Key Papers

CCSVI Key Scientific Papers

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Poster presented at the 2013 annual meeting of the American Academy of Neurology and Dr. Hubbard's response.

(figures did not reproduce)

Percutaneous Transluminal Venous Angioplasty (PTVA) is Ineffective in Correcting Chronic Cerebrospinal Venous Insufficiency (CCSVI) and May Increase Multiple Sclerosis (MS) Disease Activity in the Short Term: Safety and Efficacy Results of the 6-Month, Double-Blinded, Sham-Controlled, Prospective, Randomized Endovascular Therapy in MS (PREMiSe) trial

Adnan H. Siddiqui1, Robert Zivadinov2,3, Ralph HB. Benedict3, Yuval Karmon1, Yu Jihnhee4, Karen Marr2, Vesela Valnarov2, Cheryl Kennedy2, Murali Ramanathan5, Deepa P. Ramasamy2, Kresimir Dolic2, David Hojnacki3, Ellen Carl2, Michael G. Dwyer2, Niels Bergsland2, Elad I. Levy1, Nelson L. Hopkins1, Bianca Weinstock-Guttman3 1Departments of Neurosurgery and Radiology, University at Buffalo, State University of New York; Buffalo, NY, USA; 2Buffalo Neuroimaging Analysis Center and 3The Jacobs Neurological Institute, Department of Neurology, University at Buffalo, State University of New York, Buffalo, NY, USA; 4Department of Statistics, University at Buffalo, State University of New York, Buffalo, NY, USA; 5Department of Pharmaceutical Sciences, State University of New York, Buffalo, NY, USA



• Multiple sclerosis (MS) is a disease of uncertain etiology characterized by demyelinating lesions affecting the central nervous system.

• In 2009, Zamboni et al. described an association between MS and extracranial venous outflow restrictive lesions detected by extracranial and intracranial venous duplex studies.1

• They named this venous outflow restriction chronic cerebrospinal venous insufficiency (CCSVI). In addition, they introduced endovascular treatment for CCSVI in an open-label study that included 65 MS patients with postprocedure followup of over 18 months.2

• Several subsequent prospective open-label, non-randomized studies investigated safety and efficacy of venous angioplasty in MS. 3-9 Findings from these studies have generated considerable controversy but remain unproven.


• To investigate the safety and efficacy of percutaneous transluminal venous angioplasty (PTVA) for correcting CCSVI in MS in the setting of a prospective, double-blind, sham-controlled, randomized pilot trial.


Study Design and Patient Selection

• The study, Prospective Randomized Endovascular Therapy in Multiple Sclerosis (PREMiSe; NCT01450072), was planned in two phases. Phase 1 was an open-label safety study of endovascular venous angioplasty with an intended enrollment of 10 MS patients with CCSVI, whereas phase 2 was sham-controlled, randomized, double-blind, including up to 20 CCSVI-MS patients undergoing either angioplasty or sham procedure. Both phases were of 6 months’ duration.

• The study was approved by the University at Buffalo Institutional Review Board and overseen by an independent datasafety monitoring committee. Written informed consent was obtained from all subjects.

• All screening, diagnostic, interventional, and follow-up procedures and visits were performed at no cost to the patients. Data were collected by the investigators and analyzed by an independent statistician.

• Inclusion criteria were as follows: age 18-65 years, Expanded Disability Status Scale (EDSS) score11 of 0-8.5 (0-5.5 for phase 2), active-relapsing MS (only for phase 2) or secondary progressive and/or progressive-relapsing MS,12 and fulfilling, at the time of screening, ≥2 CCSVI venous hemodynamic (VH) duplex criteria in phase 1 and ≥2 VH extracranial criteria in phase 2.13 Active-relapsing disease was defined as one relapse within the past 12 months or presence of contrast-enhancing (CE) lesion(s) on postcontrast magnetic resonance imaging (MRI) within the previous 3 months (only for phase 2) and concomitant treatment with disease-modifying treatments excluding natalizumab (only for phase 2).

• Patients were also required to fulfill screening criteria on catheter venography (CV) defined as azygous vein or internal jugular vein (IJV) luminal diameter reduction ≥50%. CV findings were confirmed by intravascular ultrasound (IVUS), and both studies were performed under conscious sedation with local anesthesia, preceding the endovascular venous angioplasty treatment or sham procedure.

• Randomization in phase 2 was performed by an independent statistician in 1:1 fashion, using sealed and numbered envelopes with predetermined treatments (10 angioplasty, 10 sham angioplasty). No preplanned replacement for subjects not fulfilling invasive screening criteria was included in the protocol. In phase 2, all study personnel, with the exception of the interventional neurosurgeons, were blind to the assigned procedure as were the patients.

