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Issue 20 - An Update on the Investigation of Chronic Cerebrospinal Venous Insufficiency for the Treatment of Multiple Sclerosis

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Context

Multiple sclerosis (MS) is a chronic progressive neurological disease common in young adults.1 Canada has one of the highest prevalence rates of MS in the world.2 MS causes significant disability due to mobility and vision problems, fatigue, incontinence, and cognitive impairment.1 The Public Health Agency of Canada estimated that the total costs associated with MS in 2000-2001 for hospitalization, treatment, and lost productivity due to morbidity and premature mortality were $950.5 million.1 Treatments involve suppressing or modifying the immune response, but there is currently no cure for MS.3

Although MS is commonly believed to be an autoimmune disease, the evidence to support this concept has been questioned.4 An alternative hypothesis has been put forth by Dr. Paolo Zamboni, a former vascular surgeon and professor at the University of Ferrara in northern Italy. Dr. Zamboni believes a phenomenon termed chronic cerebrospinal venous insufficiency (CCSVI), an abnormality in blood drainage from the brain and spinal cord due to the narrowing of veins, may cause the buildup of iron deposits and contribute to inflammation and nervous system damage.5 Initial findings that CCSVI may be associated with MS were published in 2009 from a study of 65 patients with MS.6 Results from a second study suggested that treating CCSVI with endovascular angioplasty (the insertion of a tiny balloon or stent into blocked veins to improve blood flow), also referred to as the liberation procedure, is feasible and safe.7

Results from other studies have not supported the hypothesis that CCSVI is present in patients with MS.8-12 Findings from a clinical trial published in April 2011, involving 499 participants, indicate that CCSVI may be a consequence rather than a cause of MS.13 The results showed that only 56.1% of MS patients had CCSVI. Furthermore, 42.3% of participants who had other neurological diseases and 22.7% of healthy controls also had CCSVI. It was also noted that CCSVI prevalence was significantly higher in patients with advanced progressive MS than those with non-progressive MS.

The CCSVI surgery for MS patients has not been approved by Health Canada and is not covered by provincial health insurance plans. In 2010, an estimated 3,000 Canadians travelled to clinics in the United States, Bulgaria, Poland, India, Costa Rica, and Mexico, each paying thousands of dollars for the procedure.14 Among them was an Ontario man who died in October 2010 from complications of the procedure, which he received in Costa Rica.15 Based on the risks associated with the CCSVI surgery and the inconclusive results of preliminary research, there have been recommendations that rigorous large-scale clinical trials are required to determine whether CCSVI is a clinically important factor in the development or progression of MS.16,17

In light of the high prevalence of MS in Canada, the CCSVI procedure has sparked unprecedented interest and generated considerable debate in the medical and scientific communities. Politicians have faced increasing pressure from the public to provide funding for clinical trials.

Objectives

The purpose of this report is to review recent developments in the investigation of CCSVI for the treatment of MS. This report will update information presented in a previous Environmental Scan, released in December 2010.18 The following questions will be addressed:

Which clinical trials in North America are currently studying the association of CCSVI with MS?

What is the status of funding for CCSVI research in Canada?

What other initiatives are taking place in Canada with regard to CCSVI?

Findings

It is not intended that the findings of this Environmental Scan provide a comprehensive review of the topic. The results of this report are based on a limited literature search. This report is based on information gathered as of April 21, 2011.

Ongoing Clinical Trials

In June 2010, the National MS Society (USA) and the MS Society of Canada committed over $2.4 million to support seven diagnostic studies focused on the role of CCSVI in MS.19 The purpose of these studies is to examine the structure and function of veins draining the brain and spinal cord in individuals representing a spectrum of MS types, severities, and durations. Healthy volunteers and people with other diseases will be used for comparison. These diagnostic studies are not designed to treat CCSVI, but rather to confirm whether CCSVI contributes to MS disease activity, to identify the best imaging technology to evaluate the condition, and to resolve conflicting data from previous studies. The studies may also be used to design protocols for possible exploratory therapeutic trials that may be undertaken if blockages are found.

The two-year grants began in July 2010 and results are being closely monitored by a scientific expert working group to determine whether clinical trials are warranted. In January 2011, the MS Society of Canada published the first in a series of six-month progress reports from the seven research teams (Appendix 1).20 The research teams have established rigorous protocols, are successfully recruiting participants, and are on track to deliver data upon completion of the two-year projects. Diagnostic scanning procedures are underway at all but one of the study sites. The next update is expected in July or August 2011.

In addition to the studies funded by the MS societies, Canadian researchers in Ontario21-23 and British Columbia24 are studying the prevalence of CCSVI in MS patients compared with healthy people (Appendix 2). Three clinical trials are currently evaluating the safety and efficacy of endovascular angioplasty for the treatment of MS.25-27

Federal and Provincial Funding for CCSVI Clinical Trials

In September 2010, federal Minister of Health Leona Aglukkaq announced that the federal government would not fund a pan-Canadian clinical trial until the results of studies currently underway and guidance from a scientific expert working group had been considered.28 This decision was based on recommendations formulated in August 2010 by an expert panel convened by the Canadian Institutes for Health Research (CIHR) and the MS Society of Canada.29 CIHR is also supporting a systematic review of diagnostic and therapeutic issues related to CCSVI. Results of this report are expected to be available in May 2011.

