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        Patient-Reported Benefits of Extracranial Venous Therapy: British Columbia CCSVI Registry
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Objective Chronic cerebrospinal venous insufficiency (CCSVI) has been hypothesized to be a risk factor for multiple sclerosis (MS). Venoplasty has been proposed as a treatment for CCSVI. The aim of our study was to gain a better understanding of the “real-world” safety and longitudinal effectiveness of venoplasty Methods: British Columbia residents who self-reported having had venoplasty and consented to participate in the study were interviewed and followed for up to 24 months post-therapy using standardized structured questionnaires Results: Participants reported procedure-related complications (11.5%) and complications within the first month after the procedure (17.3%). Initially, more than 40% of participants perceived that the venoplasty had had positive effects on their health conditions, such as fatigue, numbness, balance, concentration/memory and mobility. However, this improvement was not maintained over time Conclusions: Follow-up patient-reported outcomes indicated that the initial perception of the positive impact of venoplasty on the health conditions of MS patients was not sustained over time. In addition, venoplasty was not without associated morbidity.


The aetiology of multiple sclerosis (MS) is unclear, but the important factors include genes, the environment and the interactions thereof.Reference Noseworthy, Lucchinetti, Rodriguez and Weinshenker 1 , Reference Ebers 2 MS is a demyelinating chronic inflammatory disorder of the central nervous system (CNS), primarily affecting white matter in the brain and spinal cord, and is characterized by myelin loss and axonal pathology.Reference Noseworthy, Lucchinetti, Rodriguez and Weinshenker 1 Approximately 100,000 Canadians have MS, a rate nine times higher than the global average. 3

In 2009, chronic cerebrospinal venous insufficiency (CCSVI), characterized by stenoses and occlusions in the extracranial veins that drain the CNS, including the internal jugular veins and the azygos veins,Reference Zamboni, Galeotti and Menegatti 4 , Reference Zamboni, Menegatti and Weinstock-Guttman 5 was proposed to be important in the pathogenesis of MS. CCSVI, as described by Zamboni et al,Reference Zamboni, Menegatti and Galeotti 6 is detectable by transcranial and extracranial Doppler ultrasound. Specific to MS patients, it was reported that the large veins draining blood from the brain and spinal cord appear to be narrowed compared to people without MS, the hypothesis being that CCSVI causes congestion of blood in the brain and triggers inflammation, possibly by causing iron deposition.Reference Zamboni 7 Thus, percutaneous transluminal angioplasty of extracranial veins, a CCSVI treatment termed “liberation therapy” (hereafter referred to as “venoplasty”), was proposed (based on a pilot study with nonrandomized data) as an alternative treatment for MS.Reference Zamboni, Galeotti and Menegatti 8 Venoplasty involves the insertion of a catheter with a balloon into the vein with stenosis. The balloon is then inflated to dilate the stenosis. Stenting can be done after dilation.

To date, there is little evidence that venoplasty is an effective MS treatment. A recent reviewReference Tsivgoulis, Faissner and Voumvourakis 9 reported that the majority of studies could not reproduce the initial reports and that venoplasty as a treatmentReference Zamboni, Galeotti and Menegatti 4 - Reference Zamboni, Galeotti and Menegatti 8 has no proven efficacy, may in fact exacerbate underlying disease activity, and has been complicated with serious adverse events.Reference Tsivgoulis, Faissner and Voumvourakis 9 Nevertheless, out-of-country venoplasty has continued to attract Canadian MS patients, especially through internet-based resources.Reference Vera, Herr, Mandato, Englander, Ginsburg and Siskin 10

The British Columbia (BC) CCSVI Registry (hereinafter “the Registry”), funded by the BC Ministry of Health, was designed to allow for a better understanding of the “real-world” longitudinal safety and effectiveness of venoplasty as an MS therapy. Our study was approved by the University of British Columbia (UBC) Research Ethics Board, the Vancouver Coastal Health Research Institute (VCHRI) and the Information Privacy Office (VCH IPO).

Materials and Methods

Participants and Data Collection

Information on the Registry was disseminated through the official VCHRI website, UBC MS clinic visits and its website, multimedia interviews (radio, television, print), and the BC and Yukon Division newsletter of the MS Society of Canada.

BC residents with MS who self-reported venoplasty were invited to telephone or email the Registry and leave their contact information. They were then contacted in order to explain the study and to invite them to participate. All participants provided informed consent.

Information about venoplasty was obtained from (1) consenting volunteers who had at least one venoplasty and (2) their BC physicians.

