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Goodbye to all that: a short history of CCSVI

 
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PostPosted: Wed Sep 25, 2013 11:05 pm    Post subject: Goodbye to all that: a short history of CCSVI Reply with quote

This editorial refers to two articles in the same issue of Multiple Sclerosis Journal. More information from these articles appear in separate threads:

http://msspeaks.easyphpbb.com/viewtopic.php?t=3993

http://msspeaks.easyphpbb.com/viewtopic.php?t=4238



From Multiple Sclerosis Journal, September 23, 2013:

Quote:
Goodbye to all that: a short history of CCSVI

Michael Rasminsky1
Karel terBrugge2

1Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
2Department of Radiology, University of Toronto, Toronto, Canada
Michael Rasminsky, Division of Neurology, Montreal General Hospital, 1650 Cedar Ave., Montreal, QC, Canada, H3G 1A4 Email: michael.rasminsky@mcgill.ca

Alice laughed: “There’s no use trying,” she said; “one can’t believe impossible things.” “I daresay you haven’t had much practice,” said the Queen. “When I was younger, I always did it for half an hour a day. Why, sometimes I’ve believed as many as six impossible things before breakfast.”

--Lewis Carroll. Alice in Wonderland

The current issue of the MS Journal contains carefully performed studies by the group from the University of Texas1 and by the Italian CoSMo Collaborative Study Group2 that together with the previous study by the Texas group3 will hopefully finally definitively put paid to the hypothesis that multiple sclerosis (MS) is caused by chronic cerebrospinal venous insufficiency (CCSVI). It could be argued that such studies would have been unnecessary in a rational society, but they were unfortunately absolutely required in the hyper-connected society in which we live.

In the last 4 years the CCSVI hypothesis has turned the MS world upside down. The initial report of venous abnormalities in MS purported to demonstrate that 100% of individuals with MS had significant constrictions of veins draining the brain.4 This quickly and logically led to attempts to correct the abnormality by vein dilation and/or stenting.5 Elements of the media, ever anxious for a heartwarming story of a new and simple solution to a tragic problem that has played havoc with many lives, quickly trumpeted the story of the intrepid Italian investigator who had invented an enticingly labeled “liberation procedure” for the treatment of MS.6,7

From the outset there was healthy skepticism in the neurologic community. Not only did the contention that a venous anomaly was present in 100% of individuals with MS send up red flags, but the theory that a venous anomaly, even if indeed present, could cause MS seemed biologically implausible for many reasons: the fact that the redundancy of the cerebral venous drainage system would be expected easily to accommodate obstruction in single veins; the lack of similarity of the pathology in MS to the brain pathology known to occur with severe cerebral venous obstruction; the failure of the hypothesis to account for the relapsing–remitting character of MS; and the implicit dismissal of the well-established consensus8 that MS is an inflammatory disorder reflecting some as yet incompletely understood derangement of the immunological system.

Nonetheless, the enthusiasm within a substantial part of the MS patient community for the “liberation procedure,” fanned by social networking sites and the blogosphere, generated enormous pressures on granting agencies such as the MS Societies and government funding agencies in North America, Europe and Australia to pursue the possibility that CCSVI was a viable explanation for MS. The discussion became particularly animated in Canada where the prevalence of MS is high and the media-generated interest in CCSVI was much greater than elsewhere.9,10 Although the Canadian MS Society expressed no enthusiasm for the concept of CCSVI, it adopted a publically agnostic position about the hypothesis, no doubt in well-justified fear of antagonizing the large constituency within the MS community whose hopes of a miraculous cure had been aroused by the fevered publicity.

The evolution of the discussion in Canada offers a particularly instructive, and at times disheartening, example of a complex interaction among patient advocacy groups, scientists, non-governmental and governmental funding agencies, politicians, the press and the blogosphere.

In 2010 the Canadian Institutes of Health Research (CIHR) together with the Canadian MS Society created an expert panel with a watching brief re CCSVI. This panel initially advocated funding only studies that would examine the hypothesis that there was indeed a venous anomaly in MS, and has carefully monitored those studies which have been published. A similar stance was taken by the US and other MS Societies, without the involvement of government funding agencies. An initial CIHR-sponsored meta-analysis of the initially published studies of CCSVI ostensibly indicated an increased level of CCSVI in patients with MS;11,12 however, the reviewing panel was careful to note that any conclusions were precluded by the heterogeneity of the studies and the lack of reporting of the success of blinding in most of the studies. The authors of the papers published in this issue of the journal have offered detailed penetrating critiques2,3 of the methodological difficulties inherent in many of the early papers that purported to offer evidence for the existence of CCSVI at high frequency in MS patients, papers that were included in the CIHR meta-analysis.

