The panel has agreed that there is currently not enough information on the specific parameters required to run a large-scale, pivotal multicentre trial. However, these types of trials are the “mandatory goal” for the study of CCSVI, it states.
JVIR has recently published the proceedings as a special communication titled “The Development of a Research Agenda for Evaluation of Interventional Therapies for Chronic Cerebrospinal Venous Insufficiency: Proceedings from a Multidisciplinary Research Consensus Panel. The panel comprises Gary P Siskin (New York, USA), Ziv Haskal and Walter Royal III (both from Baltimore, USA), Gordon McLennan (Cleveland, USA), Michael Dake (Palo Alto, USA), Mark Haacke (Detroit, USA), Sandy McDonald (Barrie, Canada) Suresh Vedantham (St Louis, USA), Salvatore Sclafani (Brooklyn, USA), R Torrance Andrews (Seattle, USA), David Hubbard and Heidi Sauder (San Diego, USA).
The panel further recommends that prospective safety and efficacy trials should be conducted in well-defined and potentially smaller controlled populations under institutional review board approval. It advocates that it is critical to support and continue the basic science work which seeks to clarify the relationship between venous stenoses and hypertension and the subsequent contribution of CCSVI to patients with multiple sclerosis.
Treatment for the unproven syndrome of CCSVI is controversial, with some interventional radiologists believing that this could be a new and rewarding area to contribute their services in. Others feel strongly that while rigorous scientific data are lacking, any treatment for this putative theory must be limited to the setting of a randomised trial.
The JVIR special communiqué also states that “there was near-universal agreement that randomised trials would be required to confirm the role of venous interventions in multiple sclerosis.” However, the proceedings say “It was equally clear from the discussion that several factors could be better understood before large-scale randomised trials are initiated. Among these are […] confirmatory prevalence and diagnosis data, but also the need to define the appropriate study population, the need to optimise the interventional techniques for diagnosis and treatment, and to agree on appropriate endpoints for primary and secondary endpoint analysis.” The panel has encouraged the performance of investigator-initiated single-centre and multicentre studies so that safety and outcome data can be reported. They write that “a foundation of knowledge in these areas can be gathered. This knowledge will help provide the information necessary to appropriately power a prospective randomised trial.”
There are also interventionalists who are already calling for randomised controlled trials. Lindsay Machan, Vancouver, Canada, told delegates at the Charing Cross Symposium in London in April,“To answer the question if the CCSVI syndrome is real, I still have absolutely no idea, but what I do know is that a sham controlled trial is urgently needed.” He also said, “There is no consensus on the criteria for diagnosis of venous stenosis in the upper body, we do not know what we are treating and we do not have a documented durable method to treat jugular venous stenosis.”
The JVIR communication also notes that there are likely to be practitioners who will offer endovascular therapy to patients with multiple sclerosis before definitive peer-reviewed data backing this practice is available. The panellists write: “It was the general hope of the committee that this work would lead to additional peer-reviewed studies generating data that clarify the role in multiple sclerosis of treating venous disease with angioplasty and possibly stent placement and the potential adverse events associated with these interventions.”
Some interventionalists might question the panel’s recommendation by asking whether further non-randomised studies would really satisfy the conditions set, and how treating more patients would facilitate issues such as agreeing on primary and secondary endpoints. The explanations of the panel could also be viewed as procrastination.
A CIRSE commentary published on 7 December 2010 in CVIR, by authors Jim A Reekers (Amsterdam, The Netherlands), Michael J Lee (Dublin, Ireland), Anna Maria Belli (London, UK), and Frederik Barkhof, (The Netherlands) takes the view that while there has been widespread promotion of balloon dilatation to treat CCSVI, and alleviate multiple sclerosis symptoms, “This theory does not fit into the existing bulk of scientific data concerning the pathophysiology of multiple sclerosis.”
Reekers et al question whether the anecdotes of successful outcomes which are widely being disseminated on the Internet could be the result of a placebo effect. They write: “In itself, there is nothing with the placebo effect as long as we recognise that this is at play. […] Furthermore, multiple sclerosis can affect emotional and labile responses and is characterised by spontaneous relapses and remissions. This makes the gathering of scientific evidence to support CCSVI theory difficult in anything other than a randomised controlled trial.”
