10/03/2011 12:01 EDT | Updated 12/03/2011 05:12 EST

Data point to a link between CCSVI and MS, but can't say if condition causes MS

TORONTO - The science available to date supports the idea there may be a link between a condition called CCSVI and multiple sclerosis, says a new study that nevertheless warns it is too soon to draw "definitive conclusions."

The study, which informed the federal government's decision to go ahead with clinical trials into a possible treatment for the condition, was published Monday in the Canadian Medical Association Journal.

The research was led by Dr. Andreas Laupaucis, director of the Li Ka Shing Knowledge Institute at Toronto's St. Michael's Hospital. Laupaucis, an internal medicine specialist, admitted he was doubtful about CCSVI when he started the study.

"I went into this pretty skeptical, thinking we'd find nothing there. I'm not personally still convinced that there's an association, but looking at this now I guess I'd sort of say: Well, I'm a little more willing to accept that maybe there is something there," he said in an interview.

The work is what is called a meta-analysis. Rather than run new clinical trials, the researchers amalgamated data from eight previously conducted trials into a controversial treatment for CCSVI. The idea behind this type of study is that by combining data from a number of similar small studies, a clearer picture can sometimes come into focus.

Multiple sclerosis is a degenerative neurological disease long thought to be the result of problems with the autoimmune system. But in the past few years an Italian vascular surgeon named Paolo Zamboni has taken the MS world by storm, theorizing that the disease is caused by blocked veins in the neck and spinal cord.

Zamboni said those blockages, seen using ultrasound, are actually a medical condition. He dubbed it chronic cerebrospinal venous insufficiency, or CCSVI.

The blockages prevent blood from draining from the brain, allowing a buildup of substances such as iron, Zamboni suggested. He argues that opening the veins using angioplasty significantly alleviates the debilitating symptoms MS patients experience.

Scores of Canadians with MS have travelled to Europe and beyond to undergo the procedure, which is not currently licensed in Canada.

While Zamboni's theory has met with enthusiasm on the part of many desperate patients, neurologists — the medical specialists who treat MS — have been skeptical about the new notion of what is causing the disease.

The Laupaucis meta-analysis looked at data from 644 people with MS, compared in the eight studies to an equal number of people who didn't have the disease, called "controls" in the language of studies. Some of the controls were healthy adults. Some had other neurological conditions.

The analysis found a statistically significant association between MS and CCSVI. That means more people with MS had blocked veins than did the controls. The term statistically significant means that the findings don't look like they could be the product of chance.

To try to ensure that the findings weren't being driven by Zamboni's original study — which found CCSVI in 100 per cent of MS patients but in none of the controls — the researchers ran some additional analyses looking at what happened if Zamboni's cases were left out of the calculations. Even without them, it looked like more MS patients than non-MS patients had CCSVI.

That was not true, though, when MS patients were compared to controls who had other neurological conditions. In that comparison the difference was not statistically significant.

A puzzling aspect of the study related to the enormous differences between the rates of CCSVI in MS patients in the various trials. At one end, Zamboni found the condition in all of his MS patients. But another group found it in none of the MS patients they examined.

"I think the striking thing is just this incredible inconsistency, which is almost greater than anything I've seen in any meta-analysis I've done," Laupaucis said.

"Which I think means — I hate to say this as a researcher because it drives people crazy — but this is one of those areas where I think more research is needed. Because it's not clear why that difference is so large."

Tim Coetzee, chief research officer for the U.S. National Multiple Sclerosis Society, agreed that more data are needed to answer the question Zamboni's work poses. He suggested by next summer some of those answers may start to come into view. A number of studies co-funded by the U.S. and Canadian MS societies will begin to report then.

"My take-away from it," — the Laupaucis study — "is the assessment does make the best analysis of the data available at hand," Coetzee said.

Part of the problem the study identified may relate to what's known as blinding. Wherever possible, clinical trials are supposed to be designed so that the people running and interpreting them don't know whether a subject falls into this group or that. That's because knowing whether a subject got a drug or a placebo — in a drug trial, for instance — could influence a researcher's assessment of how well or poorly he or she was doing.

In the case of CCSVI and MS, ideally the researchers conducting the eight studies should not have known if the subjects they were checking for vein abnormalities had MS or not. But blinding was not undertaken in three of the trials and in the others it was unclear how well the blinding actually worked, Laupaucis and his co-authors wrote.

"Ultrasound is a fairly subjective test. You can push a little harder or a little less hard on the neck when you're assessing the veins (and) it affects the results," Laupaucis said.

"If you know that a patient has MS or you know that a patient doesn't have MS, it might inadvertently affect your judgment about whether a subtle difference or a subtle abnormality is CCSVI or not."

Laupaucis and others cautioned that seeing a link or an association between a condition and a disease doesn't mean that the one caused the other. In fact, a commentary also published Monday warned against drawing that conclusion.

Dr. Robert Fox, a neurologist at the Mellon Center for Multiple Sclerosis at the Cleveland Clinic, noted the blocked veins could be the result of dehydration. MS often affects the bladder and as a result MS patients often prefer to remain a bit dehydrated so that they don't have to constantly run off to the bathroom, Fox noted in an interview from Cleveland, Ohio.

That may cause veins to look different in an ultrasound, he said. But that doesn't mean opening the blockages will resolve the symptoms that plague MS patients.

"If it (CCSVI) is there more commonly in MS patients, it doesn't mean that fixing it is going to help people feel better. We think a lot of MS is from permanent nerve injury from the inflammation. Permanent nerve injury to the spinal cord, to the brain, to the optic nerve," said Fox.

Fox is conducting a number of studies aimed at trying to test the CCSVI hypothesis, including looking at the veins of MS patients who have died and who donated their bodies to his program for research purposes. "If this is really a true thing, we should see something under the microscope so to speak when we look at the tissue."

Patient groups in Canada have lobbied hard to try to persuade federal and provincial governments to green light the treatment here — or at least conduct clinical trials into it.

After initially saying there wasn't enough evidence to warrant trials, the Canadian Institutes of Health Research and federal Health Minister Leona Aglukkaq announced in late June that Canada would conduct a preliminary clinical trial to see if opening venous blockage does improve the health or quality of life of MS patients.

CIHR and an expert advisory group it set up are working on terms of reference for the trial. They also need to select a research team to conduct the work.

Fox's work is one of the studies being funding by the MS societies. He has also done consultancy work for several drug companies. Laupaucis's study was funded by CIHR. He has received honoraria for serving as a member of data safety monitoring boards for two drugs for MS; the trials were funded by Novartis Pharmaceuticals. Laupaucis is also on the editorial board of the Canadian Medical Association Journal.