In October 2010, Saskatchewan invested $5 million to fund province-based clinical trials for the CCSVI procedure.30 The Saskatchewan Health Research Foundation launched a call for research proposals in December 2010.31 Funding decisions are expected to be announced in May 2011. The Yukon has expressed interest in teaming up with Saskatchewan. In April 2011, Yukon’s Minister of Health and Social Services, Glenn Hart, announced a $250,000 contribution to the Saskatchewan trials to ensure that Yukoners can participate in the trials.32

In April 2011, Manitoba announced that it would join Saskatchewan by contributing $5 million to advance clinical trial research on the CCSVI procedure.33 Both provinces had been calling for a nationally coordinated trial, but Manitoba Minister of Health Theresa Oswald said they couldn’t wait any longer.34 The Manitoba Health Research Council will issue a call for research proposals and will follow protocols already developed by the Saskatchewan Health Research Foundation in a complementary research process. The registration of patients for the trials is expected to start before the end of 2011.

Provincial Ministries of Health in Quebec, Nova Scotia, and Prince Edward Island have expressed interest in supporting a pan-Canadian clinical trial, provided that evidence from ongoing studies is positive.35-38 Ontario has remained cautious, citing the need for more scientific research and consensus in the scientific community before proceeding with funding for clinical trials.39

The MS Society of Canada has announced it is reserving $1 million for a pan-Canadian therapeutic clinical trial if preliminary results indicate such a trial is warranted.40 The organization hopes to work with the provinces and federal government to secure the remaining funds if the trial is approved.

Provincial Funding for the CCSVI Procedure

New Brunswick is the only province currently funding the CCSVI procedure. In November 2010, New Brunswick Premier David Alward announced the creation of a $500,000 fund to help MS patients receive the CCSVI procedure outside Canada.41Members of the medical community have voiced concerns over the decision to provide funding for medical treatment outside Canada, and the New Brunswick Medical Society hopes to be consulted as to how the money should be allocated.42 In December 2010, New Brunswick Minister of Health Madeleine Dubé communicated that details on how the fund would be dispersed were still being worked out, but the intent was for the money to be matched by contributions from the public.43

Provincial CCSVI Registries and Follow-Up Care

Many Canadians with MS have reported difficulties in receiving follow-up care in Canada after undergoing the CCSVI procedure abroad.44,45 This includes the Ontario man who died from complications in October 2010, upon returning from the Costa Rican clinic where he received the procedure.46 It has been reported that he was unable to find a local physician who was willing to treat him. With no national standards for follow-up care, Newfoundland, Alberta, British Columbia, and Ontario are taking steps to improve the monitoring of patients who undergo the CCSVI procedure.

In September 2010, Newfoundland committed $320,000 to fund a provincially based observational study to track the progress of MS patients who have travelled overseas at their own expense to have the CCSVI procedure.47 In February 2011, New Brunswick Minister of Health and Community Services Jerome Kennedy announced that the budget for the study had increased by $80,000, and that 29 of the 40 proposed participants were enrolled.48 Participants will undergo an MRI exam before the procedure and will receive follow-up from local neurologists to collect data on their condition.

In December 2010, Alberta Minister of Health and Wellness Gene Zwozdesky announced that the Government of Alberta would commit up to $1 million for a three-year observational study to determine the safety and patient-reported impact of CCSVI treatment procedures received outside Canada.49 The study intends to track at least 500 Albertans who have MS, including those who have travelled overseas for the CCSVI procedure. Researchers at the University of Alberta and the University of Calgary will conduct the study in collaboration with other experts. As of March 2011, the research team is awaiting ethics approval for their research proposal and anticipates the enrolment of participants to start in May 2011.50 Once underway, those who participate will be asked to complete a questionnaire on their symptoms, medical history, and possible complications following surgery. This information will help health authorities better understand the requirements for follow-up care for those who have undergone the CCSVI procedure abroad. The province hopes to use information from this study to determine the future need for clinical trials.

In March 2011, Alberta released guidelines on how to monitor patients for complications following the CCSVI procedure.51 The document was created by a multidisciplinary group of Alberta physicians and is being distributed to members of the College of Physicians & Surgeons of Alberta. The document notes that the guidelines do not represent official College policy and should not be used by physicians as a substitute for individual clinical judgment. Alberta Health Services issued a position statement in August 2010, urging MS patients not to seek the CCSVI procedure.52

In April 2011, the MS Clinic at the University of British Columbia Hospital received $700,000 over three years in provincial funding to establish a voluntary registry for MS patients who have undergone the CCSVI procedure in clinics outside Canada.13The information will be used to assess the benefits and complications of the procedure and help establish province-wide post-care treatment guidelines.

In March 2011, the Ontario government announced that it is setting up a panel of medical experts to establish best practice guidelines for follow-up care and treatment of patients who receive the CCSVI procedure outside Canada.53 Medical experts and MS advocates expect the guidelines to be adopted across the country.54

Canadian MS Monitoring System

In March 2011, federal Minister of Health Leona Aglukkaq announced that the Canadian Institute for Health Information (CIHI) will develop a nationwide system for measuring and monitoring the evolution and treatment of MS in Canada.55 The Canadian MS Monitoring System will be developed with initial funding from the Public Health Agency of Canada in collaboration with the Canadian Network of MS clinics and the MS Society of Canada. CIHI and its partners in the MS community will work with clinical and technical experts across Canada, patient representatives, and provincial and territorial governments to design and develop the monitoring system.56

A standardized data collection approach will be built on existing provincial/territorial data systems, to avoid duplication. Information will be collected on a voluntary basis from the Canadian Network of MS Clinics, which treat an estimated 80% of MS patients in Canada.