At the Society of Interventional Radiology’s meeting Dake said, “Personally, I want to know if a patient with multiple sclerosis has CCSVI, and if the narrowing is successfully treated, is it possible to objectively demonstrate physiological improvement in relevant parameters and an associated relief of symptoms.”
Dake set out some of the unknowns and uncertainty surrounding CCSVI diagnosis. He asked: Is CCSVI something we are born with, develop, or both? What percentage of multiple sclerosis patients and healthy controls has CCSVI? Is CCSVI a consequence of multiple sclerosis or part of the disease pathogenesis? How do we reliably diagnose CCSVI and know if it is physiologically relevant? How does CCSVI fit into the current immune concept of multiple sclerosis pathogenesis or does it not? How can we engage neurologists in meaningful collaboration to study a concept they truly regard as total lunacy?
With regard to the treatment and endpoint assessment, Dake outlined yet another series of questions: Are any lesions outside the valves important? Is angioplasty the best possible treatment? What about oversized balloons, cutting balloon and when are stents warranted, if at all? What per cent of lesions respond to angioplasty, how do you judge? How do we know intraprocedurally if CCSVI is adequately treated? Is it necessary to treat all lesions? What are the risks and complications of the procedure? Do individuals ever get worse after treatment? Is post-treatment with angioplasty or a stent? What is the ideal regimen for adjunctive medications to prevent thrombus formation?
Questions also remain with regard to the potential benefits of endovascular treatment and follow-up. “How do we know if there is any real benefit from treating CCSVI, i.e. that it is not a placebo? What percentage of patients notice improvement; in what percentage of patients do these symptoms return? Do cerebral perfusion, tissue oxygenation and venous flow measurements improve post-treatment? What evaluations should be monitored on follow-up? If symptoms return, what is the typical timeframe for this? What should interventionalists do when they return and why do they return? Is there any evidence that the trajectory of disease progression is slowed post-therapy?,” Dake asked.He referred to the scepticism the CCSVI theory has met with from several neurologists, and illustrated it with an editorial published in the American Journal of Neuroradiology (AJNR2011;32: 424–427) which said: “CCSVI is a sonographic construct that is poorly reproducible and questionable in terms of known pathophysiologic factors established in multiple sclerosis. The neuroimaging findings reviewed here do not support the CCSVI theory in multiple sclerosis [...]. As a consequence, endovascular treatment of presumed vascular abnormalities in multiple sclerosis should be discouraged violently.”
Dake told delegates, “The current state of CCSVI discussions in the medical literature is centred in two silos: its frequency/diagnosis/association with multiple sclerosis and the results of endovascular treatment. The former is highly contentious, confusing and still quite hypothetical, with positions often being argued by those with a pre-existing agenda/bias. In either case, new metrics are needed to specifically address the effects of treatments on new targets—studies that allow an acceleration of the current cycle time to determine if the desired effect of therapy is achieved,” he said.
Siskin, who presented some results from the latest literature on CCSVI, said that it was important to differentiate between “what we know and what we do not know in order to help effective communication with potential patients, to make sure that discussions with neurology are balanced and to be certain that research is directed towards answering the unanswered questions.”
At the SIR session, Haskal cautioned against close mindedness on both ends of the spectrum both from the “opposers” of the theory and the “converted.” He noted that reproducibility of results was vital.
Haskal stated that there was a broad need and opportunity for methodical disassembly of the problem into research elements. “Ultrasound protocols need to be validated and others created that can be accomplished and validated locally. Magnetic resonance screening protocols need to be defined at the highest level and set for local reproducibility; reporting standards must be defined for uniformity; and we need to define appropriate endpoints for studies,” he said.
With regard to therapeutic gray areas, Haskal questioned: “Are the endpoints being used currently in studies suitable/correct? Are the diagnostic tools not restrictive or too fine? Is the technology adequate? Is investigator bias introduced early regarding mechanism? Can early trials truly mimic existing standards, at this point? We need to identify objective measures: MRI lesions, exams, cytokines, immune mediators,” he said.