The study, published Tuesday in The Lancet, is the latest to question the validity of a controversial theory put forth in 2009 by Dr. Paolo Zamboni that MS is related to narrowed neck veins, which prevent blood from properly draining from the brain.
The Italian vascular surgeon named the condition "chronic cerebrospinal venous insufficiency," or CCSVI. He suggested iron deposits from backed-up blood cause the lesions in the brain that are the hallmarks of MS. The disease causes inflammation that destroys the myelin sheath around nerves, leading to widespread disability.
Zamboni said patients treated with a procedure to open up their neck veins — called balloon venoplasty — saw a significant reduction in symptoms.
News of Zamboni's "liberation therapy," generated through traditional and social media, sent thousands of MS patients from Canada and elsewhere to private clinics around the world, where they spent thousands of dollars each for the unproven treatment.
In the Lancet study, researchers at the universities of British Columbia and Saskatchewan found CCSVI was a rare phenomenon: out of 177 MS patients, unaffected siblings and healthy volunteers, only one in each group was found to have CCSVI as defined by Zamboni.
"And this was a big surprise to all of us," said Dr. Anthony Traboulsee, medical director of the UBC Hospital MS Clinic, who headed the study. "We were really expecting to find many more people with this feature."
What they did find, however, was that at least two-thirds in each group — so both those with MS and those without MS — had a 50 per cent or greater narrowing in a jugular or other neck vein.
Among 79 subjects with MS, 74 per cent had neck vein narrowing, while the same was true for 66 per cent of 55 unaffected siblings and 70 per cent of the 43 healthy volunteers.
"So there weren't really any significant differences between the three groups," said Traboulsee, noting that the study was done with catheter venography, considered the gold standard for radiologists to view the inside of veins — and the one Zamboni used, along with ultrasound imaging.
"So using the best method available, we were unable to confirm Dr. Zamboni's theory that MS is caused by CCSVI," he said. "And our conclusion is that the narrowing of the neck veins is common and a normal finding in most people.
"We recognize that for many people with MS, this will be a great disappointment. Many people were hoping that this was really a breakthrough in terms of knowledge of MS."
In an accompanying commentary, Dr. Friedemann Paul of NeuroCure Clinical Research Center in Berlin and radiologist Mike Wattjes of the MS Center Amsterdam said the Canadian study "sounds a death knell for the hypothesis of chronic cerebrospinal venous insufficiency as a disease entity."
"Chronic cerebrospinal venous insufficiency is not highly prevalent in multiple sclerosis," they write. "The disorder is neither specific to the disease nor does it have a causative role."
Paul and Wattjes also said the findings should put an end to discussions about whether millions of dollars spent on researching CCSVI in relation to MS has been a waste of valuable time and intellectual energy.
The study should be viewed as "the definitive conclusion to this discussion ... now it is absolutely clear that no reason exists to allocate any further resources to chronic cerebrospinal venous insufficiency research, be they financial or intellectual."
However, the MS Society of Canada, which primarily funded the $450,000 study, said in a statement that it "remains committed to funding research that will answer the questions of those who live with the disease."
And Traboulsee said a federally supported clinical trial of the so-called liberation therapy is going ahead as planned.
The cross-Canada study will enrol 100 MS patients with evidence of narrowed veins to receive either the venoplasty treatment — in which a tiny balloon is fed into the neck veins to widen them — or a sham treatment. Neither patients nor the doctors who assess them will know which treatment they received.
Researchers will follow patients for two years to assess whether they experience sustained improvement in symptoms and whether tests, such as MRI brain imaging, show evidence of a reduction or halt in the progression of lesions.
Traboulsee said it is critical that researchers determine whether many of the MS patients who have sought the treatment — including at least an estimated 3,000 Canadians — truly had improvement or experienced a placebo effect, as some critics of the procedure contend.
"People might want to discount this as a placebo effect," he said. "I think that's being a bit patronizing to people and we need to do the proper research to fully address if there is any treatment benefit. And if we determine treatment benefit, then we have to figure out why."
Yet Traboulsee admits he has struggled with the issue, given that Zamboni's theoretical basis for the therapy appears after many studies to have no validity. "If the original theory is now faulty, why continue down this pathway?"
"Sometimes these things can become separated, and what we've found is that although CCSVI as defined by Zamboni doesn't really exist ... we still have the situation where thousands of Canadians have gone abroad and have had a treatment ... (and many have) reported significant improvement."
Other underlying theories in medicine have been proven wrong but have still led to benefit for patients, he said. "I think it justifies going forward.
"But I'll be honest — I don't fully understand how they're feeling better," admitted Traboulsee, suggesting that opening up veins may set off a process in the nerves or cause the release of substances that reduce symptoms like fatigue and brain fog.
A spokeswoman for the Canadian Institutes of Health Research, which has earmarked $6 million for the clinical trial, said the study will continue "because we still need to determine the safety of venous angioplasty and better evidence on patient outcomes."
So far, seven MS patients have been randomized to receive either the treatment or the sham procedure. All 100 patients should be recruited by next summer and preliminary results should be ready by fall 2015, Traboulsee said.
His message to MS patients is the same as it's been from the beginning: "Please do not rush out and spend your hard-earned money, mortgage your house, (spend) your life savings to get this procedure done out of country at private clinics.
"Research is the way to answer this," he said. "We're doing the research. We're doing it as rapidly as possible. We will have answers to these questions, but hang tight."
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