Hrev_master Veins and Lymphatics 2014; volume 3:4195 [page 74] [Veins and Lymphatics 2014; 3:4195] How to objectively assess jugu- lar 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 arti- cle by Traboulsee et al. Prevalence of extracra- nial venous narrowing on catheter venography in people with multiple sclerosis, their sibil- ings, 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 cri- terion never published to assess stenosis, in alternative to the classic measurement of the diameter in the segment immediately preced- ing 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 anato- my findings, how the jugular bulb diameter normally exceeds 50% of the minimum diame- ter 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 unrelat- ed 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 conse- quence of intraluminal obstacles, as a consid- erable part of truncular venous malformations, and/or compression; rarely of external hypopla- sia. 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 assess- ment 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 con- trol study, by Traboulsee et al.1 In that particular circumstance, I felt con- strained to reply to Traboulsee and colleagues, because the article repeatedly cites me person- ally, making comparison with the data pub- lished by my group. In the name of a transparent scientific debate, I prayed the Editor to publish my com- ment letter to the article, last October 16, 2013. The article of Traboulsee et al. was subse- quently published last January,1 and approxi- mately 2 weeks later the senior Editor of The Lancet communicated me to refuse my reply letter. I am still surprised of the editorial deci- sion 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 dila- tion 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 insuffi- ciency hypothesis, despite 13 out of 19 preva- lence studies and 3 meta-analysis papers testi- fies 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 subdivid- ed in intraluminal obstacles (septa, webs, fixed and rudimental valves) or in wall steno- sis (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 condi- tion 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 preva- lence 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 cri- terion 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 evalua- tions 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 coro- nal 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 cal- iber 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 end- point. 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 nar- rowing of the wall. In the vast majority of CCSVI patients, the venous drainage impair- ment 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 intravas- cular 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 ultra- sound, but never detected by Traboulsee et al, yet.14,15 In our papers, measuring the stenosis by comparing the narrowest tract with the diame- ter 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 con- trols. 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 condi- tion. 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 multi- modal diagnosis has been recently proposed in a position statement of the International Society for NeuroVascular Disease (ISNVD), indicating a group of invasive and non inva- sive tests giving comprehensive and comple- mentary information leading to a final CCSVI diagnosis.16 The multimodality diagnostic sys- tem 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 inva- sive screening method is highly desirable. From this point of view cervical plethysmogra- phy, 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 nor- mality of venograms. They introduced the con- cept of the clearance time of the contrast dye when injected in the veins by a standardized and reproducible protocol. These Authors cal- culated in a group of healthy controls that a standardized injection of contrast dye is elimi- nated 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 repro- ducible, 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 posi- tion 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 narrow- ing 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 malfor- mations 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 hepato- cavopathy). J Gastroenterol Hepatol 2001;16:1179-83. 7. May R, Thurner J. The cause of the pre- dominantly sinistral occurrence of throm- bosis of the pelvic veins. Angiology 1957;8:419-27. 8. Raju S, Neglen P. High prevalence of non- thrombotic iliac vein lesions in chronic venous disease: a permissive role in path- ogenicity. J Vasc Surg 2006;44:136-43. 9. Furukawa S, Nakagawa T, Sakaguchi I, Nishi K. The diameter of the internal jugu- lar 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 multi- ple sclerosis. Intraluminal jugular septa- tion”. Ann Neurol. 2010;68:969. 12. Zivadinov R, Ramanathan M, Dolic K, et al. Chronic cerebrospinal venous insufficiency in multiple sclerosis: diagnostic, patho- genetic, clinical and treatment perspectives. Expert Rev Neurother 2011;11:1277-94. 13. Karmon Y, Zivadinov R, Weinstock- Guttman B, et al. Comparison of intravas- cular ultrasound with conventional venog- raphy for detection of extracranial venous abnormalities indicative of chronic cere- brospinal 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 patho- genetic 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 nonin- vasive and invasive screening for detec- tion of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency: a position statement of the International Society for Neurovascular Disease. J Vasc Interv Radiol 201425:1785- 94. 17. Beggs C, Shepherd S, Zamboni P. Cerebral venous outflow resistance and interpreta- tion of cervical plethysmography data with respect to the diagnosis of chronic cere- brospinal 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 venogra- phy study. J Vasc Interv Radiol 2013;24: 1790-7. No n c om me rci al us e o nly