 11. rabe e, pannier f. clinical, aetiological, anatomical and pathological classification (ceap): gold standard and limits. phlebology 2012;27:114-8. 12. bradbury aw. epidemiology and aetiology of c4-6 disease. phlebology 2010;25:2-8. 13. maurins u, hoffmann bh, losch c, et al. distribution and prevalence of reflux in the superficial and deep venous system in the general population—results from the bonn vein study, germany. j vasc surg 2008;48:680-7. 14. stucker m, reich s, robak-pawelczyk b, et al. changes in venous refilling time from childhood to adulthood in subjects with apparently normal veins. j vasc surg 2005;41:296-302. 15. chiesa r, marone em, limoni c, et al. chronic venous disorders: correlation between visible signs, symptoms, and presence of functional disease. j vasc surg 2007;46:322-30. 16. shepherd ac, gohel ms, lim cs, davies ah. a study to compare disease-specific quality of life with clinical anatomical and hemodynamic assessments in patients with varicose veins. j vasc surg 2011;53: 374-82. 17. lattimer cr, azzam m, kalodiki e, et al. saphenous pulsation on duplex may be a marker of severe chronic superficial venous insufficiency. j vasc surg 2012;56:1338-43. 18. o’hare jl, parkin d, vandenbroeck cp, earnshaw jj. mid term results of ultrasound guided foam sclerotherapy for complicated and uncomplicated varicose veins. eur j vasc endovasc surg 2008;36:109-13. 19. rasmussen lh, lawaetz m, bjoern l, et al. randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins. br j surg 2011;98:1079-87. 20. darvall ka, sam rc, bate gr, et al. changes in health-related quality of life after ultrasound-guided foam sclerotherapy for great and small saphenous varicose veins. j vasc surg 2010;51:913-20. 21. neglen p, egger jf, olivier j, raju s. hemodynamic and clinical impact of ultrasound-derived venous reflux parameters. j vasc surg 2004;40:303-10. 22. yamaki t, nozaki m, fujiwara o, yoshida e. comparative evaluation of duplexderived parameters in patients with chronic venous insufficiency: correlation with clinical manifestations. j am coll surg 2002;195:822-30. 23. lattimer cr, kalodiki e, azzam m, geroulakos g. reflux time estimation on air-plethysmography may stratify patients no nco mm er cia l tionnaire studies which use descriptors withno nco mm er cia l tionnaire studies which use descriptors withand disadvantages in comno nco mm er cia l and disadvantages in comparison to studies where patients are examno nco mm er cia l parison to studies where patients are examhowever, the use of no nco mm er cia l however, the use of photographs outside a clinical setting may be no nco mm er cia l photographs outside a clinical setting may be beneficial because it standardizes the availno nco mm er cia l beneficial because it standardizes the available information from which judgments areno nco mm er cia l able information from which judgments are made. clinicians are therefore less likely tono nco mm er cia l made. clinicians are therefore less likely to 4. kundu s, lurie f, millward sf, et al. no nco mm er cia l 4. kundu s, lurie f, millward sf, et al.recommended reporting standards for no nco mm er cia l recommended reporting standards for endovenous ablation for the treatment of no nco mm er cia l endovenous ablation for the treatment of venous insufficiency: joint statement of no nco mm er cia l venous insufficiency: joint statement of the american venous forum and the no nco mm er cia l the american venous forum and the society of interventional radiology. j vasc no nco mm er cia l society of interventional radiology. j vasc surg 2007;46:582-9. no nco mm er cia l surg 2007;46:582-9. 5. antignani pl, cornu-thenard a, allegra c, no nco mm er cia l 5. antignani pl, cornu-thenard a, allegra c, et al. results of a questionnaire regarding no nco mm er cia l et al. results of a questionnaire regarding improvement of ‘c’ in the ceap classificano nco mm er cia l improvement of ‘c’ in the ceap classification. eur j vasc endovasc surg 2004;28: no nco mm er cia l tion. eur j vasc endovasc surg 2004;28: us e 3. eklof b, rutherford rb, bergan jj, et al. us e 3. eklof b, rutherford rb, bergan jj, et al.revision of the ceap classification for us e revision of the ceap classification forchronic venous disorders: consensus us e chronic venous disorders: consensus statement. j vasc surg 2004;40:1248-52.us e statement. j vasc surg 2004;40:1248-52. 4. kundu s, lurie f, millward sf, et al.us e 4. kundu s, lurie f, millward sf, et al. on ly 15. chiesa r, marone em, limoni c, et al. on ly 15. chiesa r, marone em, limoni c, et al. chronic venous disorders: correlation on lychronic venous disorders: correlationbetween visible signs, symptoms, and on lybetween visible signs, symptoms, andpresence of functional disease. j vasc on lypresence of functional disease. j vasc surg 2007;46:322-30.on ly surg 2007;46:322-30. 16. shepherd ac, gohel ms, lim cs, davieson ly 16. shepherd ac, gohel ms, lim cs, davies article [page 54] [veins and lymphatics 2013; 2:e15] with early superficial venous insufficiency. phlebology 2013;28:101-8. 24. navarro tp, delis kt, ribeiro ap. clinical and hemodynamic significance of the greater saphenous vein diameter in chronic venous insufficiency. arch surg 2002; 137:1233-7. 25. lattimer cr, kalodiki e, azzam m, geroulakos g. the aberdeen varicose vein questionnaire may be the preferred method of rationing patients for varicose vein surgery. angiology 2013. [epub ahead of print]. 26. ratcliffe j, brazier je, campbell wb, et al. cost-effectiveness analysis of surgery versus conservative treatment for uncomplicated varicose veins in a randomized clinical trial. br j surg 2006;93:182-6. 27. rutherford rb, padberg ft jr, comerota aj, et al. venous severity scoring: an adjunct to venous outcome assessment. j vasc surg 2000;31:1307-12. 28. cornu-thenard a, uhl jf, carpentier ph. do we need a better classification than ceap? acta chir belg 2004;104:276-82. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2019; volume 8:7789 [page 10] [veins and lymphatics 2019; 8:7789] minimally-invasive procedure for pelvic leak points in women roberto delfrate, massimo bricchi, claude franceschi surgical unit, figlie di san camillo hospital, cremona, italy abstract pelvic leak points (plp) may be responsible for vulvar, perineal and lower limb varicose veins, in women during and/or after pregnancy. the accurate anatomical and hemodynamic assessment of these points, the perineal (pp), inguinal (ip) and clitoral points (cp) and their surgical treatment under local anesthetics as defined by claude franceschi is a new therapeutic option. the aim of this study was to assess the reliability and durability of the plp reflux ablation using a minimally-invasive surgical disconnection at the plp level in women with varicose veins of the lower limbs fed by the plp. in this open-label trial 273 pelvic leak points free of pelvic congestion syndrome, with at least a 12-month follow-up, were assessed. 273 plp treated: pp (n=177), ip (n =91) and cp (n=5). followup: period =12 to 92 months (mean =30.51 months). age from 29 to 77 years (mean=45). the only 3 patients over 70 years (71, 74, 77) showed a high-speed reflux from a i point that fed symptomatic varicose veins of the lower limb. exclusion criteria: pelvic congestion syndrome, bmi>24, venous malformations, a post thrombotic varicose vein. diagnosis was performed using echo duplex and plps selected for treatment when refluxing at valsalva + paraná + squeezing maneuvers. a surgical skin marking of the plp had been performed using echo duplex before surgery. surgery consisted of minimally invasive dissection and selective division and ligation with non-absorbable suture of the refluxing veins and fascias at the pp, ip and cp pelvic escape points, under local anesthesia in a single center. the follow-up consisted of an echo duplex ultrasound, searching for reflux at the plp treated thanks to the valsalva maneuver, within 2 weeks, after 6 and 12 months and then yearly. the main endpoint of the study was the immediate elimination of the reflux at the plp treated. the second endpoint was the long-term durability of the reflux ablation at the plp treated. 267 (97.8%) without plp reflux redo. 6 (2.2%) plp reflux recurrences (pp=4, ip=1, cp 1). 3 patients with plp reflux recurrence undergo a redo surgery (1.1%) where pp=2 (0.7%) and ip=1 (0.3%). this study shows the feasibility and durability of reflux ablation at the plp level thanks to a minimally-invasive surgical treatment of the plp and it demonstrates that there is no need for pelvic varicose embolization in patients without clinical signs of pelvic congestion syndrome. the accurate ultrasound assessment of each specific pelvic leak as well as a special surgical technique (vein division, non-absorbable suture of veins and fascias) seems to be the key for satisfactory outcomes. introduction pelvic leak points (plp) reflux may be responsible for vulvar and/or lower limb varicose veins, as defined by claude franceschi.1-5 plp treatment represents 8.3% of all the chiva treatment we performed. according to the chiva strategy the treatment of all the escape points is mandatory, and possible through a minimally-invasive surgical treatment as an alternative to parietal sclerotherapy and pelvic veins embolization. several studies6-9 based on various assessments (clinical, ultrasound, venography) consider around 10% of pelvic leaks in women with varicose veins. it has been reported in literature that the number pelvic leaks in multiparous are 4 times more frequent than in nulliparous.7 particularly the recurrences after stripping were related to pelvic venous reflux and evaluated as 17% but not specifically anatomically defined and not specifically treated.10,11 beside the obturatory and gluteal refluxes, claude franceschi, thanks to duplex ultrasound scan (dus), detected three different main pelvic leak points (plp) responsible for varicose veins of the lower limbs in mono and multiparous women.1-5 these plp are called perineal points (pp), inguinal points (ip) and clitoral points (cp) as represented in figure 1a. a perineal point (pp) is the superficial perineal vulvar fascia hole crossed by the perineal vein that collects the posterior labial vein, then connects to the internal pudendal vein. the perineal vein drains the skin of the perineum, then receives the posterior labial veins and passes through the superficial aponeurosis of the perineum (fascia perinalis) by way of an orifice that we call pp.12-14 after crossing the pp, the vein ascends with bulbar and cavernous veins to the pudenal vein in the alcock’s canal. in case of leakage, reflux follows the same pathway in the opposite direction. reflux can not only cause dilatation of the labial and perineal veins but also extend to the ipsilateral saphenous network through either perineal-to-labial and perineal-to-external pudendal vein anastomoses or through any other incompetent vein in between. it can also feed a contralateral varicosity through labiolabial and perineoperineal anastomoses. reflux in the medial pudendal vein is itself fed either actively or potentially by any constitutionally incontinent ipsilateral and contralateral upstream genital, visceral iliac, and ovarian vein and by the inferior vena cava. an inguinal point (ip) is the superficial inguinal annulus crossed by the mons veneris veins that connects to the uterine round ligament vein. reflux of the round ligament vein of the uterus can feed vulvar (labial) and perineal varicose veins and lower extremity varicose veins via residual branches of the nuck’s canal that reflux directly or indirectly to the subcutaneous abdominal, external pudendal, superficial dorsal of the clitoris, and labial veins, then possibly toward varices in the saphenous network. once again, reflux in the round ligament vein is itself fed either actively or potentially by any constitutionally incontinent ipsilateral and contralateral upstream genital, visceral, iliac, or ovarian vein and by the inferior vena cava. a cp is the anastomotic plexus between the bulbar vein and superficial dorsal clitoris that connects to the medial pudendal vein.15 reflux can feed ipsilateral or contralateral perinal and anterior labial veins and or the lateral pudendal then the gsv (figure 1b). as the plp reflux is usually fed by hypogastric tributaries and/or ovarian incompetent veins, and the plp reflux occurs as a result of recurrence after conventional stripping, some authors suggest embolization of these veins as a first step treatment of peripheral varicose veins of the lower limbs.16,17 in this correspondence: roberto delfrate, surgical unit, figlie di san camillo hospital, via fabio filzi 56, 26100 cremona, italy. e-mail: roberto.delfrate@icloud.com key words: pelvic leak points; inguinal point; perineal point; clitoral point. received for publication: 28 august 2018. revision received: 28 january 2019. accepted for publication: 30 january 2019. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright r. delfrate et al., 2019 licensee pagepress, italy veins and lymphatics 2019; 8:7789 doi:10.4081/vl.2019.7789 no nco mm er cia l u se on ly article study, the first step in treatment was surgical ablation of the plp reflux in patients free of pelvic congestion. plps represent the escape point of the shunts type 4 and 5, according to the teupitz chiva classification.18 these types of shunts are characterized by an escape point external to a saphenous axis with a direct re-entry point located on a saphenous axis in the type 4, and indirect re-entry point in type 5. materials and methods study design in this open-label trial a group of 273 plps treated with at least a 1-year followup were evaluated: pp (n=177), ip (n=91) and cp (n=5). the follow up period varied from 12 to 92 months (mean=30.51 months). age ranged from 29 to 77 years (mean=45). the group included 3 patients over 70 years (71, 74, 77) as they showed a high-speed reflux from a i point that fed symptomatic varicose veins (ceap 4) of the lower limb. ceap classification 2-4: visible varicose veins, or painful varicose veins, itch, oedema, skin pigmentation. the exclusion criteria were the evidence of a pelvic congestion syndrome, bmi>24; furthermore, all patients with congenital varicose veins due to venous malformations, varicose veins secondary to prior deep vein thrombosis, associated systemic pathologies, those who refused surgical treatment, who could not participate in long-term follow-up or had given birth less than 9 months previously were excluded from the study. a written informed consent was provided to all the patients. the study was conducted by the same surgical team who performed ultrasound diagnosis, mapping and pre-operatory marking as well as the procedures. the diagnosis was assessed with duplex ultrasound scan (dus) by the surgeons thanks to a 10-18 mhz linear probe. the prf was set between 0.75 and 1 khz, capable of detecting even low-speed reflux from 0.05 to 0.10 m/s. aim of the study this study aimed to assess the immediate elimination and the long term persistence of pelvic reflux ablation at the plp treated with a minimally invasive surgical operation under local anesthesia, in uniparous or multiparous women, free of pelvic congestion syndrome (chronic pelvic pain and continuous reflux at the plp level without any breath modulation, in standing and supine position), regardless of the degree and configuration of the varicosities. the plp reflux was partly (existence of other escape points) or totally responsible for lower limbs varicose veins. plp diagnosis and description clinical data allow diagnosis of vulvar and perineal varices but cannot determine the leak point, since leakage from i, p or c points lead to the same clinical manifestations. a full color duplex scan allows precise identification of i, p and c points. the specific criteria of reflux at the plp was a valsalva descending flow provoked by having the women blow into a blocked straw while standing.19 conversely, the diastolic figure 1. a) frontal view of the pelvis passing through the perineal and inguinal leak points (points pp, cp and ip). note the number of anastomoses. lov (left ovarian vein); rov (right ovarian vein); icv (iliac common vein); iv (internal iliac vein); eiv (external iliac vein); the white lines represented the internal pudendal veins feeding the cp (clitoral points) and the pp (perinea); gsv great saphenous vein; ip inguinal point, with the venous plexus of the round ligament passing through the superficial ring of the inguinal canal; ov (obturator veins) feeding the medial muscular circumflex vein; igv inferior gluteal veins an veins of the sciatic nerves snv; b) perineal view showing the perineal and inguinal leak points (points p and i). note the number of anastomoses (a). 