Information from the monitoring system will be used to measure disease patterns across Canada, identify variations in the use of treatments, and monitor long-term patient outcomes associated with different treatment options, including complications associated with the liberation procedure. The data will be used to support patient care and decisions on health care resource allocation, and to identify priority areas for research. The registry will begin compiling data in April 2011 and it is hoped that its first findings will be reported in the fall. It is expected to be fully operational in early 2012. CIHI will produce publicly available reports once sufficient information is collected. The system will cost the federal government approximately $2 million to establish and an estimated $1.5 million in ongoing annual costs.57

Other New and Emerging Therapies for MS

In March 2011, fingolimod (Gilenya, a sphingosine-1-phosphate analog) was approved by Health Canada as the first oral disease-modifying therapy for MS.58 Fingolimod was approved by the Food and Drug Administration (FDA) in September 201059 and by the UK’s drug regulator in April 2011.60

Cladribine (a purine nucleoside analog) was granted a priority review designation by the FDA in July 2010.61 However, in March 2011, the FDA announced its decision not to approve cladribine without additional safety information.62

Other health technologies currently being studied in clinical trials include monoclonal antibodies (such as rituximab, daclizumab, alemtuzumab, ocrelizumab, and ofatumumab), statins (such as atorvastatin and simvastatin), laquinimodoral fumarate, teriflunomide, firategrast, and autologous hematopoietic stem cell transplantation.3,63,64

Conclusion

It is not yet established whether CCSVI contributes to MS disease activity, and there have been conflicting data as to the frequency of this condition in people with MS. Recent results from a large clinical trial suggest that CCSVI may be the result of the disease rather than a cause. It is hoped that findings from ongoing studies will provide clarity regarding the need for pan-Canadian therapeutic clinical trials.

Several provinces have provided funding for various studies to determine the safety and effectiveness of the CCSVI procedure for MS. Saskatchewan and Manitoba are in the process of launching clinical trials. Newfoundland, Alberta, and British Columbia are funding observational studies to track patients who have received the procedure overseas. Provincial Ministries of Health in Ontario, Quebec, Nova Scotia, and Prince Edward Island have all expressed interest in supporting a pan-Canadian clinical trial, provided that evidence from ongoing studies is positive. The federal government intends not to fund a pan-Canadian clinical trial until ongoing studies indicate that CCSVI is indeed a hallmark in the disease process of MS.

Federal funding has been provided to develop the Canadian Multiple Sclerosis Monitoring System, which will track long-term patient outcomes associated with different treatment options, including complications associated with the CCSVI procedure. Alberta, British Columbia, and Ontario have taken steps to improve follow-up care for Canadians who travel abroad for the treatment. New Brunswick is the only province to promise funding to aid access to the CCSVI procedure outside Canada.

Scientific and medical organizations and experts across Canada have uniformly urged caution and rigorous study before the CCSVI procedure is recommended for use outside of clinical trials in MS patients. The recent approval of fingolimod has provided a new treatment choice for patients who have not responded to other MS therapies. Several other technologies are currently in the pipeline for the management of MS.

Complementing this Environmental Scan, CADTH prepared an Environmental Scan in December 2010 on the investigation of CCSVI for the treatment of MS, and a Rapid Response in December 2009 on surgical procedures targeting CCSVI for the treatment of MS. Both reports are available free of charge on the CADTH website.18,65

North American Guidelines and Recommendations

Managing patients with Multiple Sclerosis after out-of-country endovascular treatment for “CCSVI,” March 2011.

http://www.cpsa.ab.ca/Libraries/Res/Managing_patients_with_MS_after_out-of-country_endovascular_treatment_for_CCSVI.pdf

Canada Institutes of Health Research and MS Society of Canada. Joint Invitational Meeting on Multiple Sclerosis Research — Summary Report, August 2010.

http://www.cihr-irsc.gc.ca/e/42381.html

Interventional Endovascular Management of Chronic Cerebrospinal Venous Insufficiency in Patients with Multiple Sclerosis: A Position Statement by the Society of Interventional Radiology, Endorsed by the Canadian Interventional Radiology Association, August 2010.

http://www.sirweb.org/news/newsPDF/SIR_MSstatement_JVIR.pdf

Ontario Ministry of Health and Long-Term Care for the Ontario Health Technology Advisory Committee. OHTAC Recommendation: Multiple Sclerosis and Chronic Cerebrospinal Venous Insufficiency, May 2010. 

http://www.health.gov.on.ca/english/providers/program/ohtac/tech/recommend/rec_ccsvi_20100611.pdf


References

   1.   Canadian Institute for Health Information. The burden of neurological diseases, disorders and injuries in Canada [Internet]. Ottawa: CIHI; 2007. [cited 2011 Apr 15]. Available from: http://secure.cihi.ca/cihiweb/products/BND_e.pdf

   2.   Multiple Sclerosis Society of Canada [Internet]. Toronto: MS Society of Canada. MS experts estimate number of Canadians with MS is 55,000 to 75,000: medical update memo; 2006 May 2 [cited 2011 Apr 15]. Available from:http://mssociety.ca/en/research/medmmo-prev-may_02.htm

   3.   Niino M, Sasaki H. Update on the treatment options for multiple sclerosis. Expert Rev Clin Immunol. 2010 Jan;6(1):77-88.

   4.   Miravalle A, Corboy JR. Therapeutic options in multiple sclerosis: five new things. Neurology. 2010 Nov 2;75(18 Suppl 1):S22-S27.

   5.   Singh AV, Zamboni P. Anomalous venous blood flow and iron deposition in multiple sclerosis. J Cereb Blood Flow Metab. 2009 Dec;29(12):1867-78.

   6.   Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Tacconi G, Dall'Ara S, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry [Internet]. 2009 Apr [cited 2011 Apr 18];80(4):392-9. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2647682

   7.   Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Gianesini S, Bartolomei I, et al. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg. 2009 Dec;50(6):1348-58.