Sham and Venous Angioplasty

• All endovascular procedures were performed under conscious sedation with local anesthesia. The goal of angioplasty was to restore venous outflow of the stenotic IJVs and azygous vein to <50% of normal proximal venous diameter at the time of intervention. Angioplasty was performed only in the treated, not in the sham arm.

Endpoints and Follow-up Assessment

• Primary endpoints of the study were safety at 24 hours and 1 month, venous outflow restoration of >75% at 1 month compared to baseline, as measured by changes in venous hemodynamic insufficiency severity score (VHISS), and effect of angioplasty on new lesion activity and relapse rate over 6 months. Secondary endpoints included changes in EDSS, brain volume, cognitive tests, and quality of life (QoL), including MS Functional Composite (MSFC) scores.



Screening, randomization, and blinding:

• In total, 15 patients signed informed consent in phase 1 and 30 in phase 2 after prescreening qualification procedures were completed. Of those, 5 in phase 1 and 10 in phase 2 did not fulfill noninvasive screening procedure requirements on duplex examination.

• As preplanned, 10 patients were enrolled in open-label phase 1 and 20 in sham-controlled, randomized, double-blind phase 2. Of those, 1 patient in phase 2 did not fulfill invasive screening criteria for endovascular intervention. Hence, 10 patients in the sham-treatment arm and 9 in the angioplasty-treated arm were randomized to phase 2.

Demographic, hemodynamic, MRI, and clinical characteristics at baseline:

• The sham and angioplasty treatment arms in phase 2 were well matched for various demographic, clinical, and duplex characteristics with no statistically significant between-group differences (Table 1).

Safety and tolerability of treatment procedures:

• All patients in phases 1 and 2 tolerated the endovascular procedure well, and no operative or postoperative complications (vessel rupture, thrombosis, or side effects to contrast media) were identified. No serious adverse events (AEs) weredetected at any time point in phase 1 (Table 2). Half of the patients in phase 1 reported a non-serious AE, but none were related to the treatment procedure (Table 2).

Venous outflow restoration outcomes:

• Venous angioplasty restored venous outflow to at least 50% of normal proximal venous diameter in all phase 1 and 2 patients at the time of intervention.

• In phase 1 (Figure 1), there was significant improvement of VHISS (p<0.0001) over 6-months that resulted in >75% restoration of the venous outflow compared to baseline.

• In phase 2, improvement was observed also in treatment (p=0.02) and sham (p=0.04) arms at month 1 but did not reach >75% restoration of the venous outflow compared to baseline. No differences in VHISS improvement were detected between phase 2 treated and sham groups (p=0.894).

Changes in clinical outcomes:

• No relapses occurred in phase 1. In phase 2, there were 4 relapses in the treated arm (among 3 patients) and 1 in the sham arm (p=0.389). The relapses occurred at 1, 3 (2 relapses), and 6 months in the treated arm and at 5 months in the sham arm.

• In phase 2, no significant within- or between-group changes in EDSS, MSFC, or 6-minute walked distance were detected.

• No significant between-group changes in cognitive and QoL outcomes were detected in phase 2 patients.


Changes in MRI outcomes:

• Table 3 and Figure 2 show changes in MRI measures in the PREMiSe study over 6 months.


• This is the first double-blind, sham-controlled, randomized trial evaluating PTVA to address CCSVI in patients with MS.

• We found that the procedure was not associated with any serious AEs.

• However, it failed to provide any sustained improvement in venous outflow as measured through duplex and/or clinical and MRI outcomes.

• To the contrary, more sizable change in venous outflow was associated with increased disease activity primarily noted on MRI.

• This study was a limited pilot trial, the results of which caution against widespread adoption of venous angioplasty in the management of patients with MS outside of rigorous clinical trials.

• It also provides validation for conduct of sham-controlled, double-blind trials in the evaluation of novel interventions in complex diseases.


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. 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.

3. Ludyga T, Kazibudzki M, Simka M, et al. Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? Phlebology 2010;25:286-95.

4. 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.

5. Hubbard D, Ponec D, Gooding J, Saxon R, Sauder H, Haacke M. Clinical improvement after extracranial venoplasty in multiple sclerosis. J Vasc Interv Radiol 2012;23:1302-8.

6. Petrov I, Grozdinski L, Kaninski G, Iliev N, Iloska M, Radev A. Safety profile of endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Endovasc Ther 2011;18:314-23.

7. Salvi F, Bartolomei I, Buccellato E, Galeotti R, Zamboni P. Venous angioplasty in multiple sclerosis: neurological outcome at two years in a cohort of relapsing-remitting patients. Funct Neurol 2012;27:55-9.

