The Rorschach test of CCSVI research

Experts and journalists are reading whatever they want into a new study examining CCSVI in MS patients

F. Scott Fitzgerald once famously wrote “The sign of a first-rate intelligence is the ability to hold two opposing ideas in the mind at the same time and still retain the ability to function.” That line comes to mind surveying reaction to the much buzzed-about study in the current issue of Neurology, the journal of the American Academy of Neurology, that concludes CCSVI is not a primary cause of multiple sclerosis.

The study, whose initial results were announced last year, came just as the AAN held its annual meeting in Honolulu last week. There’s a nice symmetry here. It was a year ago that Italian vascular specialist Paolo Zamboni appeared at the AAN meeting in Toronto, fresh off having rocked the medical boat with his claim that MS, long considered an autoimmune condition, had vascular roots: he theorized narrowed or blocked veins in the neck and chest of MS patients, a condition he dubbed chronic cerebrospinal venous insufficiency (CCSVI), lead to reflux of blood back to the brain. That in turn resulted in iron deposits, he posited, which caused the neural lesions that characterize MS.

After administering a balloon venoplasty to clear the blockage, many patients’ symptoms abated, he reported, sometimes dramatically; in some cases, the disease’s progression halted altogether. Since then, an estimated 12,000 MS patients have had CCSVI treatment, which is not available in Canada, many of whom have reported improvements. Still, many neurologists, the traditional MS gatekeepers, dismiss the Zamboni hypothesis as yet another in a long line of quack MS cures and chalk up any salutary treatment benefits to the “placebo effect.”

The newly published study, lead by University of Buffalo neurologist Robert Zivadinov who has worked closely with Zamboni, looked at 449 patients with Doppler ultrasound—289 people with MS, 163 healthy controls, 26 people with other neurological diseases, and 21 who had experienced a clinically isolated syndrome (or CIS), defined as one “neurological episode.” It found 56.1 per cent of MS patients and 38.1 per cent of CIS patients had CCSVI. Meanwhile, 42.3 per cent of participants who had other neurological diseases and 22.7 per cent of controls also had CCSVI. It also found that far more patients with advanced MS—some 80 percent—had CCSVI, which suggests “CCSVI may be a consequence rather than a cause of MS.”

Of course, the chicken-egg conundrum gives rise to endless speculation. For instance: If CCSVI is the result, rather than the cause of MS, then why did 22 per cent of the control group have it? The fact that the control group in the Zivadinov study included front-line relatives of MS patients raises another set of questions given genetic predisposition to the disease.

Meanwhile, the study itself has become a Rorschach test, read differently depending on bias. Barrie, Ont. vascular surgeon Sandy McDonald, an advocate of CCSVI treatment, says it answers two important questions: “One, is CCSVI associated with MS? Answer: yes. Two, is CCSVI a contributing agent in the progression of the diseases? Answer: yes.” McDonald says the relationship in the presence of CCSVI in advanced MS (in more than 80 per cent of cases), suggests the condition may contribute to the disease’s progression. Not everyone agrees. Halifax neurologist Jock Murray, a vocal critic of the CCSVI hypothesis, told the CBC it suggests CCSVI is a “normal variation” and not even an actual condition. The two polarized takes on CCSVI are nicely summed up in this video.

Media reaction called to mind another idiomatic cliché: the one about the baby and the bathwater. The Vancouver Sun’s “Study Shoots Hole in Liberation Theory for Multiple Sclerosis” and Dr. Brian Goldman’s comment on that “new research is casting doubt on a controversial treatment for Multiple Sclerosis” conflate the CCSVI hypothesis with CCSVI treatment, which is where Fitzgerald’s line comes in: it’s possible CCSVI might not be a primary cause of MS and still be a piece of the mysterious MS puzzle. Even Zivadinov has stepped up to point out that his study doesn’t invalidate Zamboni’s hypothesis but rather that it calls for more study.

“More study” has become a mantra, as has the call for refinement in the techniques and criteria for CCSVI diagnosis which is all over the map. One AAN study led by neurologist Katayoun Alikhani of the University of Calgary that used magnetic resonance venography (MRV) found venous abnormalities in only 20 per cent of people with MS and 20 per cent of healthy controls. “This first independent Canadian MRV study confirms neck vein abnormalities are infrequent and independent of the diagnosis of MS,” the study’s authors concluded. Yet Zivadinov himself has questioned the efficacy of MRV scanning. Robert Fox, medical director of the Cleveland Clinic’s multiple sclerosis centre, chalked up discrepancies to “wrestling with a new technique.” Even how a knob is turned can influence outcomes, he observes.

While scientists calibrate knobs and investigate causal relationships, the crucial question of whether CCSVI treatment is useful for people suffering from a devastating, degenerative condition remains unanswered. That requires actual treatment trials. The Buffalo study concluded balloon venoplasty should be restricted to “a blinded, controlled clinical trial,” a position also held by Zamboni. The MS Society of Canada, too, recommends patients seek out clinical trials, though it has yet to advocate these take place in Canada. (Currently the society is conducting seven CCSVI studies, none involving treatment, with its U.S. counterpart. Results aren’t expected until July 2012.) An MS Society spokesman refers patients to the World Health Organization’s website  or for information.

Provincial governments, variously setting up post-treatment observation trials and clinical treatment trials, haven’t been deterred by the Buffalo research. The New Brunswick government stands by its promise to provide funding to help MS patients get treatment. Urgency exists, says health minister Madeleine Dubé: “While this is being researched and debated, those people still need support and we are committed to that,” she said. Alberta’s health minister, Gene Zwozdesky, says plans to study CCSVI treatment remain “a go.”

Given such movement, a remark in the editorial accompanying the Buffalo study seems almost quaint: “It behooves the clinical research community to carefully pursue CCSVI to its end; we should neither jump on the bandwagon as it passes through town, nor assiduously miss the parade.” Anyone who sees CCSVI as a circus rolling through the medical landscape hasn’t been paying attention. Other neurodegenerative diseases such as Alzheimer’s and Parkinson’s are being looked at as potential diseases of impeded cerebral blood flow. Meanwhile, most of the AAN conference devoted to MS focused on breakthroughs in new drugs, all of which are designed to alleviate MS symptoms. None treat the underlying cause, a continuing mystery.

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