   8.   Sundstrom P, Wahlin A, Ambarki K, Birgander R, Eklund A, Malm J. Venous and cerebrospinal fluid flow in multiple sclerosis: a case-control study. Ann Neurol. 2010 Aug;68(2):255-9.

   9.   Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ. No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol. 2010 Aug;68(2):173-83.

10.   Baracchini C, Perini P, Calabrese M, Causin F, Rinaldi F, Gallo P. No evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset. Ann Neurol. 2011 Jan;69(1):90-9.

11.   Mayer CA, Pfeilschifter W, Lorenz MW, Nedelmann M, Bechmann I, Steinmetz H, et al. The perfect crime? CCSVI not leaving a trace in MS. J Neurol Neurosurg Psychiatry [Internet]. 2011 Apr [cited 2011 Apr 18];82(4):436-40. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061048

12.   NeuroSens. CCSVI supporting evidence lacking; 2011 Available from:http://neuro-sens.com/congress-news/3-general/209265

13.   Zivadinov R, Marr K, Cutter G, Ramanathan M, Benedict B, Kennedy C, et al. Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. Neurology. 2011;76(15). Available from:http://www.neurology.org/content/early/2011/04/13/WNL.0b013e318212a901.abstract?sid=2775e0f3-1e21-40e0-969d-dc042717fbaf

14.   CTV News [Internet]. Toronto: Bell Media; c2011. Studies in 2011 could decide MS theory's validity; 2010 Dec 27 [cited 2011 Apr 15]. Available from:http://www.ctv.ca/CTVNews/Health/20101227/ms-liberation-treatment-studies-101227/

15.   The Globe and Mail [Internet]. Toronto: The Globe and Mail Inc.; c2011. Death of MS patient fuels debate over new treatment; 2010 Nov 19 [cited 2011 Apr 15]. Available from: http://www.theglobeandmail.com/news/national/death-of-ms-patient-fuels-debate-over-new-treatment/article1807127/

16.   Vedantham S, Benenati JF, Kundu S, Black CM, Murphy KJ, Cardella JF, et al. Interventional endovascular management of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a position statement by the Society of Interventional Radiology, endorsed by the Canadian Interventional Radiology Association. J Vasc Interv Radiol. 2010 Sep;21(9):1335-7.

17.   Ontario Health Technology Advisory Committee. OHTAC recommendation: multiple sclerosis and chronic cerebrospinal venous insufficiency [Internet]. Toronto: Queen's Printer for Ontario; 2010 May. [cited 2011 Apr 15]. Available from:http://www.health.gov.on.ca/english/providers/program/ohtac/tech/recommend/rec_ccsvi_20100611.pdf

18.   Ndegwa S. Investigating chronic cerebrospinal venous insufficiency for the treatment of multiple sclerosis: environmental scan 15 [Internet]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2010. [cited 2011 Apr 15]. Available from:http://www.cadth.ca/media/pdf/Chronic_Cerebrospinal_Venous_Insufficiency_MS_es-15_e.pdf

19.   Multiple Sclerosis Society of Canada. Over $2.4 million committed to support seven operating grants to explore the relationship of CCSVI to multiple sclerosis [news release on the Internet]. Toronto: MS Society of Canada; 2010 Jun 11. [cited 2011 Apr 18]. Available from:http://mssociety.ca/en/releases/nr_20100611.htm

20.   Multiple Sclerosis Society of Canada. Medical update memo: research teams report progress from first six months of 2-year projects focusing on CCSVI and MS [Internet]. Toronto: MS Society of Canada; 2011 Jan 31. [cited 2011 Apr 15]. Available from:http://mssociety.ca/en/research/pdf/medmmo_20110131.pdf

21.   Rodger IW. MS CCSVI study information [Internet]. Hamilton (ON): St. Joseph's Health System; 2010 Mar 31. [cited 2011 Apr 15]. Available from:http://www.stjosham.on.ca/media/Res%20Admin/MS%20CCSVI/MS%20CCSVI%20Study%20Info%20on%20website%2031%20Mar'10.doc.pdf

22.   Frketich J. 100 local MS patients will get special treatment. thespec com [Internet]. 2010 Mar 26 [cited 2011 Apr 15]. Available from:http://www.thespec.com/news/article/24055--100-local-ms-patients-will-get-special-treatment

23.   Coles P. Study to get underway will look at clogged veins as a cause of MS. Niagara Advance [Internet]. 2011 Jan [cited 2011 Apr 15]. Available from:http://www.niagaraadvance.ca/ArticleDisplay.aspx?e=2910512

24.   False Creek Health Care Centre [Internet]. Vancouver: False Creek Healthcare Centre; c2011. CCSVI research: Vancouver diagnostics centre;  [cited 2011 Apr 15]. Available from: http://www.falsecreekdiagnostics.com/ccsvi-ms-studies/ccsvi-blood-flow-study/

25.   University at Buffalo: the state university of New York [Internet]. Buffalo (NY): University at Buffalo; c2011. News release: University at Buffalo launches clinical trial of new multiple sclerosis treatment; 2010 Jun 30 [cited 2011 Apr 18]. Available from: http://www.buffalo.edu/news/11500

26.   ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); 2000 Feb 29 -. Identifier NCT01201707, Evaluation of angioplasty in the treatment of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis; 2010 Sep 20 [cited 2011 Apr 18]. Available from:http://clinicaltrials.gov/ct2/show/NCT01201707

27.   ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); 2000 Feb 29 -. Identifier NCT01089686, Study to evaluate treating chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis patients; 2010 Aug 31 [cited 2011 Apr 18]. Available from:http://clinicaltrials.gov/ct2/show/NCT01089686