1, internal pudendal vein; 2, perineal vein; 3, vena rectalis inferior (inferior rectal vein); 4, vena bulbi vestibuli et clitoridi (vein of bulb of vestibule and clitoris); 5, vena pudenda externa (external pudendal vein); 6, ligamentum teres uteri vena (round ligament vein of the uterus); 7, vena saphena magna (great saphenous vein); 8, gluteal vein; 9, sciatic vein; 10, obturator vein; 11, vena femoralis (femoral vein). [veins and lymphatics 2019; 8:7789] [page 11] no nco mm er cia l u se on ly article flow at the descending tributaries of the great saphenous veins (gsv) arch evoked by calf squeezing or paraná maneuver is not specific and may be present in the absence of refluxing plp, so it is a source of false positives. continuous reflux at rest (without any dynamic maneuver) may be due to a collateral compensatory draining flow caused by a downstream obstacle and thus prohibits any disconnection. the patient’s evaluation was completed by an exhaustive ecd in order to achieve a complete hemodynamic mapping of the venous insufficiency. with the patient in a standing position, ip can be located approximately 1 to 3 cm above the femoral vein and just medially to the epigastric veins and cp medially to the sfj towards the clitoris. the reflux is seen outwards throughout the inguinal canal (figure 2). pp is generally located at the junction of the posterior fourth and anterior three-fourths of the labia majora. it can be detected if the patient is in a standing position with her foot resting on a platform 20 cm high or in a lithotomy position for a transperineal ultrasound (not intravaginal because the probe imaging would be too deep compared to the superficial pp). the reflux activated by valsalva maneuver induces backflow from the alcock’s canal to the perineal and labial veins (figure 3). the alcock’s canal is located medially to and just above the ischiopubic branch. interventions the patients were ambulatory. the same surgeon performed the marking and intervention. the anesthesia was local: less than 3 ml of a mixture of lidocaine (2%) and ropivacaine (7.5 mg/dl). incision according to skin marking: from 10 to 14 mm (figures 4 and 5). effective treatment of lower extremity superficial venous reflux of pelvic origin can only be achieved by ligation of the leak points in the same way as is necessary to ligate a refluxing perforating vein or junction. proximal or distal ligation without ligation at pp and/or ip level will be followed by recurrence due to collateral flow. the perineal and inguinal leak points (points p and i) act as perforating veins (figure 6). remote disconnection (b, c) invariably fails either immediately or secondarily because of the presence of many branches and anastomoses (figure 7). perineal and genito-crural nerves were preserved respectively at the pp and ip. division and stump ligation of the refluxing vein with non-absorbable braided coated suture and additional polypropylene 6 zero monofilament transfixed suture for the pp, and 4 zero for the ip. furthermore, the stump of round ligament was positioned and overturned inside the inguinal canal, figure 2. a) the venous plexus of the round ligament in the inguinal canal, its relationship with the inferior epigastric vessels, the subcutaneous ring (red dashed line) is the ip through which a pelvic reflux is transmitted during valsalva to the lower limbs. the external oblique muscle fascia is the hyperechoic line above the plexus (blue dashed line), while the hyperechoic line corresponding to the trasversalis fascia is clearly visible below it (yellow dashed lines); b) valsalva maneuver. clearly detectable reflux from the deep pelvic plexuses towards the surface through the inguinal canal and its superficial ring; c) left ip dissection. the venous plexus of the round ligament on a white vessel loop. the genitocrural nerve on a blue vessel loop. [page 12] [veins and lymphatics 2019; 8:7789] no nco mm er cia l u se on ly article [veins and lymphatics 2019; 8:7789] [page 13] sutured with a polypropylene stitch to the fascia of the oblique external muscle. the fascia hole of the posterior labial vein was also closed with a n° six zero polypropylene suture. this procedure was associated at the same time or later with additional shunt disconnections and gravitational hydrostatic pressure segmentation tailored to each specific hemodynamic configuration according to the chiva strategy.20-23 a washing with a rifampicin solution had been done in every surgical procedure, without any systemic antibiotic therapy. all patients were discharged 2-3 hours after surgery. all patients wore elastic stockings for 4 weeks, and took enoxaparin 4000 iu for 1 to 2 weeks, according to the distal correction performed in the lower limbs. we recommended the use of paracetamol (1 g tablet) if they were having pain. all patients were assessed 2 weeks after surgery, after 6 and 12 months, and then yearly. the efficacy of the intervention was evaluated checking the doppler response provoked by the valsalva maneuver at the treated plp. reflux was considered a failure; no reflux was considered a success. results of the 273 plp treated 267 (97.8%) did not show any plp reflux redo. a plp reflux recurrence was detected in 6 (2.2%) plp reflux (pp=4, ip=1, cp 1). 3 patients with plp reflux recurrence undergo a redo surgery (1.1%) where pp=2 (0.7%) and ip=1 (0.3%). in the remaining 3 patients with reflux redo sclerotherapy was proposed. no deep vein thrombosis, pulmonary thromboembolism, or death occurred. considering possible surgical complications, no bruises, subcutaneous inguinal or perineal hemorrhage, saphenous nerve neuralgia, wound infection or superficial phlebitis occurred; there was only one inguinal bleeding that needed an immediate surgical exploration of the inguinal canal and hemostasis thanks to a vessel legation: after this clinical case the ligation technique has been modified and currently we do a double ligation with a non-absorbable braided coated suture and a transfixed polypropylene suture of the stump. discussion thanks to claude franceschi’s diagnostic experience with echo color doppler ultrasound, it was possible to highlight anatomical parietal points of passage of refluxes from the veins of the pelvis to the figure 3. valsalva reflux from the left perineal point (posterior labial vein). the vulvar tissue is the black dishomogeneous part in the lower half of the picture. the white dashed line represent the position of the labia minora frenulum. figure 4. minimally invasive surgical access to the fascia hole of the posterior labial vein. no nco mm er cia l u se on ly article lower limbs. the experience in the anatomical exploration with ultrasounds, supported by the re-evaluation of the knowledge of human anatomy, has allowed us to propose a minimally invasive therapeutic approach, under local anesthesia, of the pelvic refluxes that feed varicose veins of the lower limbs based on the disconnection of venous collectors in well-defined anatomical areas, constant and easy to access surgically, but not perfectly known by both radiologists and vascular or general surgeons. this minimally invasive therapeutic strategy consists of three different phases: diagnosis, preoperative marking and surgical treatment. the diagnostic phase allows the creation of precise hemodynamic maps in order to detect the escape points, escape routes and reentry points of each shunt. the preoperative skin marking, besides allowing a check of the accuracy of cartography, identifies the exact site of the surgical access and allows a pre-operative visual assessment thanks to the ultrasounds, useful for the surgical dissection, and finally the surgical implementation of the disconnections at the level of the pelvic escape points. in the absence of pelvic congestion syndrome the interruption of the reflux from the pelvis to the lower limbs is without negative consequences on pelvic drainage, which will continue to occur regularly as in the physiological conditions according to the pressure gradient existing with the right atrium. the primary objective of this study was to verify the elimination of reflux at the level of the treated pelvic escape points and the secondary objective was to verify the stability of the result over time. it should be noted that there were almost no complications in the procedures performed, except for the only complicative event detected of postoperative bleeding during the correction of a groin point, which was followed by a modification of the technique of ligation of the stumps of the venous plexus of the round ligament aimed at making the section and ligation very reliable. unlike our experience in the surgical treatment of pelvic escape points, the endovascular method is burdened with well-known complications. these are mechanical complications, the consequence of puncturing a central vein (haematomas, pneumothorax, arthymia, gas embolism, arterial puncture), and other adverse events typical of the method, for instance the migration of coils, or in case of use of other agents such as mousse or glue, injections, the migration even in districts other than the desired one. another point to be clarified about endovascular procedures is the possible effect on fertility reported in the literature although not confirmed in the experifigure 5. comparison between the skin incision and the skin mark of the fascia hole of the posterior labial vein. figure 6. the posterior labial vein crossing the vulvar fascia hole to reach the vulvar venous plexuses. [page 14] [veins and lymphatics 2019; 8:7789] no nco mm er cia l u se on ly article ence of some authors. this study shows that echo-guided minimally-invasive surgery of pelvic leaks responsible for vulvar and/or lower limbs varicose veins is reliable and durable. this study suggests that pelvic varicose embolization prior plp reflux ablation is not necessary and indicated only in case of resistant plp reflux or when plp is associated with pelvic congestion syndrome, according to others.24 on the other hand, prior pelvic vein embolization leaves behind a plp reflux, even if reduced, which needs complementary superficial treatment.25 sclerosing agents and foam are also used to treat the plp by injecting the extra pelvic veins. no long-term study has been published so far.26-30 this study does not report the additional chiva disconnections nor their specific outcomes because they do not determine the persistence of the plp treatment. the low rate of failures may be due to the surgical technique: vein division-ligation and fascia/superficial inguinal channel suture with no absorbable monofilament suture, which is supposed to avoid both collateral reflux and neoangiogenesis (inflammatory reaction to absorbable suture), as well as the accurate ultrasound detection of the leaking points that allows for a very minimally invasive operation. in order to reduce possible mistake in case of pp treatment an accurate dus control of the skin marking is necessary in the operative theatre with the patients in lithotomy position. conclusions this study shows that echo-guided minimally-invasive surgery of pelvic leaks responsible for vulvar and/or lower limbs varicose veins is reliable and durable. this study also suggests that pelvic varicose embolization prior to plp reflux ablation is not necessary. the accurate ultrasound assessment of each specific pelvic leak as well as a special minimally invasive surgical technique (ambulatory patient, local anesthesia, non-absorbable suture of vein stumps and fascias, low surgical risk and low percentage of complications) seems to be the key to satisfactory outcomes. references 1. franceschi c, bahnini a. points de fuite pelviens viscéraux et varices des membres inférieurs. phlébologie 2004; 57:37-42. 2. franceschi c, bahnini a. treatment of lower extremity venous insufficiency due to pelvic leak points in women. ann vasc surg 2005;19:284-8. 3. franceschi c. anatomie fonctionnelle et diagnostic des points de fuite bulboclitoridiens chez la femme (point c). j mal vasc 2008;33:42. 4. franceschi c, zamboni p. principles of venous haemodynamics. new york: nova science; 2008. 5. ricci s. phlebology in 21st century. veins and lymphatics 2014;3:2268. 6. jiang p, van rij am, christie ra, et al. non-saphenofemoral venous reflux in the groin in patients with varicose veins. eur j vasc endovasc surg 2001; 21:550-7. 7. barros fs, perez jmg, zandonade e, et al. evaluation of pelvic varicose veins using color doppler ultrasound: comparison of results obtained with ultrasound of the lower limbs, transvaginal ultrasound, and phlebography. j vasc bras 2010;9:15-23. 8. garcía-gimeno m, rodríguezcamarero s, tagarro-villalba s, et al. duplex mapping of 2036 primary varicose veins. j vasc surg 2009;49:681-9. 9. labropoulos n, tiongson j, pryor p, et al. nonsaphenous superficial vein reflux. j vasc surg 2001;34:872-7. 10. perrin n, labropoulos n, leon l. presentation of the patient with recurrent varices after surgery (revas). j vasc surg 2006;43:327-34. 11. reich-schupke s, mendoza e, dörler, m. stücker m. frequency of refluxive tributaries of the junction region in the groin in patients with recurrent varicose veins of the thigh. phlebologie 2016;45:149-53. 12. hüffer a. lehrbuch der topographischen anatomie. berlin, heidelberg, new york: springer-verlag; 1969. 13. sala l, bruni c. trattato di anatomia umana. vol. 4. milano: ed. vallardi; 1932. 14. fusari r, bruni ac. trattato di anatomia umana topografica. torino: ed. utet; 1936. 15. pernkopf e. atlas of topographical and applied human anatomy. vol. ii; 222223. 16. leal monedero j, zubicoa ezpeleta s, castro c, et al. embolization treatment of recurrent varices of pelvic origin. figure 7. ligation of leak points. the perineal point (upper part of the figure) and inguinal leak points (lower part of the figure) act as perforating veins. remote disconnection as represented on the left side, invariably fails either immediately or secondarily because of the presence of many branches and anastomoses. on the right side of the figure the correct level of disconnection is shown. [veins and lymphatics 2019; 8:7789] [page 15] no nco mm er cia l u se on ly article [page 16] [veins and lymphatics 2019; 8:7789] phlebology 2006;21:3-11. 17. greiner m. varices des membres inférieurs d’origine pelvienne: traitement et résultats à long terme. j mal vasc 2006;31:c2, 26. 18. criado e, juan j, fontcuberta j, escribano mj. haemodynamic surgery for varicose veins: rationale, and anatomic and haemodynamic basis. phlebology 2003;18:158-66. 19. delfrate r, bricchi m, franceschi c, goldoni m. multiple ligation of the proximal greater saphenous vein in the chiva treatment of primary varicose veins. veins and lymphatics 2014;3:1922. 20. franceschi c. theorie et practique de la cure conservatrice et hemodynamique de l’insuffisance veineuse en ambulatroire. precy-sous-thil, france: edition de l’armançon; 1988. 21. franceschi c, cappelli m, ermini s, et al. chiva: hemodynamic concept, strategy and results. int angiol 2016;35:8-30. 22. delfrate r. a new diagnostic approach to varicose veins: haemodynamic evaluation and treatment. folgaria (tn): lorena dioni publishing; 2014. 23. zamboni p, mendoza e, gianesini s. saphenous vein-sparing strategies in chronic venous disease. berlin: springer international publishing; 2018. 24. rabe e, pannier f. embolization is not essential in the treatment of leg varices due to pelvic venous insufficiency. phlebology 2015;30:86-8. 25. lopez aj. female pelvic vein embolization: indications, techiques and outcomes. cardiovasc intervent radiol 2015;38:806-20. 