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March 5, 2010 06:52  by Dr. Lorne Brandes

Readers of my postings know that I have followed with interest, and (hopefully) reported objectively, on Dr. Paolo Zamboni’s hypothesis that multiple sclerosis may be triggered by blocked neck or chest veins, resulting in a back-flow of blood into, and leakage from, the brain’s venous system, a condition that he has called chronic cerebrospinal insufficiency (CCSVI).

A vascular surgeon by training, Zamboni’s CCSVI theory evolved from his years of research on patients with chronic venous obstruction in the extremities, and the eventual realization that the tissue inflammation and iron deposition he observed in the legs of severely affected individuals was very similar to that reported in the brains of patients with MS.

Although completely “outside the box” of conventional wisdom, the suggestion that MS may have a vascular cause is not incompatible with the widely-held view that it is an autoimmune disorder: in patients with CCSVI, the immune response could be triggered by iron, and possibly, other inflammation-promoting blood constituents that leak from damaged veins into brain tissue.

Zamboni’s postulate also jibes remarkably with the decades-old anatomical finding that MS lesions (or “plaques”) tend to cluster along the brain’s venous system and usually progress in a “backwards” direction. Indeed, new MRI studies indicate that most, if not all, MS plaques have a vein in their centre, and contain significant amounts of iron.

Although some critics have suggested that any neck (jugular) or chest (azygous) vein abnormalities may result from, rather than cause, MS, a recent panel of international experts has concluded that the anomalies associated with CCSVI are congenital in origin, resulting from abnormal development in the fetus. Therefore, while much remains to be learned, it is conceivable that, as has been found in many cases of MS, developmental vein defects could be familial.

Furthermore, while we don’t know whether vitamin D plays a role in the normal development of veins, research shows that it is certainly important for cardiovascular health. Is it not reasonable, therefore, to wonder whether, like MS, abnormal vein development could be more frequent in northern latitudes where pregnant mothers have decreased exposure to sunshine vitamin D? Lots of food for thought here!

Spurred on by excitement over the Zamboni hypothesis, and recent confirmatory data from the University of Buffalo that blocked neck and chest veins are two to three times more common in patients with MS than normal people, thousands of MS patients, dissatisfied with currently-available immunosuppressive treatment, have asked their neurologists to test them for CCSVI. Based on the reaction of Winnipeg neurologists, along with what I have gleaned from online chat groups, the response to that request has been overwhelmingly negative. Why? Most neurologists want definite proof that treating CCSVI will help patients with MS before they carry out such investigations.

Patients argue that if their doctors are not at least prepared to test for CCSVI, no progress will be made. It’s clearly a catch-22 situation, totally unacceptable to many MS sufferers and their advocates.

One such person is geologist Dr. Ashton Embry, a Canadian MS activist with his own website. Extrapolating from the Buffalo data, which suggested that 80% of patients with progressive MS have venous blockage, Embry has gone so far as to develop and post an “integrated” hypothesis (unproven) that MS is primarily an autoimmune disease but that, when present, CCSVI potently accelerates its downhill course. Moreover, concerned that time is running out for many patients, especially those with progressive forms of the disease, Embry is advising them to be tested for CCSVI now and seek treatment if blocked veins are found.

However, before proceeding, I would suggest that Dr. Embry, and those he advises, read a news report, just published in the Annals of Neurology, on two patients with CCSVI who had what are called serious adverse events (SAEs) following stenting  procedures to unblock their veins at California’s Stanford University. A stent is a tiny metal mesh tube that is placed in blood vessels to keep them from closing back up again. It’s designed to stay in the blood vessel permanently to improve blood flow.

One of the patients, a 51 year-old woman named Holly Shean, had the most serious of all SAEs: she suffered a sudden brain hemorrhage and died a few days after being treated.

While her family has publicly stated that the placement of two stents in her right jugular vein by Dr. Michael Dake, chief of Stanford’s Catheterization and Angiography Center, had nothing to do with her death, the article notes that Ms. Shean had been placed on coumadin, a blood thinner, following the procedure (although this is standard practice after arterial stenting, there is much less published literature about the use of coumadin following venous stenting). While an autopsy did not reveal an anatomical cause of the hemorrhage, there can be no doubt that being on coumadin following insertion of the stents caused, or contributed to, the fatal bleeding.

The second patient, also treated for CCSVI by Dr. Dake, required open heart surgery after the stent became dislodged from the wall of the vein in the neck and travelled to the right ventricle of his heart.

As a result of these very serious complications, as well as pressure to stop from colleagues, Dr. Dake cancelled all further procedures until an approved clinical trial was in place “sometime in early 2010”. However, Paul Costello, a spokesman for Stanford Medical Center, was somewhat less definite, stating, “… Dr. Dake and Stanford have determined that the initiation of a clinical development program leading to a possible clinical trial will be the next step, as we examine the possible risks and benefits of the procedure for patients with multiple sclerosis.”

What I believe everyone should focus on here is that two SAEs occurred in a total of only 35 patients in Dake’s study. If a highly eminent and qualified expert like Dr. Michael Dake has an almost 6% rate of serious complications associated with treating CCSVI, what would the rate be among vascular surgeons of lesser ability?

But that’s not all there is to consider. How many know that fully 50% of patients whose neck veins were “liberated” by Dr. Zamboni suffered a restenosis (recurrent vein blockage) in the first year after the procedure? Dr. Zamboni views that as a real stumbling block; he also feels that stents, in their current form, should not be used. What that tells me is that not even the experts know for sure how to treat the blocked veins, let alone whether the procedure really benefits patients with the disease. After all, placebos are as effective as treatment of any type in one-third of people! That’s pretty sobering, isn’t it?

Finally, Dr. Zamboni’s preliminary human study did not show a benefit of unblocking veins in patients with progressive forms of MS. That is not to say that better-designed, larger studies might not show a benefit, only that there are no current data demonstrating one. From my point of view as an oncologist, once any disease passes a point of “no return”, be it cancer or progressive MS, it is unrealistic to think that any therapy, no matter how effective in earlier stages of disease, will help those in advanced stages.

So listen-up Dr. Embry and all those who want immediate action: for the sake of everyone (including me) who hopes that the diagnosis and treatment of CCSVI will be a very important step forward in MS, recognize that the scientific method demands the utmost scrutiny and proper testing of any new hypothesis. As exemplified by the unfortunate Stanford experience, running before we can crawl is more likely to set a good cause back than move it forward.

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