28.   Health Canada. Government of Canada accepts recommendations on MS research [Internet]. Ottawa: Health Canada; 2010 Sep 1. [cited 2011 Apr 18]. Available from: http://www.hc-sc.gc.ca/ahc-asc/media/nr-cp/_2010/2010_148-eng.php

29.   Canadian Institutes for Health Research [Internet]. Ottawa: CIHR; 15 Apr 2011. Joint invitational meeting on multiple sclerosis research - summary report; 2010 Aug 26 [cited 2011 Apr 18]. Available from: http://www.cihr-irsc.gc.ca/e/42381.html

30.   Government of Saskatchewan [Internet]. Saskatoon (SK): Government of Saskatchewan; c2011. News release: Province of Saskatchewan slates $5 million for MS liberation trials; 2010 Oct 19 [cited 2011 Apr 18]. Available from: http://www.gov.sk.ca/news?newsId=a14ba963-a810-45e4-9ffa-3f3bcf64148f

31.   Saskatchewan Health Research Foundation [Internet]. Saskatoon (SK): Saskatchewan Health Research Foundation; c2010. Call for proposal for MS clinical trials; 2010 Dec 17 [cited 2011 Apr 18]. Available from:http://www.shrf.ca/index-subpage-633.html

32.   Saskatchewan: Government of Saskatchewan. Yukon signs on to Saskatchewan's MS libertation clinical trials; 2011 Available from: http://www.gov.sk.ca/news?newsId=496418cc-abf1-4505-a554-ef08bceb5914

33.   Province of Manitoba [Internet]. Winnipeg (MB): Province of Manitoba; c2010. News release: Saskatchewan and Manitoba partner on MS liberation clinical trial research; 2011 Apr 5 [cited 2011 Apr 18]. Available from:http://news.gov.mb.ca/news/index.html?archive=&item=11189

34.   Turenne P. MB. to start trials of MS 'liberation treatment'. Winnipeg Sun [Internet]. 2011 Apr 5 [cited 2011 Apr 18]. Available from:http://www.winnipegsun.com/news/manitoba/2011/04/05/17885026.html#/news/manitoba/2011/04/05/pf-17885021.html

35.   Province of Manitoba [Internet]. Winnipeg (MB): Province of Manitoba; c2010. News release: Manitoba invests in multiple sclerosis support and research -- province pushes forward on multiple fronts for people living with MS: Oswald; 2010 Oct 15 [cited 2011 Apr 18]. Available from:http://news.gov.mb.ca/news/index.html?archive=week&item=9963

36.   CTV News Montreal [Internet]. Toronto: Bell Media; c2011. Quebec willing to test multiple sclerosis treatment; 2010 Aug 18 [cited 2011 Apr 18]. Available from:http://montreal.ctv.ca/servlet/an/local/CTVNews/20100818/mtl_ms_100818/20100818/?hub=MontrealHome

37.   Bouzane B. Nova Scotia supports debated MS trials. Ottawa Citizen [Internet]. 2010 Aug 23 [cited 2011 Apr 18]. Available from:http://www.ottawacitizen.com/health/Nova+Scotia+supports+debated+trials/3431738/story.html

38.   Coyne T. BC-NDP pushes for 'liberation therapy' trials for MS sufferers. Vancouver Sun [Internet]. 2010 Aug 24 [cited 2011 Apr 18]. Available from:http://www.vancouversun.com/health/pushes+liberation+therapy+trials+sufferers/3438060/story.html

39.   Matys F. Premier discusses 'liberation'. Simcoe com [Internet]. 2010 Oct 22 [cited 2011 Apr 18]. Available from:http://www.simcoe.com/news/article/891858--premier-discusses-liberation

40.   Multiple Sclerosis Society of Canada [Internet]. Toronto: MS Society of Canada. MS Society of Canada commits $1 million for CCSVI clinical trial; 2010 Sep 16 [cited 2011 Apr 18]. Available from:http://mssociety.ca/en/releases/nr_20100916.htm

41.   Many health care promises for new NB government. Health Edition [Internet]. 2010 Oct 1 [cited 2011 Apr 18];14(38). Available from:http://www.healthedition.com/article.cfm?articleID=8603&strKeyword=many%20health%20care%20promises%20for%20new%20NB

42.   Liberation Treatment CCSVI [Internet].  Liberation Treatment CCSVI; c2011. Controversy continues to surround MS liberation treatment; 2010 Dec [cited 2011 Apr 18]. Available from:http://liberationtreatmentccsvi.com/2010/12/controversy-continues-to-surround-ms-liberation-treatment/

43.   New Brunswick 'liberation' fund for MS based on politics, not science: expert. Truro Daily News [Internet]. 2010 Dec 5 [cited 2011 Apr 18]. Available from:http://www.trurodaily.com/News/Canada%20-%20World/Society/2010-12-05/article-2018808/New-Brunswick-liberation-fund-for-MS-based-on-politics-not-science-expert/1

44.   CBCnews [Internet]. Toronto: CBC/Radio-Canada; c2011. MS patients lack followup after vein therapy: angioplasty treatment not approved in Canada; 2010 Nov 16 [cited 2011 Apr 18]. Available from:http://www.cbc.ca/news/health/story/2010/11/15/multiple-sclerosis-ccsvi-complications.html

45.   Alphonso C. MS patients complain of inadequate care in Canada after liberation therapy. The Globe and Mail [Internet]. 2011 Feb 18 [cited 2011 Apr 18]. Available from: http://www.theglobeandmail.com/life/health/ms-patients-complain-of-inadequate-care-in-canada-after-liberation-therapy/article1913973/

46.   Jeffrey S. Guidance on neurologic after-Care for CCSVI procedures. Medscape Med News [Internet]. 2011 Mar 21 [cited 2011 Apr 18]. Available from:http://www.medscape.com/viewarticle/739340 Subscription required.