26. kim as, greyling la, davis ls. vulvar varicosities: a review. dermatol surg 2017;43:351-6. 27. sofler m, hayes m, smith c. central venous catheterization training: current perspectives on the role of simulation. adv med educ prat 2018;9:395-403. 28. parienti jj. intravascular complications of central venous catheterization by insertion site. n engl j med 2015;373: 1220-9. 29. mcgee dc, gould mk. preventing complications of central venous catheterization. n engl j med 2003; 348:1123-33. 30. rando k. ultrasound-guided internal jugular vein catheterization: a randomized controlled trial. heart lung vessel 2014;6:13-23. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2012; volume 1:e11 [veins and lymphatics 2012; 1:e11] [page 51] an extremely rare case of an incidentally detected renal vein aneurysm and review of literature dilliraj prabakar, nupur bit, thiruvengadam vidyasagaran, joesph amalorpavanathan, narayanan sritharan, kalyanaraman elancheralathan department of vascular surgery, madras medical college and rajiv gandhi government general hospital, chennai, tamil nadu, india abstract congenital renal vein aneurysms are a truncular type of venous malformation and are believed to be the outcome of defective development during the later stage of embryogenesis while the venous trunk is being formed. there have been 9 case reports so far. here, we add the report of a patient who was incidentally detected to have a renal vein aneurysm on computed tomography angiogram. in addition, this is the first description of inferior vena cava thrombosis associated with a thrombosed saccular aneurysm of the renal vein. case report a 29-year old asian male underwent preemployment medical screening and was detected to have inferior vena cava (ivc) thrombosis on ultrasound abdomen. he was asymptomatic and had no co-morbid illnesses. his physical examination was unremarkable. there was no varicocoele. basic blood laboratory investigations were all normal. serum virology markers were negative. his procoagulant workup was negative. contrast-enhanced computed tomography (ct) abdomen revealed a thrombosed saccular venous aneurysm of size 3.9x3.7 cm arising from the mid-segment of the left renal vein (figure 1). retrohepatic ivc was thrombosed; infrahepatic ivc, common iliac and external iliac vein were dilated. since he was asymptomatic and the renal vein aneurysm was already thrombosed, it was decided to manage him conservatively. at follow up 1-year later, he remains asymptomatic and the aneurysm has maintained the same size. our radiology colleagues contributed ct angiogram images of another patient with renal vein aneurysm (figure 2). however, his clinical details could not be retrieved. discussion and conclusions primary venous aneurysms are an uncommon entity. aneurysms involving the popliteal, jugular, superior vena cava, intracranial, and axillary veins have been described. however, involvement of visceral veins is considered rare. nevertheless now due to the easy availability of advanced diagnostic methodologies, an increasing number of asymptomatic venous aneurysms are being detected and their management debated. the potential complications of these untreated venous aneurysms are rupture, thrombosis and pressure effects on adjacent structures.1 the risk of pulmonary embolism also cannot be ignored. in a systematic review, sfyroeras et al. identified 93 reports, including 176 patients with 198 visceral venous aneurysms.1 portal venous system (3%) was found to be the commonest site of involvement, often associated with cirrhosis and portal hypertension. the extremely high operative risk precludes their surgical management. complete thrombosis occurred in 24 (13.6%) and non-occlusive thrombus was found in 6 patients. four of the visceral aneurysms ruptured (2.2%), one of them during the postpartum period. two of these four ruptures were splenic vein aneurysms, one intrahepatic and one aneurysm of the right portal vein. the authors concluded that those who present with rupture or thrombosis warrant surgical intervention. renal vein aneurysms are rare. syfroeras et al. discovered only 6 case-reports.1-7 the ages of the patients ranged from 33 to 73 years. five were male and 3 had abdominal pain. the remaining 3 were discovered incidentally or during laparotomy. in 4 cases, the aneurysm was located in the left renal vein. aneurysm diameter ranged from 4 to 5.5 cm. three patients were operated; aneurysm resection and reconstruction of the renal vein (two) and nephrectomy (one). there was no report of aneurysm rupture or associated ivc thrombosis. a medline search revealed an additional 3 cases which were published after the review by syfroeras.1 in 2007, chung et al. described a venous aneurysm which was discovered on pathological evaluation after laparoscopic resection of a 3 cm retroperitoneal mass at the junction of the left para-aortic and perirenal hilar regions.8 another 3.5¥3.1 cm saccular lesion was described on duplex and magnetic resonance imaging in a 36-year old taiwanese woman by lin et al. in 2010. the patient opted for conservative management and had no complications till follow up at 18 months.9 in the latest report in 2011, rao et al. have described a similar left renal vein aneurysm detected incidentally during a laparoscopic radical nephrectomy in a 66-year old male with a 5 cm right upper pole renal mass.10 it is interesting to note that these lesions are usually asymptomatic and the left renal vein is most often involved, which has been attributed to its more complicated embryologic development.1,2,11 visceral venous aneurysms can hypothetically result in thrombosis, rupture, pressure effects and thromboembolism.1 however, there is no published report of a renal vein aneurysm presenting with either of these complications. there have been reports of pulmonary embolism arising from popliteal vein aneurysms. spontaneous or intraoperative inadvertent rupture is a possibility and may result in massive bleeding and difficulties in surgical repair. true renal vein aneurysms are related to congenital weakness of the venous wall because of lack of development of media. irace et al. describe that in a true aneurysm the venous wall is quite thin because of marked medial atrophy, with loss of elastic fibers and inconspicuous intima, whereas the histology in a renal varix shows both hypertrophy and thinning of the media with fibrous thickening.7 our two cases add to the slowly expanding list of renal vein aneurysms (table 1). our case is probably unique in that the ivc thrombosis could have been due to embolism or progression of thrombus from the renal vein aneurysm. the aneurysm also subsequently thrombosed, presumably due to obstructed outflow. it could also be debated that both the thrombosis of the cava and the renal vein may have occurred simultaneously due to a common etiology. moreover, the thrombosis of the aneurysm may have occurred independently of an obstructive flow. it lends credence to the theory that visceral vein aneurysms require correspondence: nupur bit, department of vascular surgery, madras medical college and rajiv gandhi government general hospital, chennai, tamil nadu, india. e-mail: nupur.bit@gmail.com key words: renal vein aneurysm, inferior vena cava thrombosis. received for publication: 15 november 2012. revision received: 21 january 2013. accepted for publication: 22 january 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright d. prabakar et al., 2012 licensee pagepress, italy veins and lymphatics 2012; 1:e11 doi:10.4081/vl.2012.e11 no nco mm er cia l u se on ly case report [page 52] [veins and lymphatics 2012; 1:e11] intervention to prevent future complications. however, since our patient has remained asymptomatic on conservative management, watchful waiting maybe advocated for thrombosed venous aneurysms. conclusions renal vein aneurysms are being detected more often now due to advancements in imaging methodologies. they are potentially at risk of thrombosis, rupture, pressure effects on adjacent structures and pulmonary embolism. management has to be individualized to the patient. the patient should be carefully monitored for embolism to ivc and pulmonary vasculature. a thrombosed renal vein aneurysm maybe managed conservatively. references 1. sfyroeras gs, antoniou ga, drakou aa, et al. visceral venous aneurysms: clinical presentation, natural history and their management: a systematic review. ejves 2009;38:498-505. 2. yoneyama t, baba y, fujiyoshi f, et al. left renal vein aneurysm: imaging findings. abdom imaging 2003;28:233-5. 3. val-bernal jf, fernández n, lópez-rasines g. symptomatic solitary right renal vein aneurysm: a case report. cardiovasc pathol 2000;9:29-32. 4. khader sm, saleeb sf, teplick sk. general case of the day. left renal vein aneurysm. radiographics 1999;19:1683-5. 5. kabaalio�lu a, yilmaz s, apaydin, a et al. renal vein aneurysm: diagnosis with color doppler sonography. ajr am j roentgenol 1997;168:645-6. 6. krinsky g, johnson g, rofsky n, et al. venous aneurysms: mr diagnosis with the “layered gadolinium” sign. j comput assist tomogr 1997;21:623-7. 7. irace l, gossetti b, benedetti-valentini f, et al. aneurysm of the left renal vein: a case report. j vasc surg 1994;19:943-4. 8. chung sd. huang kh, tai hc, et al. perirenal venous aneurysm presenting as retroperitoneal tumour treated successfully by laparoscopic excision. j endourol 2007;21:1329-31. 9. lin tc, lin cm, chang hc, et al. a left circum-aortic renal vein aneurysm. am j surg 2010;200:37-8. 10. rao mv, polcari aj, sundaram v, et al. right renal vein aneurysm discovered incidentally during laparoscopic nephrectomy. urology 2011;77:332-3. 11. satyapal ks, kalideen jm, haffejee aa, et al. left renal vein variations. surg radiol anatomy 1999;21:77-81. table 1. renal vein aneurysms in literature. author year age gender side presentation size treatment of publication involved irace et al.7 1994 n.r. male left incidental during n.r. lateral clamping, aortobifemoral resection and direct repair kabaalio�lu et al.5 1997 54 male left abdominal pain 5¥4¥3 cm not mentioned krinsky et al.6 1997 n.r. male right abdominal pain n.r. n.r. khader et al.4 1999 40 male left abdominal pain n.r. n.r. val-bernal et al.3 2000 33 male right right back pain, 5.5 cm nephrectomy for suspected abdominal pain, hematuria, weight loss yoneyama et al.2 2003 57 female left asymptomatic 4 cm nil chung et al.8 2007 n.r. n.r. left on pathology 3 cm resected laparoscopically as retroperitoneal mass lin et al.9 2010 36 female left incidental 3.5¥3.1¥2.5 cm nil circum-aortic on duplex abdomen rao et al.10 2011 66 male right incidental during lap 5 cm resection, primary ivc repair nephrectomy n.r., not reported; ivc, inferior vena cava. figure 1. patient 1. a) coronal view of computed tomography (ct) angiogram showing a thrombosed saccular aneurysm arising from the left renal vein and inferior vena cava thrombosis. b) axial view of ct angiogram of the same patient. figure 2. patient 2. a) coronal view of computed tomography (ct) angiogram showing a saccular aneurysm arising from the left renal vein. b) axial view of ct angiogram of the same patient (images provided by our radiology department). a b a b no nco mm er cia l u se on ly hrev_master veins and lymphatics 2017; volume 6:6841 [page 78] [veins and lymphatics 2017; 6:6841] conventional echo color doppler versus ula-op in the assessment of venous flow model valentina tavoni,1,2 francesco sisini,1,2 giovanni di domenico,1 nadiya mohammed,1 giacomo gadda,1 francesca calderoni,1 mauro gambaccini1 1department of physics and earth sciences; 2vascular diseases center, university of ferrara, italy abstract the quantification of venous flows can be obtained by multiplying cross sectional area, measured on a b-mode video-clip, by velocity values, obtained with doppler measurements. the doppler angle between ultrasound (us) line and blood flow requires a manual adjustment. establishing this parameter is critical in order to calculate blood velocity. however, the operator dependency gives high variable results. it is worth noting that a new class of vector doppler devices can enhance the accuracy and precision of measurements. such technology uses a double us line that leads to automatically know the doppler angle. by comparing in an in vitro model of venous flow conventional echo color doppler (ecd) equipment with the new device, we found a better minimal difference between the latter and the nominal flow rate (20%). on the contrary, the comparison with conventional ecd showed a difference ranging between 2% and 43%, according to the possible settings of the equipment. our study demonstrates a better accuracy of the experimental device with respect to conventional ecd in measuring the venous flow rate. introduction ultrasound (us) devices are becoming very attractive in the clinical environment, particularly for medical diagnostics. this technology is used also in the cardiovascular field to quantify blood flows.1,2 the flow is calculated by multiplying blood velocity in a vessel, obtained with doppler measurements, by its cross sectional area (csa), measured on a b-mode video-clip.3-6 differently from other methods used for the same purpose (for example phlebography or functional magnetic resonance imaging), such technology allows to do noninvasive, cheap and safe examinations. several studies published in the last decades highlighted a good reproducibility among us technicians trained in investigation of cerebral venous return.7-9 however, highly variable results still exist because doppler measurements of blood velocity are strongly affected by two types of error, which are systematic and random.1 a systematic error depends on the instrumentation: in order to overcome such problem, a calibration of the devices is necessary. this practice allows to know any device limits and to evaluate the correction factor to apply on each measurement. since the us technology is operator dependant, a random error is related to the operating mode of the specialist who is doing the us examination. in order to reduce this dependency, several investigators attempted to measure the cerebral venous outflow by means of quantitative us protocol. nevertheless, such a protocol required very skilled personnel and a long period of time to collect measurements.2,10,11 in particular, the technician has to pay attention when positioning the us probe along the vessels. he shall avoid pressing on the subject’s skin, because the veins could collapse and change their csa. moreover, he has to manually adjust the orientation of the us cursor, which must be parallel to the blood flow.1 such operation allows the system to calculate the insonation angle between the us line and the blood flow. the choice of this parameter is fundamental, because the doppler equation, required to determine blood velocity, depends on the inverse of the cosine of the angle. furthermore, it is known that veins tend to be tortuous, making measurements a challenge. in some cases, the presence of valves within the vessels also may lead to turbulences in blood flow. for example, the internal jugular vein region right before the subclavian junction is an anatomical point exposed to flow turbulence, both because of the vessel direction and since it is the most prevalent valvular location. in this venous segment, an error of about 30% in measuring the flow rate has been estimated, which is due to the uncertain velocity assessment.2,12 another source of variability during us examination is the intrinsic spectral broadening (isb). isb is a broadening of the doppler spectrum due to the mechanism of delivering and receiving acoustic energy.13 to overcome some of these sources of errors a new experimental us platform was carried out.14,15 such device uses a double us line, that allows to measure blood velocity by calculating the doppler angle of insonation in an instantaneous and automatic way. therefore, this technology has a nominal better accuracy and precision than standard devices. the aim of this paper is to compare the accuracy and precision of conventional echo color doppler (ecd) equipment with those of the new one, in a model of