Paolo Zamboni, proponent of the controversial and unlikely claim that multiple sclerosis is caused by chronic cerebrospinal vascular insufficiency.

Paolo Zamboni, proponent of the controversial and unlikely claim that multiple sclerosis is caused by chronic cerebrospinal vascular insufficiency.

A new study published in The Lancet provides the most definitive evidence to date that chronic cerebrospinal venous insufficiency (CCSVI), a hypothetical syndrome of narrowed veins draining the brain that some believe is the true cause of multiple sclerosis (MS), is not associated with MS.

In a science-based world, this study would be yet one more nail in the coffin of this failed hypothesis. But that’s not the world we live in.

CCSVI background

CCSVI was first proposed in 2009 by Italian vascular surgeon, Dr. Paolo Zamboni – that multiple sclerosis (MS) is caused by chronic blockage of the veins that drain the brain. The current scientific consensus is that MS is a chronic autoimmune disease, and the pathology is caused by primary inflammation. Dr. Zamboni believes that the venous anomalies he has discovered are the primary cause and the inflammation is secondary.

That is a fairly radical hypothesis, up there with the notion that bacterial infection and not stress causes gastric ulcers. Of course the latter hypothesis turned out to be true. As more and more research was done on H. pylori, the evidence pointed increasingly in the direction of a correlation and causation, and the consensus of scientific opinion followed the evidence.

The story for CCSVI has been quite different. The evidence has been mixed at best, and mostly negative. Zamboni initially claimed a nearly 100% correlation between MS and narrowing of the cerebral veins. If true this could potentially change our understanding of MS and lead to new treatments. The MS research community received the claims, as they should, with intense skepticism. Many in the patient community, however, saw the claims as a ray of hope.

The key to any new claim in science is replication – do the results hold up when independently replicated? So far, no one has replicated Zamboni’s near-100% results, but that aside, what has the follow up research shown about CCSVI?

In 2011 I reviewed the major replications to date, nine of them, mostly negative. The largest study at the time did find some correlation between CCSVI and MS, but half of MS patients in the study did not have CCSVI and many subjects with other neurological disease or healthy controls also had CCSVI. So it appears that CCSVI does not always cause MS, and MS patients do not always have CCSVI. While the study left the door open for some relationship, it certainly did not support Zamboni’s claims to have found “the” cause of MS.

Since my 2011 review, additional replications have been devastatingly negative for the CCSVI hypothesis. A 2013 study of 1,767 subjects (with MS, another neurological disease, and healthy controls) was dead negative – no association between MS and CCSVI. This study used ultrasound criteria similar to Zamboni’s.

A recent meta-analysis of 9 studies (included out of 19 identified) did show a correlation between CCSVI using ultrasound criteria and MS, but the data did not establish causation. The results, in my opinion, reveal the weakness in the meta-analysis approach because it can potentially include early false positive data skewing the outcome. A best-evidence analysis is a better approach – looking at the pattern in the research, which clearly shows that later, larger, more rigorous studies (as with the latest one above) tend to be more negative.

The Lancet study

The new Lancet study by Traboulsee et al., including 177 subjects, 79 with multiple sclerosis, 55 siblings, and 43 unrelated controls from three centers in Canada is not the largest study of CCSVI and MS. However the study is large enough, and it does have the advantage of comparing ultrasound investigation of the venous system with full dye catheterization, which is the gold standard.

The results of this study are also completely negative – no correlation between CCSVI and MS. They found that:

Catheter venography criteria for chronic cerebrospinal venous insufficiency were positive for one of 65 (2%) people with multiple sclerosis, one of 46 (2%) siblings, and one of 32 (3%) unrelated controls (p=1.0 for all comparisons). Greater than 50% narrowing of any major vein was present in 48 of 65 (74%) people with multiple sclerosis, 31 of 47 (66%) siblings (p=0.41 for comparison with patients with multiple sclerosis), and 26 of 37 (70%) unrelated controls (p=0.82).

It’s interesting that about 2/3 of people had greater than 50% narrowing, meaning that such narrowing is a common occurrence and it not necessarily correlated with any disease. This study suggests that Zamboni was simply making an incidental finding of a common benign anatomical variant that is neither pathological nor related to MS. Those meeting the strict criteria for CCSVI by catheter examination, on the other hand, were rare – 2-3% of all subjects.

The study also found that ultrasound examination did not correlate well with catheter examination, showing that this technique has poor sensitivity and specificity. This calls into question all previous studies that relied upon ultrasound examination.

Conclusion: CCSVI is still a dubious hypothesis

The notion that CCSVI causes MS has always been a dubious hypothesis. It seems implausible that decades of research showing MS to be an autoimmune disease would all be wrong, and that a vascular surgeon who is not an MS specialist would discover the true vascular cause of MS.

Despite this lack of plausibility, the hypothesis was seriously researched. Early results did not replicate Zamboni’s original claims (calling the quality of the data into question), but did give mixed results with an aggregate small positive correlation. This pattern of results, however, is consistent with the null hypothesis that there is no real phenomenon here.

Furthermore, the largest, highest quality, and most definitive studies tended to be negative. This latest study, while not the largest, is of high quality, using a definitive technique for venous examination. It shows no correlation between CCSVI or venous narrowing with MS, and further shows that ultrasound studies are not reliable, partly explaining the mixed results.

Many patients suffering from MS and not responding to established treatment, however, want CCSVI to be real and to offer them a treatment. This has led to CCSVI taking on a life of its own, separate from the scientific data. Once that occurs, the data loses its ability to convince those caught in the narrative of CCSVI. Any negative data can be dismissed as a conspiracy. There are always convenient villains to be found and plugged into the narrative – Big Pharma, insurance companies, greedy doctors, and in this case, MS doctors protecting their turf.

The story of CCSVI is not yet over, even though it should be. One approach to a new medical hypothesis is to see if the underlying theory is correct – does CCSVI exist and does it correlate with MS? The other approach is to conduct treatment trials to see if treating CCSVI improves outcomes in MS.

There is a procedure of venous angioplasty, called the liberation procedure, for alleged CCSVI. A recent systematic review found:

There is currently no high level evidence to support or refute the efficacy or safety of percutaneous transluminal angioplasty for treatment of CCSVI in people with MS. Clinical practice should be guided by evidence supported by well-designed randomised controlled trials: closure of some of the gaps in the evidence may be feasible at completion of the six ongoing clinical trials.

My summary – the evidence we have so far is mostly negative, consistent with the null hypothesis, but on its own is not iron-clad evidence for lack of efficacy. This is sufficient, in my opinion, to condemn the liberation procedure as a treatment. Being generous, most scientists recommend that the procedure should not be performed outside of a clinical trial.

Further clinical trials are underway, including one by Traboulsee, the lead author in the current Lancet study. So it seems we will have to wait at least two more years for the current clinical trials to conclude before we can officially close the book on CCSVI. This will likely, unfortunately, lead to CCSVI moving to the fringe (much like chelation therapy) rather than fading into history.




Posted by Steven Novella

Founder and currently Executive Editor of Science-Based Medicine Steven Novella, MD is an academic clinical neurologist at the Yale University School of Medicine. He is also the host and producer of the popular weekly science podcast, The Skeptics’ Guide to the Universe, and the author of the NeuroLogicaBlog, a daily blog that covers news and issues in neuroscience, but also general science, scientific skepticism, philosophy of science, critical thinking, and the intersection of science with the media and society. Dr. Novella also has produced two courses with The Great Courses, and published a book on critical thinking - also called The Skeptics Guide to the Universe.