47.   Fitzpatrick M. Newfoundland launches 'observational study' of MS treatment. Postmedia News [Internet]. 2010 Sep 13 [cited 2011 Apr 18]. Available from:http://www.canada.com/health/Newfoundland+launches+observational+study+treatment/3517393/story.html

48.   News releases: Government of Newfoundland and Labrador [Internet]. St. John's (NL): Government of Newfoundland and Labrador. News releases: update provided on multiple sclerosis observational study; 2011 Feb 8 [cited 2011 Apr 18]. Available from:http://www.releases.gov.nl.ca/releases/2011/health/0208n02.htm

49.   CTV News Edmonton [Internet]. Toronto: Bell Media; c2011. Province funds study to examine safety of new treatment for MS patients; 2010 Dec 16 [cited 2011 Apr 18]. Available from:http://edmonton.ctv.ca/servlet/an/local/CTVNews/20101216/edm_treatment_101216/20101216/?hub=EdmontonHome

50.   The Reformed Multiple Sclerosis Society [Internet]. Vancouver: The Reformed Multiple Sclerosis Society; c2011. Alberta MS observational study update; 2011 Mar 28 [cited 2011 Apr 18]. Available from: http://www.reformedms.org/ms-ccsvi-news/alberta-ms-observational-study-update

51.   College of Physicians & Surgeons of Alberta. Managing patients with multiple sclerosis after out-of-country endovascular treatment for "CCSVI" [Internet]. Edmonton (AB): College of Physicians & Surgeons of Alberta; 2011 Mar. [cited 2011 Apr 18]. Available from:http://www.cpsa.ab.ca/Libraries/Res/Managing_patients_with_MS_after_out-of-country_endovascular_treatment_for_CCSVI.pdf

52.   Alberta Health Services. Multiple Sclerosis (MS) and "Chronic Cerebrospinal Venous Insufficiency" (CCSVI): Alberta Health Services information sheet [Internet]. Edmonton (AB): Alberta Health Services; 2010 Aug 6. [cited 2011 Apr 18]. Available from: http://www.albertahealthservices.ca/feat/ne-feat-ccsvi-ms-info-sheet.pdf

53.   Government of Ontario. Ontario [Internet]. Toronto: Queen's Printer for Ontario; c2008-2011. Ensuring the best possible care for MS patients: McGuinty government establishes expert panel to provide advice on best practices; 2011 Mar 1 [cited 2011 Apr 18]. Available from:http://www.news.ontario.ca/mohltc/en/2011/03/ensuring-the-best-possible-care-for-ms-patients.html

54.   Howlett K. Two provinces moving on follow-up care for MS liberation therapy. The Globe and Mail [Internet]. 2011 Mar 1 [cited 2011 Apr 18]. Available from:http://www.theglobeandmail.com/news/national/ontario/two-provinces-moving-on-follow-up-care-for-ms-liberation-therapy/article1925266/

55.   Canadian Institute for Health Information. CIHI [Internet]. Ottawa: CIHI; c1996-2010. CIHI to develop national multiple sclerosis monitoring system: information will help identify disease patterns, use of treatments and long-term outcomes for MS patients; 2011 Mar 23 [cited 2011 Apr 18]. Available from: http://www.cihi.ca/CIHI-ext-portal/internet/en/Document/types+of+care/primary+health/RELEASE_22MAR11

56.   Public Health Agency of Canada [Internet]. Ottawa: PHAC; 15 Apr 2011. Canadian multiple sclerosis monitoring system; 2011 Mar 23 [cited 2011 Apr 18]. Available from: http://www.phac-aspc.gc.ca/cd-mc/ms-sp/index-eng.php

57.   Public Health Agency of Canada [Internet]. Ottawa: PHAC. Canadian multiple sclerosis monitoring system: frequently asked questions; 2011 Mar 23 [cited 2011 Apr 18]. Available from: http://www.phac-aspc.gc.ca/cd-mc/ms-sp/faq-eng.php

58.   Multiple Sclerosis Society of Canada [Internet]. Toronto: MS Society of Canada. First oral disease-modifying therapy approved in Canada (Gilenya®); 2011 Mar 10 [cited 2011 Apr 18]. Available from:http://mssociety.ca/en/research/medmmo_20110310.htm

59.   Jeffrey S. Fingolimod receives FDA approval as first oral MS treatment. Medscape Med News [Internet]. 2010 Sep 22 [cited 2011 Apr 18]. Available from: http://www.medscape.com/viewarticle/729172 Subscription required.

60.   ITV. MS pill approved; 2011 Available from: http://www.itv.com/news/ms-pill-approved38079/

61.   Merck Serono: FDA grants priority review to Cladribine tablets for the treatment of relapsing forms of MS [Internet]. Switzerland: MerckSerono; 2010 Jul 28. [cited 2011 Apr 18]. Available from:http://www.merckserono.com/corp.merckserono/en/images/20100728_en_tcm112_55741.pdf

62.   Gandey A. FDA rejects oral Cladribine for multiple sclerosis. Medscape Med News [Internet]. 2011 Mar 2 [cited 2011 Apr 18]. Available from:http://www.medscape.com/viewarticle/738239

63.   National Multiple Sclerosis Society [Internet]. New York: National MS Society. MS researchers share progress at annual ECTRIMS conference; 2010 Nov 2 [cited 2011 Apr 18]. Available from: http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=4057

64.   Greenberg BM, Khatri BO, Kramer JF. Current and emerging multiple sclerosis therapeutics. CONTINUUM: Lifelong Learning in Neurology. 2010 Oct;16(5):58-77.