venous flow. materials and methods the comparison of scanners flow estimations was performed through an in vitro study with a closed circuit, composed by a correspondence: valentina tavoni, department of physics and earth sciences, university of ferrara, via mondaini 7, 42122 reggio emilia, italy. e-mail: valentina.tavoni@unife.it key words: diagnosis with ultrasound; echo color doppler; ula-op; venous blood flow; angle of insonation. acknowledgements: the authors would like to thank alessandro ramalli of the microelectronic systems design laboratory of the university of florence for helping during the measurements with ula-op. funding: this research was supported by grant of the ministry of health rf-2013-02358029, by the association ccsvi nella sclerosi multipla and by the university of ferrara. contributions: vt, fs, fc, gg and mg designed and implemented the experiments; vt, fc and gg collected the data; vt, fs and gdd analysed data and interpreted the results; vt and nm wrote the main manuscript; all authors reviewed the manuscript. conflict of interest: the authors declare no potential conflict of interest. award: this work was awarded with the poster first place to the 7th international society of neurovascular disease meeting, in taormina, sicily, italy. received for publication: 9 june 2017. revision received: 2 august 2017. accepted for publication: 2 august 2017. this work is licensed under a creative commons attribution 4.0 license (by-nc 4.0). ©copyright v. tavoni et al., 2017 licensee pagepress, italy veins and lymphatics 2017; 6:6841 doi:10.4081/vl.2017.6841 no n c om me rci al us e o nly article [veins and lymphatics 2017; 6:6841] [page 79] homemade neck phantom and a gear pump that generates a static volume flow (figure 1). the neck phantom was created with a plastic tube, with circular csa equal to (0.5±0.1) cm2, inserted into a pmma box (20.0×12.0×20.5 cm) full of water. the tube was fixed to a goniometer indicating the insonation angle, i.e. the angle between the us line and the flow direction. the pump was used to drive blood mimicking fluid (bmf) (cirs, model 046, norfolk, virginia, usa) simulating venous blood flow. the bmf is a liquid with the same acoustic properties of the blood. the tank containing the bmf and a turbine flowmeter were also inserted in the circuit (figure 1). the flowmeter, powered by a 9 v battery and connected to an oscilloscope, was used to calibrate the pump. the test was done using two devices: equipment a (conventional ecd device) and equipment b (ula-op platform, florence, italy) connected to a pc with ula-op starter software. the us probe used during the tests is a linear array probe (la523, esaote s.p.a., florence, italy). this was fastened over the circuit to a manual positioner, which allows moving the probe in very small steps and fixing it in the desired position. during each test the flow set in the pump was varied between (150±1) ml/min and (650±1) ml/min in steps of (100±1) ml/min. the repeatability was tested by reiterating the same measurements during one experimental session, for five times with the equipment a and for twenty times with the equipment b. moreover, the reproducibility was measured by repeating the entire procedure in different experimental sessions in order to have some statistics, for five times with the equipment a and for twenty times with the equipment b. calibration test a preliminary calibration test was taken: this procedure consists in comparing the flow values set in the pump and the values measured by the flowmeter. the flowmeter gives a pulsed electric signal for each cycle, whose frequency was measured with an oscilloscope. the fft mode of the oscilloscope provides us with the main frequency f, which is proportional to the measured flow φflowmeter, as described by the equation: φflowmeter = f/k (1) with k = 22,000 pulse/l. the flow values measured with the flowmeter and those set in the pump were verified to be not significantly different by a paired t-test. therefore, the nominal values set was constructed with flow values set in the pump (φpump). these were converted into velocity values through the csa of the tube since v = φpump/csa. test with equipment a the measurements were performed by positioning the insonation angle at 30°, 45° and 60°±1°. the choice of these angles follows the guidelines to obtain reliable measurements.16 for each flow value set in the pump, the doppler velocity was measured inside the vessel by choosing two different sizes of sample volume (sv): the smallest sv, i.e. 1 mm, and the biggest sv, which extends to include the whole diameter of the vessel, i.e. 8 mm. since the flow is assumed to be laminar, both the mean time average velocity (tav) and half of the peak tav were compared with the velocity set in the pump. the other parameters set in the system are reported in table 1. test with equipment b the us mode used to do the experiment was the b-msd-sptr-mode. this mode allows to automatically adjusting the angle of insonation using a double us line. moreover, this mode enables to calculate the peak velocity in the point within the vessel, where a marker for the focus of the measurement is located. the experiment was performed by positioning the tube at an insonation angle equal to 80°±1°. the choice of this angle is given by the best setting suggested by the manufacturer to obtain reliable measurements (personal communication). the system automatically displays only the measurement of the peak velocity. the other parameters set in the system are reported in table 2. analysis of results for every different experimental setup, a set of measurements was collected. a set is composed by five or twenty velocity measurements corresponding to the single flow values set in the pump each time. for every flow value of each set, mean values, standard deviations (sd) and coefficient of variation (cov) were calculated. moreover, a simple linear regression was obtained for each set. finally, paired t-test was used to state the null hypothesis that two set of velocity measurements were not significantly different from each other. all the tests done are reported in table 3. the tests with the equipment a were conducted with two different combination of insonation angle, sv and tav: the suggested setup and the best setup. the first one is the setting suggested by the guidelines:16 insonation angle equal to 60°, sv 8 mm and mean tav. the second one instead is the setting that reproduces the closest measurements to the nominal values. the insonation angle for this setting is equal to 30°, sv 8 mm and peak tav. results from the verification of reproducibility and repeatability of measurements, a different cov was obtained for every flow values. the range of variation of cov expressed in percentage is reported in table 4. the results of the t-test between nominal values and measurements collected with equipment b and a for the two experimentable 1. parameter setting for equipment a. frequency of us beam 5.6 mhz maximum depth displayed 72 mm focus position set by the system gain set by the system sample distance central zone of the vessel to prevent the zone in which the flow is not fully developed pulse repetition frequency (prf) between 3 khz and 10 khz with increasing flow, in order to avoid the aliasing without using excessively high values figure 1. scheme of the closed circuit composed by phantom, pump, tank and flowmeter. θ is the insonation angle. no n c om me rci al us e o nly article [page 80] [veins and lymphatics 2017; 6:6841] tal setups are reported in table 5. for the ttest the threshold of p-value for statistical significance is chosen equal to 0.05. the equations of the linear regressions applied to the curves of mean values are reported in figure 2. slope and intercept of each curve are reported in table 6. discussion the main result of this study is that the equipment b has a better performance than equipment a in estimating velocity, as shown in table 5 and 6 and in figure 2. as confirmation of this, it is worth noting that the equipment b registered values very closed to those measured with the flowmeter. nonetheless, considering the results shown in table 4, the equipment a has a better repeatability and reproducibility than the equipment b. in other words, the equipment b shows higher accuracy but lower precision. this apparently contradictory result is probably due to the fact that the equipment a displays the tav value calculated in a certain time frame, while the equipment b shows a single velocity measurement that is continually refreshed. we think that the user interface of equipment b has to be improved showing also the tav value, in order to consider the system for the clinical environment. in conclusion, the equipment b seems to produce more accurate results than the equipment a. this is an interesting outcome for all the fields where the velocity measurements play a critical role, such as diagnosis of carotid plaques and estimation of volume blood flow. for instance, our group has developed some lumped models based on volume blood flow estimation2,17,18 and one of the major limitation of such models was the low level of accuracy in flow quantification. for these reasons, we believe that more accurate velocity measurements can give a great improvement to both diagnostic responsibility and open scientific disputes. the use of equipment b could be useful for the investigation of cerebral venous return both in physiological and in pathological condition, in particular avoiding as much as possible the errors linked to the blood flow quantification. further studies will be required to analyse these issues in details. conclusions in the present work it is shown that the new type of us device could be very attractive in future clinical environment, regarding diagnosis of cardiovascular diseases. this system has the ability to measure the velocity with higher accuracy compared table 2. parameter setting for equipment b. frequency of us beam 6.25 mhz maximum depth displayed 35 mm focus position set in the same position of the marker time gain compensation (tgc) a 30 db tgc b 0 db/cm sample distance central zone of the vessel to prevent the zone in which the flow is not fully developed prf 11,996 hz speed of sound 1480 m/s table 3. tests done for the comparison between devices. verification of repeatability of measurements collected with equipment a during the same test verification of reproducibility of measurements collected with equipment a, using the same experimental setup in different sessions verification of repeatability of measurements collected with equipment b during the same test verification of reproducibility of measurements collected with equipment b, using the same experimental setup in different sessions paired t-test between the set of measurements collected with the equipment a (suggested setup), and the set of nominal values paired t-test between the set of measurements collected with the equipment a (best setup) and the set of nominal values paired t-test between the set of measurements collected with the equipment b and the set of nominal values paired t-test between the set of measurements collected with the equipment a (suggested setup) and the set registered with the equipment b paired t-test between the set of measurements collected with the equipment a (best setup) and the set collected with the equipment b calculation of intercept, slope and r2 for each curve obtained with both equipments figure 2. for each nominal velocity value, mean values of measurements collected with equipment a and b, together with nominal values and flowmeter measurements are plotted. respective sd are marked over each mean value. linear regressions are drawn over each curve: their equations are reported in legend. no n c om me rci al us e o nly article [veins and lymphatics 2017; 6:6841] [page 81] to the standard devices. further improvements could enhance the precision of doppler measurements. moreover, future developments should take into account the b-mode, in order to complete the us quality control test on the device. references 1. gill rw. measurement of blood flow by ultrasound: accuracy and sources of error. ultrasound med bio 1985;11: 625-41. 2. zamboni p, sisini f, menegatti e, et al. an ultrasonographic model to calculate the brain blood outflow through collateral vessels: a pilot study. bmc neurology 2013;13-81. 3. hoskins pr, fish pj, mcdicken wn, moran c. developments in cardiovascular ultrasound: part 2. arterial applications. med biol eng comput 1998;36:259-69. 4. sisini f, tessari m, gadda g, et al. an ultrasonographic technique to assess the jugular venous pulse: a proof concept. ultrasound med bio 2015;41:1334-41. 5. nakamura k, qian k, ando t, et al. cardiac variation of internal jugular vein for the evaluation of hemodynamics. ultrasound med bio 2016;42:176470. 6. sisini f, tessari m, menegatti e, et al. clinical applicability of assessment of jugular flow over the individual cardiac cycle compared with current ultrasound methodology. ultrasound med bio 2016;1-14. 7. menegatti e, genova v, tessari m, et al. the reproducibility of colour doppler in chronic cerebrospinal venous insufficiency associated with multiple sclerosis. int angiol 2010;29: 121-6. 8. dolic k, marr k, valnarov v, et al. sensitivity and specificity for screening of chronic cerebrospinal venous insufficiency using a multimodal non-invasive imaging approach in patients with multiple sclerosis. funct neurol 2011;26:205-14 9. ciccone mm, galeandro ai, scicchitano p, et al. multigate quality doppler profiles and morphological/hemodynamic alterations in multiple sclerosis patients. curr neurovasc res 2012;9:120-7. 10. monti l, menci e, piu p, et al. a sonographic quantitative cutoff value of cerebral venous outflow in neurologic diseases: a blinded study of 115 subjects. am j neuroradiol 2014 [epub ahead of print]. 11. thibault p, lewis w, niblett s. objective duplex ultrasound evaluation of the extracranial circulation in multiple sclerosis patients undergoing venoplasty of internal jugular vein stenoses: a pilot study. phlebology 2015;30:98104. 12. zamboni p. why current doppler ultrasound methodology is inaccurate in assessing cerebral venous return: the alternative of the ultrasonic jugular venous pulse. behav neurol 2016;2016:1-7. 13. evans dh, mcdicken wn, skidmore r, woodcock jp. doppler ultrasound: physics, instrumentation, and clinical applications. new york, ny: john wiley & sons; 1989. 14. tortoli p, bassi l, boni e, et al. ulaop: an advanced open platform for ultrasound research. ieee trans ultrason ferroelectr freq control 2009;56:2207-16. 15. tortoli p, dallai a, boni e, et al. an automatic angle tracking procedure for feasible vector doppler blood velocity measurements. ultrasound med bio 2010;36;488-96. 16. gerhard-herman m, gardin jm, jaff m, et al. guidelines for noninvasive vascular laboratory testing: a report from the american society of echocardiography and society of vascular medicine and biology. j am soc echocardiog 2006;19:955-72. 17. gadda g, taibi a, sisini f, et al. a new hemodynamic model for the study of cerebral venous outflow. am j physiol 2015;308:217-31. 