As the public discussion concerning the wisdom of further clinical trials of vein unblocking progressed, the Canadian paper of record, the Globe and Mail, editorialized that “Canada should fund medical trials of a revolutionary treatment for multiple sclerosis, and not act as if the rejection of those trials by an expert panel must be obeyed. This is a political question, not a purely scientific one.”13 Similarly, the lead medical reporter for CTV followed her initial “documentary”5 about Dr Paolo Zamboni with numerous stories on the evening news, reiterating the apparent efficacy of the “liberation procedure”, any reservations about the procedure almost invariably being preceded by an opening shot of a patient rising from a wheelchair.

The ongoing pressures (including those generated by some members of Parliament and some provincial governments) were such that within a few months CIHR modified its initial cautious stance by calling for proposals for small-scale treatment trials despite the ongoing ambiguity about the viability of the CCSVI hypothesis. These trials have now received initial funding.

There is a bewildering array of techniques for non-interventional examination of the venous drainage of the central nervous system, and as has been most recently illustrated in the study from the Italian group,2 a distressing level of intra-observer disagreement in interpretation of ultrasound data. However, it is also clear that there are enormous variations in normal patterns of cerebral venous drainage within the healthy population, and that interpretation of patterns of venous drainage and venous obstruction can be highly subjective, subject to observer bias, and discrepant from institution to institution, depending upon the particular technology used for assessment. The particular strength of the investigations by the Texas group and the Italian consortium is the meticulous care that was taken in both cases to achieve blinding to diagnoses both of ultrasonographers performing the studies and of the individuals reading the ultrasound images.

The study by the Italian group2 represents the largest multi-centered trial to date, and the paper by Brod et al.1 extends the ultrasound observations of the Texas group on a large group of patients and controls3 to studies using the more interventional techniques of contrast enhanced magnetic resonance venography and transluminal venography on a small group of patients with MS. Although the latter studies are not bolstered with the sort of statistics that one would like to see comparing patients with controls, the unsurprising conclusion is that venous anomalies and pressure gradients within veins were only rarely seen in the MS patients examined. In short, these two studies provide the most convincing evidence yet available that cerebral venous anomalies do not exist with any increased frequency in patients with MS.

The scientific process, in the face of enormous pressures, seems to have done its work. In light of these carefully done studies it should now be a settled issue that CCSVI does not offer a plausible explanation for the pathophysiology of MS.

Is there a remaining justification for ongoing clinical trials of treatment of CCSVI? Interventional clinical research trials are always fraught with ethical issues. Foremost among these is the requirement for equipoise,14 the ability to make both a theoretical and clinical case that a putative new treatment might be better than currently available treatments. From a theoretical standpoint there would now appear to be no justification for ongoing treatment trials, given that all well-controlled and well-blinded studies, including those reported in this issue of the MS Journal, have failed to show any venous anomaly characteristic of MS and not found in non-MS individuals. It is difficult to make a case that an abnormality that does not exist should be corrected. The totality of the clinical justification for further clinical trials of intervention to correct CCSVI is the anecdotal reports of improvement by some patients who have submitted to the interventional procedure, often at substantial expense and after travelling considerable distances to destinations such as Kuwait, Costa Rica, Poland, etc. The reported improvements have been for the most part highly subjective and non-specific: feelings of less fatigue, of clearing of the head, of less “brain fog,” of increased energy, of instant changes in sensory symptomatology, etc.
Although this controversy has hopefully now run its course, it has resulted in the unnecessary expenditure of significant resources, has tragically aroused false hopes in many, and has resulted in serious side-effects in some and death for others. For these reasons it may be instructive to consider why this proposal temporarily gained such a foothold in the MS patient world, if not among any significant part of the MS scientific community. The Canadian example is particularly apt insofar as it illuminates in an extreme form the problems of the healthy tension between patient concerns and priorities and more dispassionate scientific assessment of what is and is not worth pursuing in the search for cure or amelioration of disease. The enormous enthusiasm for CCSVI in Canada among patients and their families who could not reasonably be expected to have a sophisticated understanding of the cerebral venous system or the biology of MS was a result of a perfect storm of a number of factors:

~Understandable patient frustration with the lack of effective treatments, particularly for the progressive forms of MS

~Patient resentment and suspicion of physicians who, at least on the CCSVI blogs, were widely perceived to be in the pocket of the drug companies because they prescribed expensive drugs

~The sudden emergence of a procedure that offered a tantalizingly simple and attractive solution to a complex problem

~The effectiveness of a highly proactive social network, highly penetrant within a limited community

~The initially deferential response of the MS Society to the enthusiasm for a proposal that, though superficially attractive, was transparently highly questionable on scientific grounds, together with the failure of knowledgeable scientists to vigorously engage in a respectful way in the public discussion

~The perception in Canada that governments at both federal and provincial levels, responsible for health care, could be influenced by public pressure to intervene in scientific and clinical matters

