New findings from a meta-analysis may fuel the controversy over the link between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS), researchers said.

Pooled data from eight studies found a nearly 14-fold increased likelihood of CCSVI among MS patients (OR 13.5, 95% CI 2.6 to 71.4), although there was "extensive, unexplained heterogeneity" among the studies, Andreas Laupacis, MD, of St. Michael's Hospital in Toronto, and colleagues reported in CMAJ.

"The results were incredibly inconsistent, that was the most striking thing," Laupacis told MedPage Today. "When you combine, statistically, all the studies, there were more and larger studies that found an association, so that's why we found a statistical increase in the frequency of CCSVI in people with MS compared with controls."

"But we're cautious because of the inconsistent results," he said, which likely have to do with methodological variations between studies, particularly in terms of ultrasound technique, blinding, and the number of included patients.

In 2006, Paolo Zamboni, MD, of the University of Ferrara in Italy, and colleagues proposed that CCSVI causes MS, as abnormalities in vascular anatomy and flow could lead to deposition of iron in the brain, which ultimately triggers an autoimmune reaction.

Yet several recent reports haven't been able to confirm the theory.

So Laupacis and colleagues conducted the meta-analysis of eight studies done in Italy, Germany, Jordan, and the U.S.

Overall, they found that CCSVI was more frequent among patients with MS than among healthy controls (OR 13.5, 95% CI 2.6 to 71.4), but there was significant heterogeneity among the studies.

"Ultrasound is a fairly operator-sensitive technique," Laupacis said, adding that ultrasonographers are currently at work to establish a standard way of doing the test for CCSVI. The test requires screening five different vascular structures to make a diagnosis, which is called when a patient has two of the five abnormalities.

Also, he said, few of the studies explained how well their ultrasonographers were blinded, which could introduce bias.

The researchers also found that in terms of those five individual diagnostic parameters, patients with MS had significantly higher odds of having reflux in the internal jugular or vertebral veins (OR 13.7, 95% CI 2.0 to 93.8), though, again, there was extensive heterogeneity in this finding between studies, the researchers said.

The four other diagnostic parameters were also more frequent among MS patients, but those trends weren't statistically significant, they reported.

Although CCSVI was also more frequent among controls with other neurologic diseases, the association was not significant, the confidence interval was wide, and the odds ratio was less extreme after removing the Zamboni study, which was large and significantly positive, Laupacis and colleagues reported.

They added that the overall association between CCSVI and MS remained significant in the most conservative sensitivity analysis in which the initial Zamboni study was removed and a study that didn't find CCSVI in any patient was added (OR 3.7, 95% CI 1.2 to 11.0).

"I went into this thinking there wasn't much there," Laupacis told MedPage Today. "But I'm not as convinced as I was before that there's probably no association, and I think we need ... more studies."

He said that seven trials in the U.S. and Canada are under way exploring the relationship between CCSVI and MS, as well as a large Italian trial enrolling 1,200 MS patients, 400 controls, and 400 patients with other neurological disorders.

"If those studies get done, we'll have sufficient numbers and consistency among results to know what the deal is," he said.

He also cautioned that even if an association between CCSVI and MS is established, it is not necessarily causal. In fact, some observations have suggested that CCSVI may be a consequence of MS.

The analysis was limited by the small number of studies included and by the various methodological limitations of those individual studies.

"It's fair to say that the research community has strongly held views both pro and con" about the link between CCSVI and MS, Timothy Coetzee, MD, chief research officer for the National Multiple Sclerosis Society, told MedPage Today.

"This is an excellent example of using the data on hand to get at some clarity on the association between CCSVI and MS," he said, adding that the jury is clearly still out and that "more work is needed in order to arrive at stronger conclusions."