While it was anticipated that some participants would have undergone multiple venoplasties for CCSVI, the detailed survey for this study focused only on the venoplasty closest to the initial Registry interview. If multiple procedures occurred during the study period, the subject would be truncated with respect to follow-up at the time of the subsequent procedure(s) and begin again as a new case for the subsequent procedure.


“Initial” and “follow-up” questionnaires were administered by telephone. Follow-ups occurred at 6, 12 and 24 months after the initial interview.

Survey Content

Participants were asked about their most recent venoplasty. The survey included questions on the following: (1) mobility assistance prior to and post-treatment; (2) complications during venoplasty and within the first month post-treatment; and (3) perception of MS-related health conditions (e.g., fatigue, mobility, exercise level, sensory symptoms). The response choices for the patient-reported outcomes were presented as 5-point Likert-type scale items. 11

Questions on exercise levels were adapted from Ploughman et al.:Reference Ploughman, Beaulieu and Harris 12 “light”=easily done physical activity (e.g., light housework); “moderate”=causing slight breathlessness (e.g., yoga, brisk walking); and “vigorous”=causing rapid breathing (e.g., weight training).

As fatigue is one of the most common and most disabling symptoms of MS,Reference Kos, Kerckhofs, Nagels, D’hooghe and Ilsbroukx 13 the Modified Fatigue Impact Scale–5 item version (MFIS–5) from the MS Quality of Life Inventory (MSQLI)Reference Fischer, LaRocca, Miller, Ritvo, Andrews and Paty 14 was utilized. Scores range from 0 to 20, with higher scores indicating higher impact of fatigue on participants’ activities. A score <5 suggests the absence of any significant fatigue symptoms.Reference Sepulcre, Masdeu and Goñi 15

There is a high prevalence of depression in persons with MS.Reference Feinstein 16 , Reference Arnett, Barwick and Beeney 17 The Mental Health Inventory–5 (MHI–5), a five-question subscale of the general health measure the SF–36 (Short Form Health Survey),Reference Ware, Kosinski and Bandek 18 was used to assess the mental health of participants. Scores range from 0 (worst mental health) to 100 (best mental health). Scores ≤76Reference Kelly, Dunstan, Lloyd and Fone 19 indicate common mental disorder and scores ≤52Reference Bultmann, Rugulies, Lund, Christensen, Labriola and Burr 20 suggest severe depressive symptoms.

The Medical Doctor’s Adverse Effect Report Form, designed and validated for this study, collected post-venoplasty follow-up by participating BC physicians. If the participant underwent multiple venoplasties, the very first one up to the most recent one at the time of the first initial Registry interview were reported on by the BC physicians.

The Registry was launched on 8 December 2011; the enrolment cutoff was 31 December 2013; the data collection cutoff was 31 July 2014.

Statistical Analysis

Descriptive statistics were employed to describe the demographics of our participants. Nonparametric analysis of longitudinal data in factorial experiments was used to analyseReference Brunner, Munzel and Puri 21 , Reference Brunner and Puri 22 Likert-type scale data over time on health conditions (14 questions), the frequency of exercise levels (3 questions) and rating the outcome of the venoplasty (1 question) collected at the initial and follow-up interviews. Bonferroni adjustmentReference Shaffer 23 was applied to the level of significance for the 18 patient-reported outcomes; p=0.0028 (0.05/18) was considered significant. The one-way repeated-measures analysis of variance (RM ANOVA)Reference Gueorguieva and Krystal 24 was used (Mauchly’s test was utilized to assess the assumption of sphericity) to analyse the MFIS–5 and MHI–5 scores over time, with significance being set at p=0.05.


Study Participants

A total of 140 individuals were invited to participate in the study. Of these, 102 (79.2%) completed the initial interview (74 females, 28 males, sex ratio=2.6), while 38 (26 females, 12 males, F:M sex ratio=2.2) opted not to participate. There was no difference in sex ratio between participants and nonparticipants (χ2=0.23, df=1, p=0.63). Of the 102 participants, 93 (91%) were re-interviewed at 6-month follow-up (FU), 83/93 (89%) at 12 months and 55/83 (66%) at 24 months (see Figure 1).

Figure 1 Flowchart of data collection.