~The difficulty on the part of the media, patient population and politicians in distinguishing what constitutes scientific as opposed to anecdotal evidence

~The difficulty on the part of some elements of the press and some elements of government in distinguishing between the government’s obligation to make choices about the allocation of scientific resources to different fields (e.g. physics vs. medicine) and their obligation to leave funding decisions within specialized fields to those scientifically qualified to make such judgments

~Most importantly, the irresponsibility of certain elements of the mainstream media that repeatedly crossed the journalistic line between reporting the news and making the news

This is not the first putative treatment for MS that has crashed and burned, but it is the first to attract such widespread passions. Given the extent of the controversy re CCSVI, it was in this instance unavoidable to expend significant resources in order to debunk it. However, were it not for the initial publicity in the media, it is likely that this “cure” would have been yet another to sink without trace.

What can be done to prevent such fiascos from occurring in the future? It will be critically important for the informed medical community to act before such stories acquire legs. Like it or not, we are now definitively in the Facebook era of medicine. Social media and the blogosphere have completely changed this game. The medical/scientific community must become much more proactive in developing relationships with the media that will encourage them to exercise more caution in presenting possibly sensational stories that have not yet garnered significant scientific support but that have the potential to inflame the public. Scientists and physicians whose default position is avoidance of the media and controversy must learn to recognize the importance of respectful engagement with the public in order to help mold a more informed public opinion.

Unfortunately the CCSVI genie is long since out of the bottle. A reality of the Internet age of medicine is that there will undoubtedly continue to be many passionately vocal devotees of the view that treating CCSVI is a useful approach to MS. Nonetheless, it is now difficult to see how the CCSVI hypothesis should continue to animate interventional clinical trials that are expensive, possibly dangerous, almost impossible to adequately control and that divert scarce funds from the several promising lines of investigation that have begun in the last few years finally to offer some real hope to those suffering the scourge of MS.

_____________________
Article Notes

Conflict of interest

Michael Rasminsky is a former member and Karel terBrugge is a current member of the Canadian MS Society’s Medical Advisory Committee. This paper reflects the views of the authors and not those of the Canadian MS Society

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.


References

1. Brod SA, Kramer LA, Cohen AM, et al. Chronic cerebrospinal venous insufficiency: Masked multimodal imaging assessment. Mult Scler J 2013; 19: 1499–1507.

2. Comi G, Battaglia MA, Bertolotto A, et al. Observational case-control study of the prevalence of chronic cerebro-spinal venous insufficiency in multiple sclerosis: Results from the CoSMo study. Mult Scler J 2013; 19: 1508–1517.

3. Barreto AD, Brod SA, Bui T-T, et al. Chronic cerebrospinal venous insufficiency: Case–control neurosonography results. Ann Neurol 2013; 73: 721–728.

4. Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J. Neurol Neurosurg Psychiatr 2009; 80: 392–399.

5. Zamboni P, Galeotti R, Menegatti E. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg 2009; 50: 1348–1358.

6. Favaro A, Phillip E. The Liberation Treatment: A whole new approach to MS. http://www.ctvnews.ca/the-liberation-treatment-a-whole-new-approach-to-ms-1.456617(accessed June 1, 2013).

7. Picard A, Favaro A. Researcher’s labour of love leads to MS breakthrough. The Globe and Mail 2009. http://www.theglobeandmail.com/news/national/researchers-labour-of-love-leads-to-ms-breakthrough/article4196866/?page=all(accessed June 1, 2013).

8.Compston A, Coles A. Multiple Sclerosis. Lancet 2008; 372: 1502–1517.

9. Chafe R, Born KB, Slutsky S, et al. The rise of people power. Nature 2011; 472: 410–411.

10. Pullman D, Zarzeczny A, Picard A. Media, politics and science policy: MS and evidence from the CCSVI trenches. BMC Med Ethics 2013; 14:6.

11. Laupacis A, Lillie E, Dueck A, et al. Associations between chronic cerebral venous insufficiency and multiple sclerosis: A meta-analysis. CMAJ 2011; 183: 1203–1212.

12.Laupacis A, Lillie E, Dueck A. Systematic reviews of the evidence regarding chronic cerebral spinal venous insufficiency (CCSVI) and multiple sclerosis; An update for the CIHR Expert Panel December 18, 2012. http://www.ccsvireviews.ca (accessed June 1, 2013)

13.Editorial. Funding MS trials is a decision that goes beyond expertise. http://www.theglobeandmail.com/commentary/editorials/funding-ms-trials-is-a-decision-that-goes-beyond-expertise/article1379043/(accessed June 1, 2013).

14.Freedman B. Equipoise and the ethics of clinical research. NEJM 1987; 317: 141–145.
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