Balloon dilatation of a stenosed jugular vein, the "liberation procedure" promoted as treating multiple sclerosis.

Balloon dilatation of a stenosed jugular vein, the “liberation procedure” promoted as treating multiple sclerosis.

It has been very instructive, from a science-based medicine perspective, to watch the story of alleged chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS) unfold over the last three years. In 2009 Dr. Paolo Zamboni, an Italian vascular surgeon, published a paper in which he claimed that 100% of MS patients he investigated showed signs of blockage in the veins that drain blood from the brain, a condition he named CCSVI. This paper sparked immediate controversy. This controversy has been in the news again recently with the making public of the results of an observational study of the liberation procedure to treat CCSVI.

Existing research over the last half century strongly indicate that MS is primarily a disease of immune dysfunction (an autoimmune disease), resulting in inflammation in the brain that causes damage, specifically to the myelin, the insulation around nerve fibers that allows them to conduct signals efficiently. Zamboni is suggesting that MS is primarily a vascular disease causing back pressure on the veins in the brain and iron deposition which secondarily results in inflammation. This would be a significant paradigm shift in MS. It would also not be the first time such a dramatic shift in MS science has been proposed but failed in replication.

The MS community did not give much credence to the notion of CCSVI, but despite this there has been an incredible amount of research on the idea over the last three years (a PubMed search on “CCSVI” gives 103 results). Most of the research has simply attempted to replicate Zamboni’s findings, with mixed but generally unimpressive results. No one has found the 100% results that Zamboni originally reported. The studies have found a range of venous insufficiency in MS patients, down to 0%, but many finding results in the range of 20-40%. However, patients with other neurological disease and healthy controls have also been found to have similar rates of venous insufficiency. Some studies have found a positive correlation with MS, others have not.

A faint signal in the noise, but what is it saying?

Systematic reviews of CCSVI have mostly concluded that, while there is a weak signal there, it is buried in the noise of variability of study results, which seem to be dominated by variability in the techniques used. There are several ways to assess venous function (MRI scan, doppler studies, venography) and these produce different results. At this time the consensus of reviews seems to be that: Zamboni’s results have not been replicated, there may or may not be any association between CCSVI and MS, if there is any association it is only in a subset of MS patients and much smaller than Zamboni suggests. Some have suggested that perhaps the inflammation in MS (and in some other conditions) can secondarily cause venous anomalies, but this is incidental and not pathogenic in MS.

One recent study tied off the jugular veins in mice, which would be functionally analogous to severe CCSVI, and found no inflammation, changes to the blood brain barrier, or clinical signs – in other words, no signs or markers for an MS like response to a reasonable clinical model of CCSVI. This seems to undercut the plausibility of the CCSVI hypothesis.

The bottom line is that CCSVI seems to be yet another failed hypothesis attempting to change everything we thought we knew about MS.

The “liberation procedure”, the internet, and conspiracy

Yet, over the last three years there has been significant interest in treatment of CCSVI on the part of MS patients, especially those who are not responding to proven therapy. This is understandable – any potential for a new treatment or cure would be of interest to a patient with a chronic debilitating disease. The treatment is called the liberation procedure, and is essentially angioplasty to open up the veins draining the brain and relieve the alleged back pressure. Clinics are already offering the treatment to patients, despite the fact that CCSVI remains controversial at best and there is no convincing scientific evidence that the liberation procedure works.

Part of the CCSVI phenomenon is that it has been happening in the post-social media world. Perhaps that is why the controversy has exploded and seems to be playing itself out so quickly. Part of this social media phenomenon is the divisive venom with which believers in CCSVI have attacked the medical mainstream. Conspiracy theories to explain away mainstream skepticism seemed to have already been in place and were taken out, fully formed, at the first sign of scientific skepticism.

Every online article about CCSVI is full of comments from supporters claiming that neurologists are engaged in a conspiracy to suppress CCSVI, in which the government is complicit, and “Big Pharma” (of course) is behind it all. It has been instructive to listen to conspiracy theories about various medical treatments. Believers simply invent villains as needed, without any consistency of logic. In the chronic Lyme disease controversy, for example, the treatment is a pharmaceutical – antibiotics. So Big Pharma can’t be the villain in that story, therefore believers simply made the insurance companies wear the black hats. At other times proponents of alternative treatments rail against mainstream medicine’s over-reliance on invasive procedures, but now the treatment they want is an invasive procedure, so neurologists (who treat MS medically) are the villains, and the surgeons are the heroes. Somehow evidence and scientific plausibility gets left behind in all the conspiracy mongering.

Treatments, evidence, and risks

The evidence, however, is what ultimately drives mainstream thinking about a disease and its treatment. In the case of CCSVI we now have the results of a large observational study. Zamboni’s group has also published a study of the liberation procedure, with weakly positive results, but given his role in this controversy few find the results compelling.

Dr. William Pryse-Phillips, a Canadian neurologist, followed the results of patients from Newfoundland and Labrador who went overseas to have the liberation procedure done. This was not a randomized trial, although the assessments were blinded. They followed 30 patients who had the procedure, and 10 controls who did not. They found no benefits from the procedure – there was no improvement in standard measures of MS severity and no difference between treated and untreated patients. Further, several patients developed clots in their jugular veins after the procedure. If the underlying concept of CCSVI is correct then these patients should have become significantly worse – but they didn’t.

Reports of the study also indicate that two Canadians have died from the procedure, but it was not clear if they were in this study or not (probably not, considering how it was reported). In any case, the point is that the procedure is not risk free. A risk vs benefit analysis of the liberation procedure for MS does not justify the treatment, which has dubious plausibility in addition.

In the US the FDA has issued a warning that the liberation procedure is not safe and has no proven benefit. In addition to rare deaths, there are other serious complications reported. There are no reliable statistics, however, on what percentage of patients are having serious complications.

Conclusion: Enthusiasm outpaces science

CCSVI is a radical proposal seeking to fundamentally change our understanding of MS. Proponents of this new hypothesis have failed to meet the burden of evidence for such a radical change. Results of the burst of research that has taken place over the last three years display the typical variability and noise for a null hypothesis – that the notion is not true. There is no convincing evidence that CCSVI exists, and now there is no convincing evidence that treatments based upon the CCSVI theory are effective. Further, these treatments are invasive and pose serious risks.

Despite low (but not zero) prior plausibility, the medical community has dedicated a significant amount of time and effort to doing serious research into the question of CCSVI. If it has any legitimacy, they want to know about it. They also want to back up their opinions with reliable evidence. Despite this, believers in CCSVI are enthusiastically weaving conspiracy theories to explain away legitimate scientific skepticism toward this new hypothesis.




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.