Some 65 of the 102 participants (63.7%) reported relapsing remitting MS (RRMS) (Table 1). The average age at MS clinical onset was 31.9 years old (SD=11.9), and the average age at MS diagnosis was 39.4 (SD =12.7). The average age at the time of the first interview was 55.5 years old (SD=10.8); and the “progressive MS” group (primary and secondary progressive MS cases combined) was significantly older than the “RRMS” group (t=2.8; df=86; p=0.0064). The average elapsed time between the most recent venoplasty and the initial interview was 17.9 months (SD=7.9). A total of 12 individuals (11.8%: 9 females, 3 males) reported repeat venoplasty (8 had 2 procedures, 3 had 3 procedures and 1 had 4). The average elapsed time between repeat venoplasties was 10.7 months (SD=8.8). Only 2 of the 102 participants (2%) had a repeat venoplasty procedure within 6 months of the initial interview. Thus, data are reported for 102 MS patients who underwent a total of 104 venoplasties (89 balloon dilation only, 14 balloon dilation + stent, 1 unknown) during the study period.

Table 1 Participant-reported MS course before the venoplasty procedure and average age at the first “initial” interview

1 Includes 13 primary and 10 secondary progressive MS cases.

2 Includes 2 benign and 4 “other” MS cases.

Patient-Reported Outcomes (PROs)

The results varied in terms of numbers and percentages per question, as participants were unable to answer all questions. At the initial interview, between 35 and 65% of patients reported improved outcomes (e.g., “much better=1” and “somewhat better=2” for a fatigue level of 65.2% (60/92) and tingling 35.9% (33/92)) (see Table 2 for details).

Table 2 Outcomes by participant-reported MS course at “initial” interview

a Excludes two RRMS cases who had repeat venoplasty therapy during the study period.

b Excludes eight cases who “don’t know” their MS course.

c Better: “1=much better” plus “2=somewhat better.”

d Worse: “4=somewhat worse ” plus “5=much worse.”

e One participant refused to answer the question.

PROs at the initial interview (Supplemental Tables 1 to 3 show the frequency of exercise, level of stress in everyday life and rating of the outcome of the venoplasty, respectively). Selected summary results on the PROs for 83 participants followed up to 12 months post-venoplasty are presented in Tables 3 and 4. (The results on frequency of exercise are given in Supplemental Table 4). Table 5 shows the summary statistics of MFIS–5 and MHI–5 scores up to 12 months post-venoplasty.

Table 3 Patient-reported outcomes relative to pre-treatment status up to the 12-month interview in percentage (%)

a On each specific condition, the case who did not report outcomes in all three interviews was excluded.

b Better: “1=much better” plus “2=somewhat better.”

c Worse: “3=somewhat worse” plus “4=much worse.”

Table 4 Rating the outcome of venoplasty therapy for participants who completed all interviews up to 12-month follow-up

a Two cases who did not report outcomes in all three interviews were excluded.

Table 5 Summary of the scores on the Modified Fatigue Impact Scale–5 (MFIS-5) and on the Mental Health Inventory–5 (MHI–5)

a Known scores on all interviews.

The Likert-type scale showed a temporal decline in benefit from venoplasty for most PROs (see Figures 2 and 3 for the bar graphs of general health condition and fatigue level over the three interviews). Note that, for all outcomes, with the exception of rating the outcome of the venoplasty, higher scores indicate a worse outcome (“somewhat worse=4” and “much worse=5”). The results of the nonparametric analysis of the longitudinal data in the factorial experiment on patient self-reported data are presented in Table 6. After the Bonferroni adjustment, significant time effects were found for general health, fatigue level, mobility, sensory symptoms (pain, numbness and tingling), bladder/bowel control, vision, balance and concentration/memory. The relative treatment effects increased over time, indicating PROs with higher scores at the 6- and 12-month interviews compared to the initial interview. In contrast, no temporal changes were reported by PROs for tremor, exercise level and exercise frequency (“light,” “moderate,” “vigorous”), as well as the overall rating outcome of the venoplasty. This pattern persisted in the patient-reported outcomes collected for up to 24 months. When the “progressive MS” and “RRMS” patient groups were examined separately, a similar temporal pattern of decline was shown for PROs.

Figure 2 Patient-reported outcome of general health condition over time (N=83).

Figure 3 Patient-reported outcome of change in fatigue level over time (N=83).

Table 6 Results of the nonparametric analysis of longitudinal Likert-type scale data in factorial experiments

a On each specific condition, the participant who did not report outcomes in all three interviews was excluded.

b The Bonferroni adjustment was applied to the level of significance for 18 comparisons, and p=0.05/18=0.0028 was considered the level of significance.

* p value<0.0028.