8. Zamboni P, Galeotti R, Weinstock-Guttman B, Kennedy C, Salvi F, Zivadinov R. Venous angioplasty in patients with multiple sclerosis: results of a pilot study. Eur J Vasc Endovasc Surg 2012;43:116-22.

9. Alroughani R, Lamdhade S, Thussu A. Endovascular Treatment of Chronic Cerebro-Spinal Venous Insufficiency in Multiple Sclerosis: A retrospective study. Int J Neurosci 2013 (DOI 10.3109/00207454.2012.759569).


Study disclosure:

• The authors declare that their study was funded with internal resources of the Buffalo Neuroimaging Analysis Center, Jacobs MS Comprehensive and Research Center, University at Buffalo.

In addition, they received support from the Direct MS Foundation, Kaleida-Health, Volcano, ev3, Codman, the Jacquemin Foundation, and from minor donors.

Potential Conflict of Interest:

• Yuval Karmon, Yu Jinhee, Karen Marr, Vesela Valnarov, Cheryl Kennedy, Deepa P. Ramasamy, Kresimir Dolic, Ellen Carl, Michael G. Dwyer and Niels Bergsland have nothing to disclose.

• Adnan H. Siddiqui has received research grants from the National Institutes of Health and the University at Buffalo (Research Development Award); holds financial interests in Hotspur, Intratech Medical, StimSox, and Valor Medical; serves as a consultant to Codman & Shurtleff, Inc., Concentric Medical, ev3/Covidien Vascular Therapies, GuidePoint Global Consulting, and Penumbra; belongs to the speakers’ bureaus of Codman & Shurtleff, Inc. and Genentech. He serves on an advisory board for Codman & Shurtleff; and has received honoraria from Abbott Vascular, American Association of Neurological Surgeons’ courses, an emergency medicine conference, Genentech, Neocure Group LLC.

• Robert Zivadinov received personal compensation from Teva Pharmacuticals, Biogen Idec, EMD Serono, Bayer, Genzyme-Sanofi, Novartis, Bracco and Questcor Pharmaceuticals for speaking and consultant fees. He received financial support for research activities from Biogen Idec, Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Bracco, Questcor Pharmaceuticals and EMD Serono.

• Ralph RHB Benedict received research support from Biogen Idec and Shire Inc, and serves on advisory panels for Bayer, Biogen, Novartis, and Actelion.

• Murali Ramanathan received research funding or consulting fees from EMD Serono, Biogen Idec, Allergan, Netezza, Pfizer, Novartis, the National Multiple Sclerosis Society, the Department of Defense, Jog for the Jake Foundation, the National Institutes of Health and National Science Foundation. He received compensation for serving as an Editor from the American Association of Pharmaceutical Scientists. These are unrelated to the research presented in this report.

• David Hojnacki has received speaker honoraria and consultant fees from Biogen Idec, Teva Pharmaceutical Industries Ltd., EMD Serono, Pfizer Inc, and Novartis.

• L. Nelson Hopkins received grant/research support from St. Jude Medical and Toshiba; serves as a consultant to Abbott, Boston Scientific,* Cordis, Micrus, and W. L. Gore; holds a financial interest in AccessClosure, Augmenix, Boston Scientific,* Claret Medical Inc., Micrus, and Valor Medical; has a board/trustee/officer position with AccessClosure and Claret Medical Inc.; belongs to the Abbott Vascular speakers’ bureau; and receives honoraria from Boston Scientific,* Cleveland Clinic, Complete Conference Management, Cordis, SCAI, University of Southern California, and VIVA Physicians. (*Boston Scientific’s neurovascular business has been acquired by Stryker)

• Elad I. Levy received research grant support (principal investigator: Stent-assisted Recanalization in acute Ischemic Stroke, SARIS), other research support (devices), and honoraria from Boston Scientific* and research support from Codman & Shurtleff, Inc. and ev3/Covidien Vascular Therapies; has ownership interests in Intratech Medical Ltd. and Mynx/Access Closure; serves as a consultant on the board of Scientific Advisors to Codman & Shurtleff, Inc.; serves as a consultant per project and/or per hour for Codman & Shurtleff, Inc., ev3/Covidien Vascular Therapies, and TheraSyn Sensors, Inc.; and receives fees for carotid stent training from Abbott Vascular and ev3/Covidien Vascular Therapies. Dr. Levy receives no consulting salary arrangements. All consulting is per project and/or per hour. (*Boston Scientific’s neurovascular business has been acquired by Stryker.)

