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 cere- brospinal venous insufficiency (CCSVI) and its association with both neurodegenerative disor- ders 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 effective- ness of endovascular CCSVI treatment were fur- ther 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 ultra- sound. However, 12 studies, by the means of more objective catheter venography, show a prevalence >90% of CCSVI in MS. Global hypo- perfusion of the brain, and reduced cerebral spinal fluid dynamics in MS was shown to be related to CCSVI. Postmortem studies and histol- ogy 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 epidemiolog- ical data, including studies on catheter venogra- phy, 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 pathogene- sis of neurological disorders. The controversy between the vascular and the neurological com- munity is due to the great variability in preva- lence of CCSVI in MS patients by the means of venous ultrasound assessment. More repro- ducible and objective CCSVI assessment is war- ranted. 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 steno- sis 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, mal- formed valve, or septum) or dilatation (e.g., jugu- lar 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 evi- dences,21-24 in clinical practice, due to the inher- ent 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 con- siderable scientific controversy. There are a lot of opinion papers, and some original contribu- tions, 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 insuffi- ciency in multiple sclerosis The neurological community did not accept from the beginning, the intrusion of the vascu- lar 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 lit- eracy 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 preva- lence 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 measure- ments as well as anatomical imaging and has been used for the detection of CCSVI by differ- Correspondence: 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 cere- brospinal venous insufficiency, echo-color Doppler imaging, multiple sclerosis, venous mal- formations. 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 n- co mm er cia l prevalence >90% of CCSVI in MS. Global hypo- No n- co mm er cia l prevalence >90% of CCSVI in MS. Global hypo- perfusion of the brain, and reduced cerebral No n- co mm er cia l perfusion of the brain, and reduced cerebral spinal fluid dynamics in MS was shown to be No n- co mm er cia l spinal fluid dynamics in MS was shown to be related to CCSVI. Postmortem studies and histol- No n- co mm er cia l related to CCSVI. Postmortem studies and histol- ogy corroborate the 2009 International Union of No n- co mm er cia l ogy corroborate the 2009 International Union of Phlebology (UIP) Consensus decision to insert No n- co mm er cia l Phlebology (UIP) Consensus decision to insert CCSVI among venous malformations. Finally,No n- co mm er cia l CCSVI among venous malformations. Finally, safety of balloon angioplasty of the extracranialNo n- co mm er cia l safety of balloon angioplasty of the extracranial mental arrest in advanced stages of vascular No n- co mm er cia l mental arrest in advanced stages of vascular trunk formation during fetal life can result in No n- co mm er cia l trunk formation during fetal life can result insuch truncular venous malformations. Lesions No n- co mm er cia l such truncular venous malformations. Lesions caused by incomplete development of axial veins No n- co mm er cia l caused by incomplete development of axial veins result in aplasia, hypoplasia or hyperplasia of the No n- co mm er cia l result in aplasia, hypoplasia or hyperplasia of the vessel or as a defective vessel with obstruction No n- co mm er cia l vessel or as a defective vessel with obstruction from intraluminal lesions ( No n- co mm er cia l from intraluminal lesions ( formed valve, or septum) or dilatation ( No n- co mm er cia l formed valve, or septum) or dilatation ( lar vein ectasia/aneurysm). Radiological studies No n- co mm er cia l lar vein ectasia/aneurysm). Radiological studies of healthy subjects did not demonstrate these No n- co mm er cia l of healthy subjects did not demonstrate these types of lesions, No n- co mm er cia l types of lesions, were described associated to myelopathies. No n- co mm er cia l were described associated to myelopathies. Despite the above and other scientific evi- No n- co mm er cia l Despite the above and other scientific evi- us 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 n- co 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 preva- lence 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 methodol- ogy and criteria.40 Moreover, a recent meta- analysis done by Laupacis et al.41 showed a pos- itive 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 associ- ation between CCSVI and MS even after exclu- sion of the first study by Zamboni, due to the fact that it, being the first study, may be con- sidered 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 associ- ation between CCSVI and MS with marked het- erogenicity 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 signifi- cant 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 sub- jects 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 pres- ence 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 hydro- static pressure gradient.4,21 However, high quali- ty 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. communicat- ed 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 sug- gests 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 expla- nation for this great variability in CCSVI preva- lence among different groups of investigators is the amount of training and experience investi- gators have in echo-color Doppler imaging. Studies have shown39 that inter-operator vari- ability decreases post-training (from k=0.47 to k=0.80) while intra-operator reproducibility in trained operators was k=0.75. Apart from experi- ence 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 ultra- sound, 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 ele- ments 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 malfor- mation.6,7 Autoptic studies and histology actu- ally 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 con- Table 1. Prevalence of chronic cerebrospinal venous insufficiency in patients with multi- ple 