18. gadda g, taibi a, sisini f, et al. validation of a hemodynamic model for the study of the cerebral venous outflow system using mr imaging and echocolor doppler data. am j neuroradiol 2016;37:2100-9. table 4. repeatability and reproducibility of measurements, tested on both equipments. test range of coefficient of variation (%) repeatability equipment a 1-2 reproducibility equipment a (suggested setup) 7-12 reproducibility equipment a (best setup) 0-5 repeatability equipment b 7-15 reproducibility equipment b 13-17 table 5. results of comparison between equipment a, b and nominal values. paired t-test results of comparison p-value equipment a (suggested setup) nominal values significantly different <1×10–3 equipment a (suggested setup) equipment b significantly different <1×10–4 equipment a (best setup) nominal values significantly different <1×10–5 equipment a (best setup) equipment b significantly different <1×10–2 equipment b nominal values not significantly different >0.8 table 6. slope and intercept of flowmeter, equipment a and equipment b. slope intercept r2 flowmeter 1.153 4.626 1.000 equipment a (suggested) 1.433 5.650 0.999 equipment a (best) 1.016 4.348 0.998 equipment b 1.198 5.437 0.995 no n c om me rci al us e o nly hrev_master veins and lymphatics 2013; volume 2:e14 [veins and lymphatics 2013; 2:e14] [page 43] the controversy on chronic cerebrospinal venous insufficiency paolo zamboni,1 erica menegatti,1 savino occhionorelli,1 fabrizio salvi2 1vascular diseases center, university of ferrara; 2bellaria neuroscience, bellaria hospital bologna, italy abstract the objective of this review is to analyze the actual scientific controversy on chronic cerebrospinal venous insufficiency (ccsvi) and its association with both neurodegenerative disorders and multiple sclerosis (ms). we revised all published studies on prevalence of ccsvi in ms patients, including ultrasound and catheter venography series. furthermore, we take into consideration other publications dealing with the pathophysiologic consequences of ccsvi in the brain, as well as ecent data characterizing the pathology of the venous wall in course of ccsvi. finally, safety and pilot data on effectiveness of endovascular ccsvi treatment were further updated. studies of prevalence show a big variability in prevalence of ccsvi in ms patients assessed by established ultrasonographic criteria. this could be related to high operator dependency of ultrasound. however, 12 studies, by the means of more objective catheter venography, show a prevalence >90% of ccsvi in ms. global hypoperfusion of the brain, and reduced cerebral spinal fluid dynamics in ms was shown to be related to ccsvi. postmortem studies and histology corroborate the 2009 international union of phlebology (uip) consensus decision to insert ccsvi among venous malformations. finally, safety of balloon angioplasty of the extracranial veins was certainly demonstrated, while prospective data on the potential effectiveness of endovascular treatment of ccsvi support to increase the level of evidence by proceeding with a randomized control trial (rct). taking into account the current epidemiological data, including studies on catheter venography, the autoptic findings, and the relationship between ccsvi and both hypo-perfusion and cerebro-spinal fluid flow, we conclude that ccsvi can be definitively inserted among the medical entities. research is still inconclusive in elucidating the ccsvi role in the pathogenesis of neurological disorders. the controversy between the vascular and the neurological community is due to the great variability in prevalence of ccsvi in ms patients by the means of venous ultrasound assessment. more reproducible and objective ccsvi assessment is warranted. finally, current rct may elucidate the role of ccsvi endovascular treatment. the controversial problem of chronic cerebrospinal venous insufficiency in multiple sclerosis chronic cerebrospinal venous insufficiency (ccsvi) is a syndrome characterized by stenosis or obstructions of the internal jugular (ijv) and/or azygos (az) veins with disturbed flow and formation of collateral venous channels.1,2 venous narrowings are primary obstructions, mainly related to segmental hypoplasia or, more frequently, to intraluminal defects like webs, fixed valve leaflets, membrane, inverted valve orientation, etc.3-5 venous anomalies are a field in which experts still have to agree upon many things. the basis and foundation of venous anomalies are not entirely clear yet. venous lesions are described as truncular venous malformations.6-8 develop mental arrest in advanced stages of vascular trunk formation during fetal life can result in such truncular venous malformations. lesions caused by incomplete development of axial veins result in aplasia, hypoplasia or hyperplasia of the vessel or as a defective vessel with obstruction from intraluminal lesions (e.g., vein web, malformed valve, or septum) or dilatation (e.g., jugular vein ectasia/aneurysm). radiological studies of healthy subjects did not demonstrate these types of lesions,9-18 while ccsvi-like lesions were described associated to myelopathies.19,20 despite the above and other scientific evidences,21-24 in clinical practice, due to the inherent variability of the cerebral venous system and the lack of standards, it is difficult to accurately detect ccsvi using current magnetic resonance imaging (mri) and echo-color doppler (ecd) sonography techniques, as well as its possible association with neurodegenerative disorders such as ms-something that has generated considerable scientific controversy. there are a lot of opinion papers, and some original contributions, pointing against the existence and the association of ccsvi in ms.25-28 the core of the controversy: the ultrasonographic prevalence of chronic cerebrospinal venous insufficiency in multiple sclerosis the neurological community did not accept from the beginning, the intrusion of the vascular procedure for ccsvi in ms treatment. the harshest were khan et al.26 with a statement that endovascular procedures in ms were research endeavors, and that these invasive endovascular procedures should be discouraged until there is conclusive evidence to justify their indication in ms. a canadian group27 comments on call for liberation in edmonton and the mobilizing power of the media and the internet. because of the pressure from ms groups the canadian institutes of health research with ms society held an expert panel in august 2009, which concluded that in absence of clear and convincing evidence for ccsvi, the performance of an interventional venous angioplasty trial with its attendant risk to ms patients is not appropriate at this time. the authors also27 stated that more effort needs to be devoted to improving scientific literacy of the public, politicians and the media, in order to prevent an diverting public resources to testing what will probably turn out to be ineffective or harmful therapies. rikkers et al.28 state that recent randomized trials did not show a difference in the prevalence of venous stenosis between groups of patients with or without ms, comparing the studies of doepp and other authors.29-34 in an everyday growing field of studies and papers trying to demonstrate either positive or negative association of ccsvi with ms we will discuss the results of studies published so far. ultrasound in the form of duplex scanning uses a combination of physiological measurements as well as anatomical imaging and has been used for the detection of ccsvi by differcorrespondence: paolo zamboni, vascular diseases center, university of ferrara, sant’anna hospital, co. giovecca 203, 44100 ferrara, italy. tel. +39.053.2237 694 fax: +39.053.2237.443. e-mail: menegatti.erica@gmail.com key words: brain circulation, chronic cerebrospinal venous insufficiency, echo-color doppler imaging, multiple sclerosis, venous malformations. conflict of interests: the authors declare no potential conflict of interests. received for publication: 7 january 2013. revision received: 10 june 2013. accepted for publication: 13 june 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright p. zamboni et al., 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e14 doi:10.4081/vl.2013.e14 no nco mm er cia l prevalence >90% of ccsvi in ms. global hypono nco mm er cia l prevalence >90% of ccsvi in ms. global hypoperfusion of the brain, and reduced cerebral no nco mm er cia l perfusion of the brain, and reduced cerebral spinal fluid dynamics in ms was shown to be no nco mm er cia l spinal fluid dynamics in ms was shown to be related to ccsvi. postmortem studies and histolno nco mm er cia l related to ccsvi. postmortem studies and histology corroborate the 2009 international union of no nco mm er cia l ogy corroborate the 2009 international union of phlebology (uip) consensus decision to insert no nco mm er cia l phlebology (uip) consensus decision to insert ccsvi among venous malformations. finally,no nco mm er cia l ccsvi among venous malformations. finally, safety of balloon angioplasty of the extracranialno nco mm er cia l safety of balloon angioplasty of the extracranial mental arrest in advanced stages of vascular no nco mm er cia l mental arrest in advanced stages of vascular trunk formation during fetal life can result in no nco mm er cia l trunk formation during fetal life can result insuch truncular venous malformations. lesions no nco mm er cia l such truncular venous malformations. lesions caused by incomplete development of axial veins no nco mm er cia l caused by incomplete development of axial veins result in aplasia, hypoplasia or hyperplasia of the no nco mm er cia l result in aplasia, hypoplasia or hyperplasia of the vessel or as a defective vessel with obstruction no nco mm er cia l vessel or as a defective vessel with obstruction from intraluminal lesions ( no nco mm er cia l from intraluminal lesions ( formed valve, or septum) or dilatation ( no nco mm er cia l formed valve, or septum) or dilatation ( lar vein ectasia/aneurysm). radiological studies no nco mm er cia l lar vein ectasia/aneurysm). radiological studies of healthy subjects did not demonstrate these no nco mm er cia l of healthy subjects did not demonstrate these types of lesions, no nco mm er cia l types of lesions, were described associated to myelopathies. no nco mm er cia l were described associated to myelopathies. despite the above and other scientific evino nco mm er cia l despite the above and other scientific evius e and foundation of venous anomalies are not us e and foundation of venous anomalies are notentirely clear yet. venous lesions are described us e entirely clear yet. venous lesions are described6-8 us e 6-8 develop us e develop mental arrest in advanced stages of vascularus e mental arrest in advanced stages of vascular trunk formation during fetal life can result inus e trunk formation during fetal life can result in on ly venous anomalies are a field in which experts on ly venous anomalies are a field in which experts still have to agree upon many things. the basis on ly still have to agree upon many things. the basis on ly attribution 3.0 license (by-nc 3.0). on ly attribution 3.0 license (by-nc 3.0). ©copyright p. zamboni et al., 2013 on ly©copyright p. zamboni et al., 2013licensee pagepress, italy on lylicensee pagepress, italy veins and lymphatics 2013; 2:e14 on ly veins and lymphatics 2013; 2:e14 doi:10.4081/vl.2013.e14on ly doi:10.4081/vl.2013.e14 no nco mm er cia l u se on ly review [page 44] [veins and lymphatics 2013; 2:e14] ent centers with variable results. ultrasound is, of course, an ideal screening tool because it is non-invasive, economic, etc. however, these studies show very variable results, which we aim to comment. we were able to observe interesting grouping of results into two main groups; those with a ccsvi prevalence higher than 60%, from 60%-100%1,2,35-39 and those with absence of such lesions,29,30 or ccsvi prevalence under 60%31-33 (table 1). this variability could be the result of differences in technique, training, experience or criteria used.40 for future avoidance of such variable results, and in order to ensure a high reproducibility of duplex scanning with comparable accuracy between centers, all investigators are invited to follow the protocol with standard methodology and criteria.40 moreover, a recent metaanalysis done by laupacis et al.41 showed a positive association between ccsvi and ms. the group performed a systematic review and meta-analysis of all reports from 2005 till june 2011, comparing the frequency of ccsvi and ms. their findings proved a significant association between ccsvi and ms even after exclusion of the first study by zamboni, due to the fact that it, being the first study, may be considered hypothesis-generating and because of the extremely high odds ratio found in the study. the meta-analysis was repeated after inclusion of doepp’s study,33 in which none of the patients or controls had ccsvi, but the findings were similar to those in the primary analysis. the group concluded a strong association between ccsvi and ms with marked heterogenicity due to reduced reporting of patient blinding. negative studies showing traces of venous abnormalities doepp et al. reported no ccsvi in ms patients,29 but their results did show a significant reduction of venous outflow in ms patients when their position changed from supine to upright, which points towards a disturbed venous outflow. one of the major regulators of cerebral venous outflow is the posture, due to the gravitational gradient between the cerebral parenchymal veins (�30 mmhg) and the base of the neck (0 mmhg).4 doepp et al.29 demonstrate a much larger change in blood flow volume in normals compared to ms patients when the subjects go from a supine to upright position. they find a change of 128 ml/min and 56 ml/min for the right and left sides respectively for ms patients. but they find a much larger change of 266 ml/min and 105 ml/min for their normal subjects. this result actually suggests the presence of ccsvi proven with a different protocol. the causes of reduced outflow changing posture to upright can be from intraluminal septum, membrane, immobile valve affecting the hydrostatic pressure gradient.4,21 however, high quality doppler flow measurement at the terminal ijv shows a restricted outflow in ccsvi with increased flow though the collaterals respect to controls.42 the presence of such blockages in the extracranial and extravertebral cerebral veins have been proven by using catheter venography, a more objective method respect to ecd.1,43-48 more interestingly, diaconu et al. communicated at european committee for treatment and research in multiple sclerosis (ectrims) the results of a post-mortem study clearly showing a highest prevalence of jugular septimentation with possible hemodynamic consequences in ms patients in respect to controls.21 this result is confirmed by another autoptic study.22 baracchini et al. reported 16% of ccsvi in ms patients at disease onset, compared to 2% of ccsvi in healthy controls.33 this finding suggests that ccsvi represents a nine times higher risk factor for disease onset, showing increased susceptibility to ms in ccsvi subjects. zivadinov et al. recently reported ccsvi more likely to be a secondary phenomenon to ms. their results showed that ccsvi was found in 50% of pediatric ms cases as well as in 38% of clinically isolated syndrome cases, thus making the conclusion rash.36 a well-established explanation for this great variability in ccsvi prevalence among different groups of investigators is the amount of training and experience investigators have in echo-color doppler imaging. studies have shown39 that inter-operator variability decreases post-training (from k=0.47 to k=0.80) while intra-operator reproducibility in trained operators was k=0.75. apart from experience and training, ultrasound imaging still remains an operator-dependent investigation. studies that have been done so far show great variability because of operator dependency, lack of proper training in performing venous ultrasound, and differences in protocols used. however, despite all these obstacles, in more than 2000 investigated subjects, the prevalence of ccsvi was more than 70% in ms patients compared to prevalence of about 10% in healthy controls (table 1). studies claiming to be in opposition to ccsvi still show different elements of abnormality of venous outflow in ms patients compared to their healthy controls. reproducibility can be assured by performing the investigation by an accepted protocol after training the investigator. to minimize errors and variability in study results, the international society for neurovascular diseases published a protocol deriving from a consensus conference.40 pathology is necessary to establish a new medical entity the morphology seen at venography and ultrasound investigations of the ccsvi picture was considered in the 2009 uip consensus quite similar to those affecting other segments of the caval system, supporting the decision to insert ccsvi among truncular venous malformation.6,7 autoptic studies and histology actually corroborate the decision of the consensus. the presence of