A new scanning study looking at CCSVI published online today in The Lancet is destined to launch 1,000 headlines.
Its findings appear so damning a few neurologists are already playing taps for the vascular theory of MS proposed by Paolo Zamboni in 2006. The blinded, controlled three-centre study, funded by the MS Society of Canada, Saskatoon City Hospital Foundation, Lotte and John Hecht Memorial Foundation, Vancouver Coastal Health Foundation and Woldridge Foundation, was conducted by 13 researchers. They were lead by neurologist Anthony Traboulsee, the director of the University of British Columbia hospital MS Clinic and principle investigator into clinical trials into the safety and efficacy of CCSVI.
Using catheter venography, defined as the “gold-standard for the assessment of venous stenosis” on 177 subjects, the team found venous “narrowing” (defined as “greater than 50 per cent narrowing”) in 74 per cent of people with MS. But here’s the big surprise: similar narrowings were found in 66 per cent of unaffected siblings of people with MS and in 70 per cent of healthy controls. Using Zamboni’s catheter venography defintion, it found CCSVI in 2 per cent of people with MS, 2 per cent of siblings and 3 per cent of unrelated healthy controls. Using the Italian vascular specialist’s ultrasound criteria, the UBC study revealed 44 per cent of people with MS had CCSVI, 31 per cent of siblings did, as did 45 per cent of unrelated controls.
To date, CCSVI scanning studies have been all over the map. Some have found high correlation between MS and CCSVI, others low correlation. Ascanning study published by McMaster University in August found zero correlation. The UBC report presents as a new outlier: it suggests venous narrowing is normal, and that there’s a lower correlation of venous structure between family members of people with MS than with healthy controls. It’s destined to be debated, discussed and scrutinized. Questions will need to be answered. For one, the UBC study departs from Zamboni’s work in that it focuses on venous architecture, not blood flow. Zamboni uses catheter venography to enter and scan the vein only after doppler ultrasound reveals measurable problems with flow or reflux. The UBC study, on the other hand, used CV on everyone. Also unclear is how the UBC researchers measured stenosis since veins are such irregular vessels. Another question is the role valve malformation plays in causing stenosis, something that can’t be detected on venography. Then there’s an interesting inconsistency across centres: UBC found jugular stenosis in almost all subjects; the University of Saskatchewan detected as many as one-third less in its subjects. Why is unclear. Relative experience of researchers? The subjective nature of venographic observation? Epidemiological factors?
Traboulsee told the press conference today they had expected to find more CCSVI and that the finding of narrowed veins in many subjects wasn’t a concern: “We have more veins than we need,” he says. “There’s a redundancy built into the veins … It’s natural variability and unlikely to be triggering MS.” Zamboni has yet to respond to the UBC study. When he does, it will be in a a scientific journal, he said in an email, adding: ”But if narrowing is the outcome measure of this study, it does not correspond to luminal defects, and thus ultimately to CCSVI.”
An editorial accompanying the UBC study written by neurologists Paul Friedmann and Mike P Wattjes sounds the “death knell” for CCSVI and asserts “it is absolutely clear that no reason exists to allocate any further resources to [CCSVI], be they financial or intellectual.” Yet in a phone-in press conference this morning, Traboulsee says that even though the research could not validate Zamboni’s research, the Canadian clinical trial investigating the safety and efficacy of CCSVI treatment remain a go.
Just because CCSVI as defined by Zamboni “doesn’t exist by his definition,” he says, it’s not unprecedented for a theory to be disproven that can lead to something beneficial to patients. He’s interested in patients’ reports of improvement in quality of life after CCSVI treatment—reduction of fatigue, improved cognitive fog and bladder control, to name a few benefits. When asked by one reporter whether these improvements could be chalked up to placebo effect, Traboulsee demurred. “I think that’s a bit patronizing to people.” Later, however, he said a “component will be placebo effect. That’s an important part of process. Is there a true treatment beyond placebo? As to how effective it is, I still struggling with that.” He admitted he didn’t know how CCSVI treatment might help, suggesting it might have to do with stimulation of vagus nerve or cytokine released from the veins. In fairness, this is uncharted territory for a researcher used to working in the pharmaceutical model; his disclosures on the study, like many of his fellow researchers, reveal multiple ties to drug companies.
Traboulsee cautions people with MS, which he defines as “leading cause of disability in Canada,” from seeking CCSVI treatment, which is not available in Canada: “Do not rush to spend your hard earned money,” he said. He estimates as many as 5,000 Canadians have been treated out of country, though that number is impossible to confirm. A registry promised by the federal government has yet to materialize. People living with the unpredictable, degenerative condition need to be patient, Traboulsee says, and await clinical trial results. These, he hopes will be known by fall 2016. Five hundred patients have volunteered for 100 spots at four centres in B.C., Manitoba and Quebec. Seven people have been treated to date.
The UBC prof also spoke of a sea change in how research is being directed–an “evolution” in research decisions away from the “ivory tower” to more patient-based response. “Now social media determines research priorities,” he says. To listen to him speak, it seems the former vocal CCSVI skeptic has undergone an evolution as well. In 2010, like most neurologists, he shot down Zamboni’s CCSVI hypothesis, telling the Toronto Star “there isn’t a heck of a lot of evidence to support it.” In August 2010, he was member of a panel convened by the CIHR that unanimously voted against clinical trials. Interviewed on The Nature of Things in 2012 he expressed frustration that money was being directed to CCSVI that could be going to stem cells. Yet when a reporter asked today whether time and millions of dollars had been wasted researching CCSVI, Traboulsee said no. “We set forth a mandate in 2009 to fully investigate the theory and treatment.” If today’s results are any indication, that’s going to take some time and fortitude.