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 n- co mm er cia l Clinically Isolated Syndrome cases, thus making No n- co mm er cia l Clinically Isolated Syndrome cases, thus makingA well-established expla- No n- co mm er cia l A well-established expla- nation for this great variability in CCSVI preva- No n- co mm er cia l nation for this great variability in CCSVI preva- lence among different groups of investigators is No n- co mm er cia l lence among different groups of investigators is the amount of training and experience investi- No n- co mm er cia l the amount of training and experience investi- gators have in echo-color Doppler imaging. No n- co mm er cia l gators have in echo-color Doppler imaging. Studies have shown No n- co mm er cia l Studies have shown No n- co mm er cia l No n- co mm er cia l traces of venous abnormalities No n- co mm er cia l traces of venous abnormalities reported no CCSVI in MSNo n- co mm er cia l reported no CCSVI in MS but their results did show a signifi-No n- co mm er cia l but their results did show a signifi- 39 No n- co mm er cia l 39 that inter-operator vari- No n- co mm er cia l that inter-operator vari- ability decreases post-training (from k=0.47 to No n- co mm er cia l ability decreases post-training (from k=0.47 to k=0.80) while intra-operator reproducibility in No n- co mm er cia l k=0.80) while intra-operator reproducibility in trained operators was k=0.75. Apart from experi- No n- co mm er cia l trained operators was k=0.75. Apart from experi- ence and training, ultrasound imaging still No n- co mm er cia l ence and training, ultrasound imaging still remains an operator-dependent investigation. No n- co mm er cia l remains an operator-dependent investigation. Studies that have been done so far show great No n- co mm er cia l Studies that have been done so far show great variability because of operator dependency, lack No n- co 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 n- co 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 com- paring MS patients with people who dead for dif- ferent reasons, valvular and other intraluminal abnormalities with potential hemodynamic con- sequences were identified in 72% of MS patients and in 17% of controls. These abnormalities included circumferential membranous struc- tures, longitudinally-oriented membranous structures, single valve flap replacing IJV valve, and enlarged and malpositioned valve leaflets. To the contrary, vein wall stenosis occurred at simi- lar 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 tis- sue contributing to abnormalities described in CCSVI. Interestingly, no differences in inflamma- tory 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 demon- strates 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 assess- ment. They are of course invasive, and we need to develop a multimodality approach in order to use venous catheter only if a treat- ment 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 patho- physiology There are 2 proven pathophysiologic conse- quences of the presence of significant narrow- ing 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 abnormal- ities, 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 per- formed a blinded MR study which demonstrat- ed 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 cor- relation between venous outflow and CSF flow dynamics measuring the change in CSF flow and velocity after venous angioplasty in a ran- domized 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) steno- sis (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 n- co mm er cia l Chronic cerebrospinal venous No n- co mm er cia l Chronic cerebrospinal venous insufficiency assessment by No n- co mm er cia l insufficiency assessment by Catheter venography, eventually combinedNo n- co mm er cia l Catheter venography, eventually combined with intravascular sonography, is actually stillNo n- co mm er cia l with intravascular sonography, is actually stillNo n- co 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 n- co 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 parenchy- ma 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 treat- ing 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 proce- dure, whereas for stenting level of risk is slightly increased.63-65 Moreover, from 2009 the effectiveness of PTA in eventually improving the results of cur- rent 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 proce- dures.66-72 Particularly, chronic fatigue, a dis- abling 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 pro- cedures, 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 micro- circulatory 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 insufficien- cy in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:392- 9. 2. Zamboni P, Consorti G, Galeotti R, et al. Venous collateral circulation of the extra- cranial 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 multi- ple sclerosis. intraluminal jugular septa- tion. 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 malforma- tion 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 malfor- mations-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 congeni- tal 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 recur- rent 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 cervi- cal 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 phle- bography by puncture of the external jugu- lar vein with retrograde emmission of the contrast media. 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Baiocchini A, Toscano R, von Lorch W, et al. Anatomical stenosis of the internal jugular veins : supportive evidence of chro- nic cerebrospinal venous insufficiency? e- letter 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 multi- ple sclerosis patients. 4th Annual ISNVD Scientific Meeting 2011, Bologna, Italy, abstract. No n- co mm er cia l Particularly, chronic fatigue, a dis- No n- co mm er cia l Particularly, chronic fatigue, a dis- abling symptom of MS without any effective No n- co mm er cia l abling symptom of MS without any effective treatment is reported to improve practically in No n- co mm er cia l treatment is reported to improve practically in any interventional study, as well as QoL No n- co mm er cia l any interventional study, as well as QoL assessed with validated questionaires. No n- co mm er cia l assessed with validated questionaires. 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