wall stenosis, or of a greater prevalence of intraluminal defects in specimen of patients died with ms respect to patients without the disease has been recently described by pathologists.21-23 in addition, a molecular marker has been identified in the adventitial layer of ijv in ccsvi condition where there is an inverted ratio between type i and type iii collagen. the latter component, less extensible, is greatly represented contable 1. prevalence of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis and healthy controls in the main published study. author (ref) ms patients controls ccsvi total ccsvi zamboni et al., 20091 65 (100%) 65 0 zivadinov et al., 201136 162 (56.1%) 289 374 (22.7%) doepp et al., 201129 0 (0%) 56 0 (0%) mayeret al., 201130 0 (0%) 20 1 (5%) baracchini et al., 201133 8 (16%) 50 1 (2%) al omari et al., 20105 21 (84%) 25 0 (0%) simka et al., 201038 64 (91%) 70 bastianello et al., 201137 610 (86%) 710 marder et al., 201132 0 (0%) 18 zivadinov et al., 20113 10 (100%) 10 ms, multiple sclerosis; ccsvi, chronic cerebrospinal venous insufficiency. no nco mm er cia l clinically isolated syndrome cases, thus making no nco mm er cia l clinically isolated syndrome cases, thus makinga well-established explano nco mm er cia l a well-established explanation for this great variability in ccsvi prevano nco mm er cia l nation for this great variability in ccsvi prevalence among different groups of investigators is no nco mm er cia l lence among different groups of investigators is the amount of training and experience investino nco mm er cia l the amount of training and experience investigators have in echo-color doppler imaging. no nco mm er cia l gators have in echo-color doppler imaging. studies have shown no nco mm er cia l studies have shown no nco mm er cia l no nco mm er cia l traces of venous abnormalities no nco mm er cia l traces of venous abnormalities reported no ccsvi in msno nco mm er cia l reported no ccsvi in ms but their results did show a signifi-no nco mm er cia l but their results did show a signifi39 no nco mm er cia l 39 that inter-operator varino nco mm er cia l that inter-operator variability decreases post-training (from k=0.47 to no nco mm er cia l ability decreases post-training (from k=0.47 to k=0.80) while intra-operator reproducibility in no nco mm er cia l k=0.80) while intra-operator reproducibility in trained operators was k=0.75. apart from experino nco mm er cia l trained operators was k=0.75. apart from experience and training, ultrasound imaging still no nco mm er cia l ence and training, ultrasound imaging still remains an operator-dependent investigation. no nco mm er cia l remains an operator-dependent investigation. studies that have been done so far show great no nco mm er cia l studies that have been done so far show great variability because of operator dependency, lack no nco mm er cia l variability because of operator dependency, lack us e likely to be a secondary phenomenon to ms. us e likely to be a secondary phenomenon to ms.their results showed that ccsvi was found in us e their results showed that ccsvi was found in 50% of pediatric ms cases as well as in 38% ofus e 50% of pediatric ms cases as well as in 38% of clinically isolated syndrome cases, thus makingus e clinically isolated syndrome cases, thus making ultrasound investigations of the ccsvi picture us e ultrasound investigations of the ccsvi picturewas considered in the 2009 uip consensus us e was considered in the 2009 uip consensuso nlyon lypathology is necessary to on lypathology is necessary toestablish a new medical entity on lyestablish a new medical entity on ly the morphology seen at venography andon ly the morphology seen at venography and ultrasound investigations of the ccsvi picture on ly ultrasound investigations of the ccsvi picture no nco mm er cia l u se on ly review [veins and lymphatics 2013; 2:e14] [page 45] tributing to explain the reduced mechanical wall properties as well as venous narrowing.23 the studies above cited demonstrate how ccsvi is characterized by peculiar pathology. more specifically: i) in a post mortem study comparing ms patients with people who dead for different reasons, valvular and other intraluminal abnormalities with potential hemodynamic consequences were identified in 72% of ms patients and in 17% of controls. these abnormalities included circumferential membranous structures, longitudinally-oriented membranous structures, single valve flap replacing ijv valve, and enlarged and malpositioned valve leaflets. to the contrary, vein wall stenosis occurred at similar frequency in both groups;21 ii) the expression of collagen type i and iii, cytoskeletal proteins, and inflammatory markers was investigated in ijvs specimens from ms patients and controls. veins of ms patients were found with a higher expression of type iii collagen, whereas control specimen exhibited a clear prevalence of type i over type iii collagen. a reduced collagen type i/iii ratio allegedly alters mechanical stability and reduces mechanical strength of connective tissue contributing to abnormalities described in ccsvi. interestingly, no differences in inflammatory marker expression were observed. particularly, no-t cells infiltration suggesting an infective and/or autoimmune vasculitis was found in the jugular venous wall. according with the authors’ conclusions, this study demonstrates that extracranial venous lesions of ms patients could be of congenital origin, and not related to a product of ms autoimmunity.23 chronic cerebrospinal venous insufficiency assessment by catheter venography catheter venography, eventually combined with intravascular sonography, is actually still considered the gold standard for ccsvi assessment. they are of course invasive, and we need to develop a multimodality approach in order to use venous catheter only if a treatment should be planned. it seems necessary to perform a blinded study whch also includes catheter venography performed in a group of volunteers, in order to establish radiological normality. however, studies performed along the 60’s-70’s on healthy subjects did not demonstrate these types of lesions.9-18 to the contrary, catheter venography studies strongly supports the presence of ccsvi in ms because in 12 studies coming from 8 different countries the prevalence is always more than 90%.1,3,43-53 (figure 1). chronic cerebrospinal venous insufficiency and brain pathophysiology there are 2 proven pathophysiologic consequences of the presence of significant narrowing in the extracranial veins. the significance of blocked outflow has been proposed to be scored with the venous hemodynamic insufficiency severity score (vhiss). subjects with ccsvi showed higher frequency of venous reflux, blocked flow, b-mode abnormalities, and reduced ijv compliance which led to increased vhiss. the latter index was used to investigate the relationship with both csf flow dynamics and brain perfusion, both assessed with advanced and non conventional mri measure. the cerebrospinal fluid (csf) is formed in lateral ventricles and mainly flows through brain’s ventricular system, over and around cerebral hemispheres, and is absorbed by arachnoid villi into the superior sagittal sinus, connected via the transverse sinus with the jugulars. normal circulation of the csf desires an optimal balance between ultrafiltration of csf and its clearance from csf spaces into the venous system at the level of dural sinuses, which depends mainly on efficient venous drainage.54,55 in 2009 zamboni et al.56 performed a blinded mr study which demonstrated venous outflow disturbance in ms patients. the study showed that impaired csf dynamics may be a factor contributing to the increased volumes in 3rd and lateral ventricles, which was frequently observed in ms patients. this study demonstrated that ccsvi has a significant impact on brain pathophysiology, especially on intracranial fluid balance. moreover, zivadinov et al.57 demonstrated the correctness of the correlation between venous outflow and csf flow dynamics measuring the change in csf flow and velocity after venous angioplasty in a randomized group of patients. at month six from the treatment, significant improvement in csf flow (p<0.001) and velocity (p=0.013) was detected in the treated arm compared to the no treatment group. this difference persisted at month 12 of the study for both csf flow (p=0.001) and velocity (p=0.021) measures between the 2 groups. cerebral perfusion is figure 1. left) catheter venography of the internal jugular vein in healthy control; right) stenosis (arrows) and collateral circles activated in a chronic cerebrospinal venous insufficiency case, studied by the means of catheter venography. courtesy of dr roberto galeotti. no nco mm er cia l chronic cerebrospinal venous no nco mm er cia l chronic cerebrospinal venous insufficiency assessment by no nco mm er cia l insufficiency assessment by catheter venography, eventually combinedno nco mm er cia l catheter venography, eventually combined with intravascular sonography, is actually stillno nco mm er cia l with intravascular sonography, is actually stillno nco mm er cia l u se arachnoid villi into the superior sagittal sinus, us e arachnoid villi into the superior sagittal sinus, connected via the transverse sinus with the us e connected via the transverse sinus with thejugulars. normal circulation of the csf desires us e jugulars. normal circulation of the csf desires o nlycerebral hemispheres, and is absorbed by on ly cerebral hemispheres, and is absorbed by the treatment, significant improvement in csf on ly the treatment, significant improvement in csf flow (p<0.001) and velocity (p=0.013) was on lyflow (p<0.001) and velocity (p=0.013) wasdetected in the treated arm compared to the no on lydetected in the treated arm compared to the notreatment group. this difference persisted at on lytreatment group. this difference persisted at month 12 of the study for both csf flowon ly month 12 of the study for both csf flow (p=0.001) and velocity (p=0.021) measureson ly (p=0.001) and velocity (p=0.021) measures between the 2 groups. cerebral perfusion is on ly between the 2 groups. cerebral perfusion is no nco mm er cia l u se on ly review [page 46] [veins and lymphatics 2013; 2:e14] always measured as diffusely impaired in ms patients.58-61 this aspect of ms is related to the aspect of chronic hypoxia linked with increased oxydative stress and cannot be explained, of course, with the autoimmune theory.58 the hypothesis that ccsvi could be a contributory factor to cerebral hypoperfusion was further investigated in a blinded mri study.62 hypoperfusion of the brain parenchyma was measured to be proportionally decreased in ms patients with higher vhiss, demonstrating how the blocked outflow in the jugular veins is related to brain perfusion and oxygen delivery. chronic cerebrospinal venous insufficiency and interventional procedures a second reason of the controversy is the opposition to perform balloon angioplasty (pta) of the jugulars and az system, for treating ccsvi expecially in ms patients. despite the endovascular procedure was considered in an opinion paper published in a major journal of clinical neurology a dangerous procedure,26 pta can be definitely considered a safe procedure, whereas for stenting level of risk is slightly increased.63-65 moreover, from 2009 the effectiveness of pta in eventually improving the results of current medical therapy of ccsvi was assessed with prospective open label design. clinical and quality of life (qol) improvements are reported in a number of prospective and case control studies following interventional procedures.66-72 particularly, chronic fatigue, a disabling symptom of ms without any effective treatment is reported to improve practically in any interventional study, as well as qol assessed with validated questionaires. physical performance seems also to improve when the procedure is attempted in early cases and/or in relapsing remitting clinical form respect to long time disease and progressive forms. the results are quite interesting and warrant an increased level of evidence to esclude that results should be biased by the placebo effect. to this aim a double blinded randomized trial is actually in course.73 conclusions the controversy in the ccsvi issue is strongly linked with the ultrasonographic screening wich is highly operator dependent leading to a big heterogenity in prevalence studies. however, catheter venography data, despite the invasiveness of the diagnostic procedures, clearly indicates an amazing rate of ccsvi in people affected by ms. pathology, either gross anatomy or histology, supports that ccsvi is a new medical entity, needing of further improvement in the diagnostic methodology. this is the only way to decrease the actual controversy. finally, the two main consequences in brain pathophysiology linked with ccsvi are respectively the reduction of csf flow dynamics and of brain perfusion. the vascular consequences of ccsvi at the microcirculatory level may help us in interpretating several unknown aspect of ms, and expecially those at the blood brain barrier.74 finally, all the above evidences support to move to a randomized control trial in order to assess the value of vascular treatment of ccsvi in neurodegeneration. references 1. zamboni p, galeotti r, menegatti e, et al. chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j neurol neurosurg psychiatry 2009;80:3929. 2. zamboni p, consorti g, galeotti r, et al. venous collateral circulation of the extracranial cerebrospinal outflow routes. curr neurovasc res 2009;6:204-12. 3. zivadinov r, galeotti r, hojnacki d, et al. value of mr venography for detection of internal jugular vein anomalies in multiple sclerosis: a pilot longitudinal study. ajnr 2011;32:938-46. 4. zamboni p. regarding no cerebrocervical venous congestion in patients with multiple sclerosis. intraluminal jugular septation. ann neurol 2010;68:969. 5. al-omari mh, rousan la. internal jugular vein morphology and hemodynamics in patients with multiple sclerosis. int angiol 2010;29:115-20. 6. lee bb, laredo j, neville r: embryological background of truncular venous malformation in the extracranial venous pathways as the cause of chronic cerebrospinal venous insufficiency. intern angiol 2010;29:95-108. 7. lee bb, bergan j, gloviczki p, et al. diagnosis and treatment of venous malformations-consensus document of the international union of phlebology (iup)2009. intern angiol 2009;28:434-51. 8. lee bb, laredo j, lee ts, et al. terminology and classification of congenital vascular malformations. phlebology 2007;22:249-52. 9. uflacker r. atlas of vascular anatomy. an angiographic approach. philadephia, pa: lippincott williams & wilkins; 1997. 10. hamoud s, nitecky s, engel a, et al. hypoplasia of the inferior vena cava with azygous continuation presenting as recurrent leg deep vein thrombosis. am j med sci 2000;319:414-6. 11. gates j, hartnell gg. demonstration of inferior vena cava patency by retrograde azygous venography. cardiovasc intervent radiol 1995;18:419-21. 12. lane ej, heitzman er, dinn wm. the radiology of the superior intercostals veins. radiology 1976;120:263-7. 13. chasen mh, charnsangavej c. venous chest anatomy: clinical implications. eur j radiol 1998;27:2-14. 14. mammen t, keshava sn, eapen ce, et al. transjugular liver biopsy: a retrospective analysis of 601 cases. j vasc interv radiol 2008;19:351-8. 15. dilenge d, perey b, geraud g, et al. angiographic demonstration of the cervical vertebral venous plexus in man. j can assoc radiol 1975;26:77-81. 16. zelli gp, messinetti s, condorelli s. original technic of internal jugular phlebography by puncture of the external jugular vein with retrograde emmission of the contrast media. prog med 1964;15:681-8. 17. gejrot t, lauren t. retrograde venography of the internal jugular veins and transverse sinuses, technique and roentgen anatomy. acta otolaryngol 1964;57:556-70. 18. gejrot t. retrograde jugularography in the diagnosis of abnormalities of the superior bulb of the internal jugular vein. acta otolaryngol 1964;57:177-80. 