• Bianca Weinstock-Guttman received personal compensation for consulting, speaking and serving on a scientific advisory board for Biogen Idec, Teva Neuroscience and EMD Serono, Pfizer, Genzyme& Sanofi, Acorda, Questcor. She also received financial support for research activities from NMSS, NIH, ITN, Teva Neuroscience, Biogen Idec, EMD Serono, Aspreva, Novartis, Acorda.

Table 1 Legend:

Abbreviations: PREMiSe=Prospective Randomized Endovascular therapy in Multiple Sclerosis; SD=standard deviation; RR=relapsing-remitting; RP=relapsing-progressive.

SP=secondary-progressive; PR=progressive relapsing; DMT=disease-modifying therapy, EDSS=Expanded Disability Status Scale; MSFC=Multiple Sclerosis Functional Composite; CCSVI=chronic cerebrospinal venous insufficiency; VH=venous hemodynamic; VHISS=venous hemodynamic insufficiency severity score

*p value represents statistical analysis between sham and treated arms of phase 2. Analysis between these groups was performed by using chi-square test, Student’s t-test, and Mann-Whitney rank sum test, as appropriate.


Table 2 Legend:

Abbreviations: PREMiSe=Prospective Randomized Endovascular therapy in Multiple Sclerosis; AE=adverse events, UTI=urinary tract infection

AEs are listed in chronological order with individual AEs assigned an increasing number.

Legend Table 3

·       Abbreviations: MRI=magnetic resonance imaging, PREMiSe=Prospective Randomized Endovascular therapy in Multiple Sclerosis; SD=standard deviation; LV=lesion volume; CE=contrast-enhancing; sum=total number, PBVC=percentage brain volume change; GMVC=gray matter volume change; WMVC=white matter volume change


·       *p value represents statistical analysis between sham and treated arms of phase 2. The analysis between these groups was performed by using Student’s t-test.

·       Statistical analyses between phase 2 sham and treated arms were also adjusted for age, sex, disease duration, relapse rate in the year prior to study entry, and number of CE lesions at baseline. No significant differences were found between these arms, except for T2-LV % change (p=0.05).

·       Of the 5 patients with active MS assigned to the treated arm in phase 2, cumulative numbers of CE lesions per patient over 6 months were as follows: 9, 5, 3, 1, and 1 (respectively. In the sham arm, one patient had 2 CE lesions and one had 1.




March 29, 2013



201 Chicago Ave.

Minneapolis, MN 55415


Response to:

Siddiqui A, Zivadinov R, Benedict R, Karmon Y et al. Percutaneous transluminal venous angioplasty (PTVA) is ineffective in correcting chronic cerebrospinal venous insufficiency (CCSVI) and may increase multiple sclerosis (MS) disease activity in the short term: safety and efficacy results of the 6-month, double-blinded, shame-controlled, prospective, randomized endovascular therapy in MS (PREMiSe) trial. Poster presented at the annual meeting of the American Academy of Neurology, March, 2013.


As the first trial of venoplasty in MS that was randomized and double-blinded including sham treatment, it is important to analyze whether the method and analysis justify the conclusions.  Several questions arise that hopefully will be clarified when Dr. Siddiqui submits the study for journal publication:

1) How was the sham procedure done?  Presumably a catheter was inserted, but how far was it advanced, through the internal jugular valves, into the azygos vein?  How long was it left in place?

2) The inclusion criteria for pre-venoplasty diameter measured by IVUS was a reduction of  50%. Post-venoplasty diameter restored to at least 50% of normal proximal venous diameter.  . A table should provide the actual diameters and an analysis of whether the restorations were significant, e.g. is a change from 49% to 51 % meaningful?

3) A venous hemodynamic insufficiency severity score was calculated to determine flow change over time and between groups. How was this calculated? A table presenting this data would be helpful.  A statistically significant (p<0.0001) improvement from baseline to 1,3, and 6 months (combined) was found for the open-label group, but not for the treatment and sham groups (p=0.894).  It would be interesting to know whether the change in vein diameter measured by IVUS correlated with the change in flow measured by the flow change score. Why was flow restoration in the open-label group successful but not in the treatment and sham groups?  Were the operators and venoplasty method the same?

4) There were no statistically significant differences between the treatment and sham groups in MS relapses (p=0.389) and MRI lesion counts (p=0.81,0.5 and 0.079, Fig. 2). These results do not justify the conclusion the venoplasty “may increase MS disease activity in the short term.” No data is presented to support the conclusion that “more sizable change in venous outflow was associated with increased disease activity primarily noted on MRI.”

5) The poster concluded that venoplasty “failed to provide any sustained improvement in venous outflow as measured through duplex and/or clinical and MRI outcomes.”  Since the study’s objective hypothesized that correction of venous flow would improve MS, why would MS improvements be expected if venous flow was not?


David Hubbard, MD

Academy of Neurology member