A total of 77 of the 104 participants completing the initial interview (74.0%) required some type of mobility assistance (cane, walker, wheelchair) prior to venoplasty, and 75/104 (72.1%) reported this need after venoplasty (χ2=0.098, df=1, p=0.75). Six patients who previously used mobility aids no longer required them post-venoplasty, but four newly required mobility aids after treatment. At 12 and 24 months, 65/83 (78%) and 40/55 (73%) reported requiring mobility assistance, respectively.

Of the 104 procedures with an initial interview, 101 completed the MFIS–5; 66/101 (65%) scored >5; and 103 completed the MHI–5, of whom 48/103 (47%) scored≤76;Reference Kelly, Dunstan, Lloyd and Fone 19 14/103 scored ≤52,Reference Bultmann, Rugulies, Lund, Christensen, Labriola and Burr 20 suggestive of severe depressive symptoms. For all three interviews up to 12 months post-venoplasty, 79/ 83 (95%) participants completed the MFIS–5 and 81 (97.6%) completed the MHI–5.

For the MFIS–5, Mauchly’s test (p=0.53) indicated that the assumption of sphericity was holding. The results of the RM ANOVA indicated that the MFIS–5 scores remained constant over time (F=0.0611, p=0.94). The median MFIS–5 scores at the initial, 6- and 12-month interviews were 8, 8 and 9, respectively. Thus, more than 50% of participants reported that fatigue impacted their daily activity. For the MHI–5, Mauchly’s test (p=0.64) indicated that the assumption of sphericity was holding. The result of the RM ANOVA indicated that MHI–5 scores also remained constant over time (F=1.37, p=0.26). The median MHI–5 scores were 84 for the three different interviews. The average MHI–5 scores were 77.5 (SD=17.1), 79.3 (SD=15.0) and 80.0 (SD=15.1) at the initial, 6- and 12-month interviews, respectively. There were similar results when the MFIS–5 and MHI–5 scores were available at the 24-month follow-up.

Physician-Reported Outcomes

The Registry received physician-reported data forms for 72/102 (70.6%) unique participants (a total of 80 report forms, including repeat venoplasties). Some 52 of the 80 reports (65%) indicated new medication after venoplasty—anticoagulants 15/52 (28.8%); acetylsalicylic acid 16/52 (30.8%); Plavix 18/52 (34.6%); and other unspecified but not disease-modifying therapies 17/52 (32.7%).

When examining the physician perceptions of the benefit from venoplasty, 9/80 (11.3%) and 12/80 (15.0%) reports indicated significant and modest benefits, respectively. However, no physician reported temporal improvement.

A total of 20 of the 80 reports (25.0%) showed agreement between participant and physician perceptions of the benefit of venoplasty: 8 (10.0%) “significant,” 5 (6.3%) “modest” and 7 (8.8%) “none.” Physicians perceived venoplasty as less beneficial than did patients in 33/80 reports (41.3%). The remaining 26/80 (33.7%) reports had “unknown” in one or both of the patient’s and physician’s perceptions.


A total of 12 of the 104 venoplasties (11.5%) resulted in complications during the procedure. In addition, 18/104 (17.3%) complications were within the first month after the most recent venoplasty. Serious procedure-related complications included a tear in the azygos vein (n=1), thrombosis (n=1) and bursting of the balloon (n=1). Other complications within the first month after venoplasty included thrombosis (n=2), allergic reaction to blood thinner requiring hospitalization on return to Canada (n=1), bleeding and large haematoma in the right groin (n=1), chest pain and depression (n=1), stroke (n=1), and arrhythmia (n=1). Tables 7 and 8 list the complications by type of treatment (dilation only, stent and/or balloon) as reported by patients.

Table 7 Participant self-reported procedure-related complications

Patient-reported treatment: D=dilation only; S=stent.

Table 8 Participant self-reported complications within the first month after the procedure

Patient-reported treatment: D=dilation only; S=stent.

Two participants had a second venoplasty during the study period, and one of these bled and had a large haematoma in the right groin within the first month after the second procedure.

Physician-reported peri-procedure complications were indicated in 17 procedures, including azygos vein dissection (n=1), menorrhagia (n=1), bleeding and marked bruising (n=1), hypertension requiring admission to the coronary care unit for monitoring (n=1), pain (n=1), inadequate sedation for procedure (n=1) and unspecified (n=11). A total of 20 procedures had complications within the first month after the procedure, including pain (n=7), hypertension 3 to 4 hours post-operatively (n=2), anaemia secondary to anticoagulation (n=1), constipation but likely travel-related (n=1), and unspecified (n=10).