19. leriche h, aubin ml, aboulker j. cavo-spinal phlebography in myelopathies. stenoses of internal jugular and azygos veins, venous compressions and thromboses acta radiol suppl 1976;347:415-7. 20. tzuladze ii. the selective phlebography of the large tributaries of the vena cava system in the diagnosis of venous circulatory disorders in the spinal complex. zh vopr neirokhir im n n burdenko 1999;2:813. 21. diaconu c, staugaitis s, mcbride j, et al. anatomical and histological analysis of venous structures associated with chronic cerebro-spinal venous insufficiency. 5th ectrims, amsterdam, the netherands, 2011, abstract. 22. baiocchini a, toscano r, von lorch w, et al. anatomical stenosis of the internal jugular veins : supportive evidence of chronic cerebrospinal venous insufficiency? eletter jnnp; 2011. available from: http://jnnp.bmj.com/content/82/4/355.extra ct/reply#jnnp_el_7244 23. coen m, menegatti e, salvi f, et al. characterization of ccsvi lesions in multiple sclerosis patients. 4th annual isnvd scientific meeting 2011, bologna, italy, abstract. no nco mm er cia l particularly, chronic fatigue, a disno nco mm er cia l particularly, chronic fatigue, a disabling symptom of ms without any effective no nco mm er cia l abling symptom of ms without any effective treatment is reported to improve practically in no nco mm er cia l treatment is reported to improve practically in any interventional study, as well as qol no nco mm er cia l any interventional study, as well as qol assessed with validated questionaires. no nco mm er cia l assessed with validated questionaires. physical performance seems also to improveno nco mm er cia l physical performance seems also to improve when the procedure is attempted in early casesno nco mm er cia l when the procedure is attempted in early cases 2. zamboni p, consorti g, galeotti r, et al. no nco mm er cia l 2. zamboni p, consorti g, galeotti r, et al.venous collateral circulation of the extrano nco mm er cia l venous collateral circulation of the extracranial cerebrospinal outflow routes. curr no nco mm er cia l cranial cerebrospinal outflow routes. curr neurovasc res 2009;6:204-12. no nco mm er cia l neurovasc res 2009;6:204-12. 3. zivadinov r, galeotti r, hojnacki d, et al. no nco mm er cia l 3. zivadinov r, galeotti r, hojnacki d, et al. value of mr venography for detection of no nco mm er cia l value of mr venography for detection of internal jugular vein anomalies in no nco mm er cia l internal jugular vein anomalies in multiple sclerosis: a pilot longitudinal no nco mm er cia l multiple sclerosis: a pilot longitudinal study. ajnr 2011;32:938-46. no nco mm er cia l study. ajnr 2011;32:938-46. 4. zamboni p. regarding no cerebrocervical no nco mm er cia l 4. zamboni p. regarding no cerebrocervical venous congestion in patients with multino nco mm er cia l venous congestion in patients with multiple sclerosis. intraluminal jugular septano nco mm er cia l ple sclerosis. intraluminal jugular septation. ann neurol 2010;68:969. no nco mm er cia l tion. ann neurol 2010;68:969. 5. al-omari mh, rousan la. internal jugular no nco mm er cia l 5. al-omari mh, rousan la. internal jugular us e cy in patients with multiple sclerosis. j us e cy in patients with multiple sclerosis. jneurol neurosurg psychiatry 2009;80:392us e neurol neurosurg psychiatry 2009;80:3922. zamboni p, consorti g, galeotti r, et al.us e 2. zamboni p, consorti g, galeotti r, et al. on ly angiographic demonstration of the cervion ly angiographic demonstration of the cervical vertebral venous plexus in man. j can on lycal vertebral venous plexus in man. j canassoc radiol 1975;26:77-81. on lyassoc radiol 1975;26:77-81. 16. zelli gp, messinetti s, condorelli s. on ly16. zelli gp, messinetti s, condorelli s. original technic of internal jugular phle-on ly original technic of internal jugular phlebography by puncture of the external jugu-on ly bography by puncture of the external jugular vein with retrograde emmission of the on ly lar vein with retrograde emmission of the no nco mm er cia l u se on ly review [veins and lymphatics 2013; 2:e14] [page 47] 24. khan o, tselis a. chronic cerebrospinal venous insufficiency and multiple sclerosis: science or science fiction? jnnp 2011;82:355. 25. bagert ba, marder e, stueve o. chronic cerebrospinal venous insufficiency and multiple scerosis. arch neurol. published online: doi:10.1001/archneurol.2011.179. 26. khan o, fillippi m, freedman ms, et al. chronic cerebrospinal venous insufficiency and multiple sclerosis. ann neurol 2010;67:286-90. 27. chafe r, born kb, slutsky as, et al. the rise of people power. nature 2011;472:4101. 28. reekers ja, lee mj, belli am, et al. cardiovascular and interventional radiological society of europe commentary on the treatment of chronic cerebrospinal venous insufficiency. cardiovasc intervent radiol 2011;34:1-2. 29. doepp f, paul f, valdueza jm, et al. no cerebrocervical venous congestion in patients with multiple sclerosis. ann neurol 2010;68:173-83. 30. mayer ca, waltraud p, matthias wl, et al. the perfect crime? ccsvi not leaving a trace in ms. j neurol neurosurg psychiatry 2011;82:436-40. 31. floris r, centonze d, fabiano s, et al. prevalence study of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: preliminary data. radiol med 2012;117:855-64. 32. marder e, gupta p, greenberg bm, et al. no cerebral or cervical venous insufficiency in us veterans with multiple sclerosis. arch neurol 2011;68:1521-5. 33. baracchini c, perini p, calabrese m, et al. no evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset. ann neurol 2011;69:90-9. 34. wattjes mp, van oosten bw, de graaf wl, et al. no association of abnormal cranial venous drainage with multiple sclerosis: a magnetic resonance venography and flowquantification study. neurol neurosurg psychiatry 2011:82:429-35. 35. dolic k, weinstock-guttman b, marr k, et al. risk factors for chronic cerebrospinal venous insufficiency (ccsvi) in a large cohort of volunteers. plos one 2011;6:e28062. 36. zivadinov r, marr k, cutter g, et al. prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in ms. neurology 2011;77:138-44. 37. bastianello s, romani a, viselner g, et al. chronic cerebrospinal venous insufficiency in multiple sclerosis: clinical correlates from a multicentre study. bmc neurol 2011;11:132. 38. simka m, kostecki j, zaniewski m, et al. extracranial doppler sonographic criteria of chronic cerebrospinal venous insuffitiency in the patients with multiple sclerosis. int angiol 2010;29:109-14. 39. menegatti e, genova v, tessari m, et al. the reproducibility of color doppler in chronic cerebrospinal venous insufficiency associated with multiple scleroris. internl angiol 2010;29:121-6. 40. zamboni p, morovic s, menegatti e, et al. screening for chronic cerebrospinal venous insufficiency (ccsvi) using ultrasound. recommendations for a protocol. int angiol 2011;30:1-2. 41. laupacis a, lillie e, dueck a, et al. association between chronic cerebrospinal venous insufficiency and multiple sclerosis: a meta-analysis. cmaj 2011;183:e1203-12. 42. zamboni p. regarding no cerebrocervical venous congestion in patients with multiple sclerosis. intraluminal jugular septation. ann neurol. 2010;68:969; author reply 970. 43. zamboni p, sisini f, menegatti e, et al. an ultrasound model to calculate the brain blood outflow through collateral vessels: a pilot study. bmc neurol 2013;13:81. 44. petrov i, grozdinski l, kaninski g, et al. safety profile of endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j endovasc ther 2011;18:314-23. 45. beelen r, maene l, castenmiller p, et al. evolution in quality of life and epidemiological impact after endovascular treatment of chronic cerebro-spinal venous insufficiency in patients with multiple sclerosis. phlebology 2012;27:187-9. 46. mandato kd, hegener pf, siskin gp, et al. safety of endovascular treatment of chronic cerebrospinal venous insufficiency: a report of 240 patients with multiple sclerosis. j vasc intervent radiol 2012;23:55-9. 47. lugli m, morelli m, guerzoni s, maleti o. the hypothesis of patho-physiological correlation between chronic cerebrospinal venous insufficiency and multiple sclerosis: rationale of treatment. phlebology 2012;27:178-86. 48. ludyga t, kazibudzki m, simka m, et al. endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? phlebology 2010;25:286-95. 49. milic dj. liberation procedure in the treatment of chronic cerebrospinal venous insufficiency is chronic cerebro-spinal venous insufficiency related to brain congestive syndrome rather than multiple sclerosis. j vasc surg 2012:55:302-3. 50. kostecki j, zaniewski m, ziaja k, et al. an endovascular treatment of chronic cerebro-spinal venous insufficiency in multiple sclerosis patients 6 month follow-up results. neuro endocrinol lett 2011;32:557-62. 51. ludyga t, authors???? (3 names et al) et al. early results of a prospective open-label study on endovascular treatments for chronic cerebrospinal venous insufficiency in the patients with associated multiple sclerosis. phlebol rev 2011;19:9-14. 52. kipshidze n, rukhadze i, archvadze a, et al. endovascular treatment of patients with chronic cerebrospinal venous insufficiency and multiple sclerosis. georgian med news 2011;10:29-33. 53. simka m, ludyga t, latacz p, kazibudzki m. diagnostic accuracy of current sonographic criteria for the detection of outflow abnormalities in the internal jugular veins. phlebology 2012. [epub ahead of print]. 54. schaller b. physiology of cerebral venous blood flow: from experimental data in animals to normal function in humans. brain res rev. 2004;46:243–60. 55. ursino m, lodi ca. a simple mathematical model of the interaction between intracranial pressure and cerebral hemodynamics. j appl physiol 1997;82:1256-69. 56. zamboni p, menegatti e, weinstockguttman b, et al. the severity of chronic cerebrospinal insufficiency in patients with multiple sclerosis is related to altered cerebrospinal fluid dynamics. funct neurol 2009;24:133-8. 57. zivadinov r, magnano c, galeotti r, et al. changes of cine cerebrospinal fluid dynamics in multiple sclerosis patients treated with venous angioplasty. j int vasc rad 2013;24:829-38. 58. d’haeseleer m, cambron m, vanopdenbosch l, de keyser j. vascular aspects of multiple sclerosis. lancet neurol 2011;10:657-66. 59. law m, saindane am, ge y, et al. microvascular abnormality in relapsingremitting multiple sclerosis: perfusion mr imaging findings in normal-appearing white matter. radiology 2004;231:645-52. 60. brooks dj, leenders kl, head g, et al. studies on regional cerebral oxygen utilisation and cognitive function in multiple sclerosis. jnnp 1984;47:1182-91. 61. de keyser j, steen c, mostert jp, et al. hypoperfusion of the cerebral white matter in multiple sclerosis: possible mechanisms and pathophysiological significance. j cereb blood flow metab 2008;28: 1645-51. 62. zamboni p, menegatti e, weinstockguttman b, et al. hypoperfusion of brain parenchyma is associated with the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a cross-sectional preliminary report. bmc med 2011;9:22. 63. ludyga t, kazibudzki m, simka m, et al. no nco mm er cia l 33. baracchini c, perini p, calabrese m, et al. no nco mm er cia l 33. baracchini c, perini p, calabrese m, et al. no evidence of chronic cerebrospinal no nco mm er cia l no evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis no nco mm er cia l venous insufficiency at multiple sclerosis onset. ann neurol 2011;69:90-9. no nco mm er cia l onset. ann neurol 2011;69:90-9. 34. wattjes mp, van oosten bw, de graaf wl, no nco mm er cia l 34. wattjes mp, van oosten bw, de graaf wl, et al. no association of abnormal cranial no nco mm er cia l et al. no association of abnormal cranial venous drainage with multiple sclerosis: ano nco mm er cia l venous drainage with multiple sclerosis: a magnetic resonance venography and flow-no nco mm er cia l magnetic resonance venography and flowsafety profile of endovascular treatment no nco mm er cia l safety profile of endovascular treatmentfor chronic cerebrospinal venous insuffino nco mm er cia l for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. no nco mm er cia l ciency in patients with multiple sclerosis. j endovasc ther 2011;18:314-23. no nco mm er cia l j endovasc ther 2011;18:314-23. 45. beelen r, maene l, castenmiller p, et al. no nco mm er cia l 45. beelen r, maene l, castenmiller p, et al. evolution in quality of life and epidemiolono nco mm er cia l evolution in quality of life and epidemiological impact after endovascular treatment no nco mm er cia l gical impact after endovascular treatment of chronic cerebro-spinal venous insuffino nco mm er cia l of chronic cerebro-spinal venous insufficiency in patients with multiple sclerosis. no nco mm er cia l ciency in patients with multiple sclerosis. phlebology 2012;27:187-9. no nco mm er cia l phlebology 2012;27:187-9. 46. mandato kd, hegener pf, siskin gp, et al. no nco mm er cia l 46. mandato kd, hegener pf, siskin gp, et al. safety of endovascular treatment of chrono nco mm er cia l safety of endovascular treatment of chrous e ultrasound model to calculate the brain us e ultrasound model to calculate the brain blood outflow through collateral vessels: a us e blood outflow through collateral vessels: apilot study. bmc neurol 2013;13:81. us e pilot study. bmc neurol 2013;13:81. 44. petrov i, grozdinski l, kaninski g, et al.us e 44. petrov i, grozdinski l, kaninski g, et al. safety profile of endovascular treatmentus e safety profile of endovascular treatment on ly 43. zamboni p, sisini f, menegatti e, et al. an on ly 43. zamboni p, sisini f, menegatti e, et al. an blood flow: from experimental data in anion ly blood flow: from experimental data in animals to normal function in humans. brain on lymals to normal function in humans. brainres rev. 2004;46:243–60. on lyres rev. 2004;46:243–60. 55. ursino m, lodi ca. a simple mathematical on ly55. ursino m, lodi ca. a simple mathematical model of the interaction between intracra-on ly model of the interaction between intracranial pressure and cerebral hemodynamics.on ly nial pressure and cerebral hemodynamics. no nco mm er cia l u se on ly review [page 48] [veins and lymphatics 2013; 2:e14] endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? phlebology 2010;25:286-95. 64. petrov i, grozdinski l, kaninski g, et al. safety profile of endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. j endovasc ther 2011;18:314-23. 65. mandato kd, hegener pf, siskin gp, et al. safety of endovascular treatment of chronic cerebrospinal venous insufficiency: a report of 240 patients with multiple sclerosis. j vasc interv radiol 2012;23:55-9. 66. zamboni p, galeotti r, menegatti e, et al. a prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. j vasc surg 2009;50:1348-58. 67. hubbard d, ponec d, gooding j, et al. clinical improvement after extracranial venoplasty in multiple sclerosis. j vasc interv radiol 2012;23:1302-8. 68. zamboni p, galeotti r, weinstock-guttman b, et al. venous angioplasty in patients with multiple sclerosis: results of a pilot study. eur j vasc endovasc surg 2012;43:116-22. 69. salvi f, bartolomei i, buccellato e, et al. venous angioplasty in multiple sclerosis: neurological outcome at two years in a cohort of relapsing-remitting patients. funct neurol 2012;27:55-9. 70. beelen r, maene l, castenmiller p, et al. evolution in quality of life and epidemiological impact after endovascular treatment of chronic cerebro-spinal venous insufficiency in patients with multiple sclerosis. phlebology 2012;27:187-9. 71. denislic m, milosevic z, zorc m, et al. disability caused by multiple sclerosis is associated with the number of extra cranial venous stenoses: possible improvement by venous angioplasty. results of a prospective study. phlebology 2012. [epub ahead of print]. 72. radak d, kolar j, sagic d, et al. percu taneous angioplasty of internal jugular and azygous veins in patients with chronic cerebrospinal venous insufficiency and multiple sclerosis: early and mid-term results. phlebology 2013. [epub ahead of print]. 73. zamboni p, bertolotto a, boldrini p, et al. efficacy and safety of venous angioplasty of the extracranial veins for multiple sclerosis. brave dreams study (brain venous drainage exploited against multiple sclerosis): study protocol for a randomized controlled trial. trials 2012;13:183. 