65.   Clark M, Nkansah E. Surgical procedures targeting chronic cerebrospinal venous insufficiency for the treatment of multiple sclerosis: clinical effectiveness [Internet]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2009 Dec 2. [cited 2011 Apr 18]. Available from:http://www.cadth.ca/media/pdf/K0117_MS_Surgery_final.pdf

66.   Multiple Sclerosis Society of Canada. Cerebral venous hemodynamics in pediatric multiple sclerosis [Internet]. Toronto: MS Society of Canada; 2010. [cited 2011 Apr 18]. Available from:http://mssociety.ca/ccsvi/resources/funding/Paediatric_Banwell_CCSVI.pdf

67.   Multiple Sclerosis Society of Canada. Determining the relationship between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS) [Internet]. Toronto: MS Society of Canada; 2010. [cited 2011 Apr 18]. Available from:http://mssociety.ca/ccsvi/resources/funding/Calgary_Costello_CCSVI.pdf

68.   Multiple Sclerosis Society of Canada. Chronic cerebrospinal venous insufficiency in relation to multiple sclerosis [Internet]. Toronto: MS Society of Canada; 2010. [cited 2011 Apr 18]. Available from:http://mssociety.ca/ccsvi/resources/funding/Ottawa_Torres_CCSVI.pdf

69.   Multiple Sclerosis Society of Canada. Investigation into venous insufficiency in multiple sclerosis [Internet]. Toronto: MS Society of Canada; 2010. [cited 2011 Apr 18]. Available from:http://mssociety.ca/ccsvi/resources/funding/BC_Traboulsee_Knox_CCSVI.pdf

70.   National Multiple Sclerosis Society [Internet]. New York: National MS Society. Study of CCSVI in MS using quantitative time-resolved 3D MRV; 2010 [cited 2011 Apr 18]. Available from:http://www.nationalmssociety.org/research/intriguing-leads-on-the-horizon/ccsvi/ccsvi-study-by-field-team/index.aspx

71.   National Multiple Sclerosis Society [Internet]. New York: National MS Society. A multi-modal assessment of chronic cerebrospinal venous insufficiency; 2010 [cited 2011 Apr 18]. Available from:http://www.nationalmssociety.org/research/intriguing-leads-on-the-horizon/ccsvi/ccsvi-study-by-fox-team/index.aspx

72.   National Multiple Sclerosis Society [Internet]. New York: National MS Society. CCSVI and its relationship to MS; 2010 [cited 2011 Apr 18]. Available from:http://www.nationalmssociety.org/research/intriguing-leads-on-the-horizon/ccsvi/ccsvi-study-by-wolinsky-team/index.aspx

73.   Frketich J. MS patients fund study of new treatment [Internet]. Hamilton Spectator. 2010 Apr 15 [cited 2011 Apr 18]. Available from:http://www.thespec.com/news/local/article/20663--ms-patients-fund-study-of-new-treatment

74.   MS Liberation Group. MS Liberation [Internet]. Ottawa: MS Liberation Group; 14 Apr 2011. Buffalo research; 2010 Dec 10 [cited 2011 Apr 18]. Available from:http://msliberation.ca/MS_Liberation_Group/Buffalo_Research.html

Appendix 1: Six-Month Progress for Seven MS Society-Funded CCSVI Studies20  

Investigator, Location

Study Information

Dr. Brenda Banwell, Hospital for Sick Children, Toronto, Ontario66

Research Ethics Board approval has been received. Participants are currently being enrolled to compare vein abnormalities in children and teenagers who have MS with healthy controls of the same age, using non-invasive MRI, ultrasound, and novel measures of venous flow. The team’s ultrasound experts have received training in Dr. Zamboni’s original techniques. A total of 60 participants, both healthy and with MS, will be enrolled. This population will allow for an examination of disease process at an early stage where other health conditions that might affect blood flow do not exist.

Dr. Fiona Costello, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta67

Research Ethics Board approval has been received. A cross-section of individuals with MS is currently being recruited for comparison with people who have other neurological diseases and healthy volunteers. The study will compare 3 Tesla MRI venography scans with ultrasound, as originally used by Dr. Zamboni. The team will assess whether linkages exist between venous abnormalities and different aspects and measures of MS activity and tissue damage. A total of 180 participants will be enrolled.

Dr. Carlos Torres, Ottawa Hospital, University of Ottawa, Ottawa, Ontario68

Research Ethics Board approval has been received and participants are currently being recruited. The study will use 3 Tesla MRI and Doppler ultrasound technology to explore differences in the anatomy of veins in the neck, chest, and spine and to assess iron deposits in the brain. Team members are slated to be trained using the ultrasound techniques originally used by Dr. Zamboni. The study will include 50 people with MS and 50 age-matched healthy volunteers.

Dr. Anthony Traboulsee,

MS Clinic at UBC Hospital, Vancouver Coastal Health and University of BC, Vancouver, British Columbia

Dr. Katherine Knox, Saskatoon MS Clinic, University of Saskatchewan, Saskatoon, Saskatchewan69

Research Ethics Board approval has been received at both sites and research teams have begun to recruit and scan participants. Team radiologists met in February 2011 to ensure the consistency of protocols across sites. The prevalence of CCSVI in 200 people with and without MS will be studied using catheter venography, ultrasound, and magnetic resonance venography. Ultrasound technologies were trained in the techniques originally used by Dr. Zamboni. The study allows for the inclusion of family members of the MS patient, such as identical twins, in the control group. The study aims to determine the reliability and accuracy of different imaging techniques for screening of CCSVI.