This is the first longitudinal study looking at the “real-world” safety and sustained efficacy of venoplasty by systematically collecting PROs. Of the 13 symptom domains evaluated, 61.4% (51/83) of patients reported improvement with respect to fatigue initially post-procedure. Up to 19.3% (16/83) reported a worsening in their general health condition (Table 3). However, on follow-up interviews, very few patients had sustained improvement after the initial interview at 6, 12 or 24 months. Physicians reported significant or modest improvement in 26.3% of patients, but agreement between the perception of physicians and participants on venoplasty outcome with respect to MS could be found in only a quarter of the reports.

Some 84 of the 101 participants (83.2%; one did not provide information) who had venoplasty were managed at a BC MS clinic prior to treatment and subsequently returned to a BC MS clinic for ongoing care following the procedure, even though their medical tourism for venoplasty was against the advice of their MS physician.

Registry data indicated that undergoing venoplasty was not risk-free, with patients reporting adverse events, including major complications during (12/104=11.5%) and within a month of the procedure (18/104=17.3%). These complications included bleeding, hypertension, arrhythmia and stroke. It was beyond the scope of our study to inquire about supposed procedure-related complications later than a month post-venoplasty.

Our study is unique in terms of its longitudinal design and with patient-oriented standardized questionnaires administered to participants by trained interviewers, thus ensuring completeness and consistency of data as well as providing longitudinal changes in the health conditions of the patients following venoplasty. Importantly, as the patients self-reported their conditions post-treatment, there was no “physician impact” on longer-term outcomes. The availability of physician reports made comparison with patient reports possible; however, the physician reports were collected only once and not longitudinally.

The study did have its limitations. Participation in the BC CCSVI Registry was voluntary and so did not represent a random or population-based sampling, thus resulting in possible self-selection bias. However, the data show a good balance of PROs in terms of improvement and no improvement at the initial interview. Another limitation was the lack of standardization in terms of diagnosis and treatment at the various centres where the procedures were performed.

When examining MFIS–5 scores, more than 50% of patients (median MFIS–5 score ≥ 8) had fatigue symptoms. This rate remained constant over time (see Table 5), which suggested that the venoplasty was not effective in improving fatigue. When looking at MHI–5 scores, 47% of patients entering the study had an MHI–5 score ≤76,Reference Kelly, Dunstan, Lloyd and Fone 19 suggesting that they had some mental disorder. In particular, 14% had severe depressive symptoms (MHI–5 score≤52).Reference Bultmann, Rugulies, Lund, Christensen, Labriola and Burr 20 Depression is associated with increased morbidity and mortality, and is regarded by MS patients as one of the main determinants of their quality of life.Reference Feinstein 16

While patients perceived that the venoplasty had positive effects on such health conditions as fatigue, balance, vision and concentration/memory, this improvement was generally noted at the initial interview and declined over time (Table 3). If this represents, at least in part, a treatment benefit, the concern is that it does not appear to be sustained. Given the invasive nature of the therapy and the risk with stents, regular repeat therapy is not feasible in an attempt to maintain the perceived benefit seen post-treatment.

Thus, in conclusion, patient and/or physician perceptions of the positive impact of venoplasty on the health conditions of MS patients was not sustained over time. A sham controlled and blinded clinical trial is underway at four Canadian MS centres to assess the efficacy, safety and durability of balloon venoplasty for the treatment of extracranial venous narrowing in patients with MS.

Acknowledgements and Funding

This study was funded by the British Columbia Ministry of Health. We are enormously grateful to the individuals who participated in the study. We also thank Madonna de Lemos and Talitha Greenwood for data collection, and Kevin Atkins for data management and extraction.


ADS has received grant funding from Biogen Idec, Teva Canada Innovation, Sanofi Genzyme and Novartis, and she has received partial travel funds for ECTRIMS 2016 from Roche.

IMY, GK and LK have no disclosures to report.

KAP has received consultancy meeting fees from Biogen Idec, is a principal investigator for Novartis and Biogen Idec, and has received fees for seeing study patients.

ALT has received research support from Sanofi Genzyme, Roche, Biogen Idec and Chugai Pharmaceutical, and has served as consultant/advisor for Sanofi Genzyme, Roche, Teva Canada Innovation and Biogen Idec.

Statement of Authorship

ALT was principal investigator and ADS was co-principal investigator. The study was designed by ALT, ADS, IMY and KAP. GK and LK provided refinement to the study design. IMY wrote the first draft. All authors reviewed and provided input toward the final version, prepared by ADS and ALT. The data were reviewed and analysed by ALT, ADS and IMY. Statistical analysis was conducted by IMY. Literature searches were performed by IMY, ADS and ALT.

Supplementary materials

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