74. singh av, khare m, gade wn, zamboni p. theranostic implications of nanotechnology in multiple sclerosis: a future perspective. autoimmune dis 2012;2012:160830. no nco mm er cia l u se on ly theranostic implications of nanotechnoloon ly theranostic implications of nanotechnology in multiple sclerosis: a future perspection ly gy in multiple sclerosis: a future perspective. autoimmune dis 2012;2012:160830. on lyve. autoimmune dis 2012;2012:160830. no nco mm er cia l u se on ly hrev_master veins and lymphatics 2013; volume 2:e13 [veins and lymphatics 2013; 2:e13] [page 39] comparison of knee-high mediven ulcer kit and mediven plus compression stockings: measurement of leg volume, interface pressure and static stiffness index changes gy�őző�szolnoky, georgina molnár, dóra nemes-szabó, enikő varga, mónika varga, lajos kemény department of dermatology and allergology, university of szeged, szeged, hungary abstract ulcer stockings are produced to have higher interface pressure and easier application compared to those of classic medical compression stockings. we aimed to compare volume decrease, pressure loss and stiffness index of a classical medical compression stocking and an ulcer stocking of the same interface pressure range in 10 patients with bilateral venous and 10 persons with lymphatic insufficiency. interface pressure measurement in supine and standing positions and optoelectronic volumetry served for primary outcome variables. both stockings were capable of inducing remarkable gradual volume reductions in different time points except classic stocking at 2 h in phleboedema care. ulcer stocking pressures in lymphand phleboedema were highly superior. in lymphedema a gradual interface pressure loss was attributed to both stockings regardless of body positions. static stiffness indices did not differ statistically except classic stocking at baseline (p=0.0312) and 2 h (p=0.0082) comprising venous edema patie nts. both stockings acted similarly but ulcer stocking had considerably higher interface pressures in each measurement and raised stiffness indices initially and the two-layer system facilitates donning therefore ulcer stocking could serve an alternative of classic medical compression stocking even in the treatment of leg edema. introduction the intensive treatment of the two prevalent causes of chronic leg edema [chronic venous insufficiency (cvi) and lymphedema] is commonly based on various bandage systems.1 inelastic bandages, especially when two or more are applied in an overlapping fashion, have high stiffness, a significant pressure loss is observed within the first hours of application due to the rapid volume reduction.2 medical compression stockings (mcss) are elastic devices with relatively low stiffness index (<10).3 unlike bandages, mcss are observed to loose original interface pressure to a lesser degree.2 there is an emerging body of evidence that mcss are also capable of efficient volume reduction even in the intensive therapeutical phase.1 taken the previous data together, mcss are presumed to possess some important features of efficient compression, however the achievable high interface pressures may associate low patient compliance as both donning and removal of the garment cause difficulties and require outstandingly high forces.4 the pressure of the two superimposed stockings was shown to roughly correspond to the direct addition of the interface pressure exerted by the single layer due to interface friction.5 overlapping stockings efficiently raise interface pressure and alleviate application. classic mcss are recommended for daily use but depending on interface pressure in supine position, patients are sometimes asked to wear their stockings overnight. the nocturnal wear of understocking of ulcer garments is preferred.5 the new generation of stockings with double-layers is preferably recommended for leg ulcer healing but its potential advances over traditional mcss give rise to a comparative study in view of stiffness. this was the background for a clinical study in which we compared interface pressures of an ulcer stocking with that of a traditional mcs belonging to the identical pressure range. materials and methods a total of 20 legs from ten out-patients with bilateral cvi [three males, seven females; age 52-75, median 61; mean body mass index (bmi) (kg/m2): 30.57 (21.52-45.84); mean disease duration (years): 5 (1-20); clinical clinical-etiology-anatomy-pathophysiology classification (ceap)-classes c3-6] and another 20 legs of ten secondary lymphedema outpatients with bilateral lower limb affections (three males, seven females; age 55-81, median 70; mean bmi (kg/m2): 36 (24-41); mean disease duration (years): 8 (4-14) were recruited. each of the bilateral secondary lymphedema cases was stage ii comprising 5 persons with gynecological cancer treatmentrelated moderate lymphedema and another 5 patients where repeated erysipelas affecting both legs at different time caused lymphedema. cvi was diagnosed using color-coded duplex ultrasonography. patients did not wear any form of compression garment 48 h before the beginning of the trial (wash-out period) and lymphedematous legs did not receive supplementary treatment (e.g. manual lymph drainage, intermittent pneumatic compression). inclusion criteria were in accordance with the recommendations of the international compression club.1 informed consent was obtained from each patient and the study protocol conformed to the regular ethical guidelines, as reflected in a prior approval by the university of szeged human research committee. according to limb girths standard belowknee stockings (mediven ulcer kit and mediven plus compression class 3) were provided by the medi company (bayreuth, germany). interface pressure was measured by kikuhime (medi trade, soro, denmark) device6 using small pressure probe placed to point b1 at baseline, 2, 4 and 24 h in standing and supine positions, as well. pressure probe was not held continuously under the stocking but was placed immediately after pulling down the compression material then stocking was redone and finally the measurement was completed. according to our standards, mediven ulcer kit was assigned to right, while mediven plus to the left leg. stockings were worn for 24 h with a surprisingly sufficient tolerability. the static stiffness index (ssi) was calculated as the difference between standing and supine pressures.7 leg volumes were assessed with infrared optoelectronic measurement using perometer (perimed, wuppertal, germany)8 at baseline and immediately after pulling down the stockings taking only 2-4 min in each case. correspondence: győző szolnoky, department of dermatology and allergology, university of szeged, 6720 szeged, korányi fasor 6., hungary. e-mail: szolnoky@dermall.hu key words: volumetry, static stiffness index, medical compression stocking, ulcer stocking. conference presentation: part of this paper was presented at the international compression club (icc) meeting on stiffness of compression devices, 2012 may 25, vienna, austria (http:// www.icc-compressionclub.com/). acknowledgments: medi (bayreuth, germany) company supported the clinical study with standard mediven plus ccl 3 ad and mediven ulcer kit stockings. received for publication: 17 january 2013. revision received: 8 march 2013. accepted for publication: 4 april 2013. this work is licensed under a creative commons attribution 3.0 license (by-nc 3.0). ©copyright g. szolnoky et al., 2013 licensee pagepress, italy veins and lymphatics 2013; 2:e13 doi:10.4081/vl.2013.e13 no nco mm er cia l u se on ly conference presentation [page 40] [veins and lymphatics 2013; 2:e13] feet and calves were subjected to volumetry. to compare ssi of the two products (right side vs left side), the non-parametric mann-whitney test was used. comparisons between the pressure and volume values at different time points using the same type of stocking were made by wilcoxon signed rank test as a nonparametric measure. p values lower than 0.05 were considered as statistically significant. results volume change both mediven ulcer kit and mediven plus stockings were capable of inducing remarkable gradual volume reductions in different time points. each of the measured volume decreases appeared to be significant except mediven plus at 2 h among patients with phleboedema. interface pressure the pressure exerted by ulcer stocking in lymphand phleboedema was highly superior to that of mediven plus at each measurement in lying and standing positions except a single assessment at 2 h in upright position (p= 0.0707) of the patients with lymphedema. pressure alteration in lymphedema a gradual interface pressure loss was attributed to both compression stockings regardless of body position positions (figure 1). mediven plus failed to cause a pressure decrease 2 h after the beginning of application in supine (p=0.1016) and standing (p=0.509) positions, as well. venous edema treatment with mediven plus associated significant pressure losses in supine positions but did not provoke any significant changes of interface pressures (p=0.0762 at 2 h, p=0.1602 at 4 h and finally p=0.0547 at 24 h) in standing posture (figure 2). static stiffness index the calculated static stiffness indices did not differ statistically regardless of compression material in lymphedema (figure 3a), however this parameter of mediven plus (median: 2.00) was significantly inferior to that of ulcer stocking (median: 4.00) at the first two measurements (baseline: p=0.0312 and 2 h: p=0.0082) comprising venous edema patients (figure 3b). discussion according to experiments in the field of compression therapy two factors play a pivotal role in setting an efficient therapy. interface figure 1. interface pressures of mediven ulcer kit and mediven plus ad ccl 3 stockings in supine (a,b) and standing (c,d) positions in lymphedema. figure 2. interface pressures of mediven ulcer kit and mediven plus ad ccl 3 stockings in supine (a,b) and standing (c,d) positions in venous edema. no nco mm er cia l u se on ly conference presentation [veins and lymphatics 2013; 2:e13] [page 41] pressure measured under the compression material is able to restore venous and lymphatic insufficiency along narrowing veins and ameliorating interstitial pressure. clinical studies demonstrated that the application of higher external pressure lead to a faster venous leg ulcer healing by efficiently counteracting the high ambulatory venous pressure thus providing an enhanced venous flow. lower extremity edema sometimes presents in a combined form including impaired venous function, lymphatic insufficiency and increased capillary permeability,1 thus the relatively high edema volume warrants fairly high external pressure. evacuation of edema and the most advanced form of venous insufficiency are preferably directed to inelastic compression bandaging in a multilayer and multicomponent fashion where interface pressure is strongly correlated with the tensile forces.9,10 mcss are usually used in the maintenance phase where achieved results (volume decrease, healed ulcer) should be preserved.1 the higher success rate in leg affection is attributed to the applied pressure. if the external pressure meets the ordinary range of ambulatory venous pressure in impaired function it might minimize the risk of recurrence. medical compression stockings are manufactured from elastic material so as to facilitate donning and positioning over bony prominences but the elastic properties possess at least two disadvantages: stockings less efficiently assist muscle pump11 and keep nearly the same pressure regardless of position having low ssis. a major burden of increasing compression pressure is the tolerability. classic medical compression stockings of higher pressures cause difficulties in donning and keeping them on legs in lying position. a new generation of stockings tends to alleviate these problems comprising an underand an overstocking with relatively low pressures. these two superimposed garments set the final pressure.5 these overlapping stockings were designed especially to treat leg ulcers but their other advantages made them interesting for other objectives like the use in chronic leg edema (e.g. phlebor lymphedema) however remained relatively poorly characterized and compared to other compression materials. beyond their relatively easy application we were able to experience that ulcer stockings also exerted significant leg volume reduction and brought up significantly higher interface pressure compared to classical mcss. the difference between lying and standing positions results ssi that is an accurate indicator of appropriate stocking selection for patients.12 low pressure at supine position and a substantial rise after standing up provides a comfortable wear and an efficient prevention against edema formation and venous dilation. we were able to show that the ssi of the given ulcer stocking was able to exceed that of compression class 3 medical stocking in venous edema during the initial phase of treatment however it remained still relatively low. stockings with higher stiffness have a higher anti-edematous efficacy.13 a previous clinical trial disclosed that the superposition of two stockings did not only increase the interface pressure, but had a further additive effect to the stiffness of the final stocking combination.3 to our knowledge this is the first comparative study examining two types of stockings from the aspect of stiffness index as one of the most emphasized primary outcome variable. from the practical point of view we recommend the use of ulcer stockings instead of classic mcs with identical interface pressure when the final pressure should be adjusted along easier doffingand in case of distinct leg edema forms. references 1. stout n, partsch h, szolnoky g, et al. chronic edema of the lower extremities: international consensus recommendations for compression therapy clinical research trials. int angiol 2012;31:316-29. 2. larsen am, futtrup i. watch the pressure it drops! ewma j 2004;4:8-12. 3. partsch h, partsch b, braun w. interface pressure and stiffness of ready made compression stockings: comparison of in vivo and in vitro measurements. j vasc surg 2006;44:809-14. 4. willenberg t, lun b, amsler f, baumgar tner i. ease of application of medical compression-stocking systems for the treatment of venous ulcers. eur j vasc endovasc surg 2010;40:129-13. 5. partsch b, partsch h. compression stockings for treating venous leg ulcers: measurement of interface pressure under a new ulcer kit. phlebology 2008;23:40-6. 6. flaud p, bassez s, counord jl. compa rative in vitro study of three interface pressure sensors used to evaluate medical compression hosiery. dermatol surg 2010; 36:1930-40. 7. partsch h. the static stiffness index. a simple method to assess the elastic property of compression material in vivo. dermatol surg 2005;31:625-30. 8. pannier f, rabe e. optoelectric volume measurements to demonstrate volume changes in the lower extremities during orthostasis. int angiol 2010;29:395-400. 9. partsch h, flour m, smith pc; interna tional compression club. indica tions for compression therapy in venous and lymphatic disease consensus based on experimental data and scientific evidence. under the auspices of the iup. int angiol 2008;27:193-219. 10. partsch h, clark m, mosti g, et al. classification of compression bandages: practical aspects. dermatol surg 2008;34: 600-9. 11. mosti g, partsch h. measuring venous pumping function by strain-gauge plethysmography. int angiol 2010;29:421-5. 12. van der wegen-franken k, tank b, neumann m. correlation between the static and dynamic stiffness indices of medical elastic compression stockings. dermatol surg 2008;34:1477-85. 13. van geest aj, veraart jc, nelemans p, neumann ha. the effect of medical elastic compression stockings with different slope values on edema. measurements underneath three different types of stockings. dermatol surg 2000;26:244-7. figure 3. comparison of static stiffness indices of mediven ulcer kit and mediven plus ad ccl 3 stockings in lymphedema (a) and venous edema (b). no nco mm er cia l u se on ly