Dr. Aaron Field, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin70

Institutional Review Board approval has not yet been received. The study will use MRI scans to generate detailed images of veins in the head and neck in 112 people with MS, 56 controls without MS, and 56 people with other neurological conditions. These images will be compared with results obtained from the ultrasound techniques used by Dr. Zamboni.

Dr. Robert Fox, Cleveland Clinic Foundation, Cleveland, Ohio71

Institutional Review Board approval has been received and recruitment is ongoing. The study will compare 90 people with MS and 80 healthy volunteers. The team will use the ultrasound techniques used by Dr. Zamboni, as well as magnetic resonance studies of the veins, MRI scans of the brain, and clinical measures to determine MS activity. The ultrasound team encountered several methodological challenges based on the published methodology and has developed a standardized protocol and analysis to achieve consistent results. To distinguish whether vein abnormalities are from atrophy (brain tissue volume loss) and not specifically MS, they are also comparing the MS group with people with atrophy from Alzheimer's disease. Neck and spinal cord tissue obtained from MS patients via autopsy will be used for tissue-based evaluation of CCSVI and its possible relationship to MS.

Dr. Jerry Wolinsky, University of Texas Health Science Center, Houston, Texas72

Institutional Review Board approval has been received and the team has already scanned a significant number of participants. This study will replicate the ultrasound methods used by Dr. Zamboni to investigate the association of CCSVI with major clinical types of MS using non-MS control groups. A total of 275 people will be recruited. The team is currently having difficulty recruiting non-MS control subjects who don’t have a personal interest in the trial. The team will also assess whether other imaging methods can confirm the ultrasound findings and determine which technique is the most reliable to screen for CCSVI.

CCSVI = chronic cerebrospinal venous insufficiency; MRI = magnetic resonance imaging; MS = multiple sclerosis.


Appendix 2: Other Ongoing CCSVI Studies in North America

Investigator, Location

Study Information

Funding

Canada

Dr. Ian Rodger, St. Joseph’s Healthcare, Hamilton, in collaboration with Hamilton Health Sciences and McMaster University, Hamilton, Ontario21-23,73

CCSVI MS Research Study

This study will use MRI and ultrasound tests to determine the prevalence of cerebrospinal venous abnormalities in 100 individuals who have MS compared with 100 people who do not have MS.

Public donations

Dr. Keith Chambers, False Creek Healthcare Centre, Vancouver, British Columbia24

CCSVI Blood Flow Study

This study will compare brain blood vessel differences in 100 individuals who have MS with 100 people who do not have MS, using MRI.

False Creek Healthcare Centre

United States

Dr. Adnan Siddiqui, University of Buffalo, Department of Neurosurgery, Buffalo, New York25

PREMiSe (Prospective Randomized Endovascular therapy in Multiple Sclerosis) Study

This randomized, double-blind, placebo-controlled study will test the safety and efficacy of interventional endovascular therapy. In the first phase, 10 MS patients exhibiting CCSVI underwent minimally invasive venous angioplasties to determine whether the procedure could be performed safely. Investigators are currently enrolling 20 more participants for the second phase of the study.74 MS patients will be randomized to undergo either venous angioplasty or a “sham angioplasty” (i.e., catheter is inserted but there is no inflation of the balloon) to test the placebo effect. These subjects will be evaluated periodically over six months. If results are positive, the researchers will approach the University of Buffalo Institutional Review Board for an extension of the protocol to study a larger group of patients.

Public donations and Direct-MS Foundation

Dr. Gary Siskin, Albany Medical Center, Albany, New York26

This double-blind, randomized, controlled trial will determine whether venous angioplasty is an effective treatment for CCSVI and expects to enrol approximately 130 patients. The outcomes of two groups of patients will be compared. One group will have CCSVI diagnosed on a venogram and treated with angioplasty, and the second group will have CCSVI diagnosed on a venogram and treated with a sham procedure. Several outcomes will be evaluated over 24 months, including safety, efficacy, and quality of life. 

Community Care Physicians, PC

Dr. Manish Mehta, The Vascular Group, PLLC, The Vascular Health Pavilion, Albany, New York27

The study is a randomized, double-blind (sham procedure), placebo-controlled feasibility clinical trial with an expected enrolment of 600. The purpose is to evaluate the safety, feasibility, and efficacy of percutaneous transluminal angioplasty in treating extracranial venous obstructive lesions, and its influence on the clinical outcomes of MS patients who have been found to have CCSVI. Outcome measures evaluated over 24 months include adverse events, neurological assessment, MRI evaluation of MS lesions, and mortality.

The Vascular Group, PLLC

CCSVI = chronic cerebrospinal venous insufficiency; MRI = magnetic resonance imaging; MS = multiple sclerosis.

Cite as: Ndegwa, S. An Update on the Investigation of Chronic Cerebrospinal Venous Insufficiency for the Treatment of Multiple Sclerosis [Environmental Scan, Issue 20]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2011.

CADTH takes sole responsibility for the final form and content of this environmental scan. The statements and conclusions in this environmental scan are those of CADTH.

Production of this report is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Prince Edward Island, Saskatchewan, and Yukon. The Canadian Agency for Drugs and Technologies in Health takes sole responsibility for the final form and content of this report. The views expressed herein do not necessarily represent the views of Health Canada or any provincial or territorial government.

Disclaimer: The Environmental Scanning Service is an information service for those involved in planning and providing health care in Canada. Environmental Scanning Service responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide information on a topic that CADTH could identify using all reasonable efforts within the time allowed. Environmental Scanning Service responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness, particularly in the case of new and emerging health technologies for which little information can be found but that may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete, and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet.

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