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What is CCSVI?

A Controversy in Neurology

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Updated October 20, 2013

Written or reviewed by a board-certified physician. See About.com's Medical Review Board.

In 2006, Paolo Zamboni reintroduced the idea of poor venous outflow leading to multiple sclerosis (MS), coining the term chronic cerebrospinal venous insufficiency (CCSVI). It had been known for decades that the inflammatory changes associated with MS surrounded veins. Zamboni theorized that venous stasis leads to red blood cells entering the white matter of the brain, with resulting iron deposits causing an immune cascade response.

This theory is not new, and dates back as far as 1868, having been revisited in different forms throughout the 20th century. Zamboni, however, went one step further by saying that reporting improvement after an endovascular procedure to open the veins.

These results piqued enormous interest in both the scientific community and the media. Many patients with MS have been happy to undergo an invasive procedure in hopes of relief of their patients. Since Zamboni's publications, however, the number of scientific papers that refute this hypothesis have outweighed those in support of the hypothesis, both in number of publications and in quality of research. Nevertheless, a fervid belief in the procedure's efficacy can be found online despite this relative lack of scientific evidence.

The purpose of this series is to explore the evidence around CCSVI, making the scientific debate more accessible to those who wonder if they should undergo "liberation therapy." There are several different levels of controversy to this debate, and I'll try to address them in series.

How Do You Define CCSVI?

The best method, according to Zamboni, to diagnose CCSVI is color-coded duplex ultrasound to examine blood flow in the veins. Neurologists use this technique to evaluate venous sinus thrombosis, for example. Zamboni suggested five criteria:

  1. Intracranial reflux-blood flowing the wrong way in the skull
  2. Extracranial reflux in the internal jugular vein and vertebral vein.
  3. Proximal stenosis of the internal jugular veins
  4. Absence of blood flow in otherwise detectable internal jugular or vertebral veins in lying and/or upright posture
  5. Lack of collapse of the venous jugularis interna in upright posture

Dr. Zamboni found that 100 percent of patients with MS had at least two of these criteria, and no normal controls did, leading to an unbelievably accurate test--better, for example, than an X-ray for pneumonia. While a few studies have also shown a high prevalence in MS alone, most others have found different results, such as a high proportion in healthy controls or other disease states, or even relatively few in any. While some of this might be a difference in how the ultrasound is performed, the technique itself is relatively simple. Other techniques looking at the veins, such as MR venography, have not found any abnormality in MS.In fact, the best study done to date, in over 100 patients using Zamboni's own methods, found no correlation whatsoever.

Experienced ultrasonographers, including some whose work he cited in the criteria's development, have systematically criticized each of the 5 criteria posited by Zamboni. For example. criteria 4 is common in normal people, and others have questioned the identification of particular veins based off images published in Zamboni's work. So in short, these criteria are questionable in their nature, are far from well established, and are not connected with MS in the majority of studies that have been done. These same extremely controversial criteria, however, are what are most commonly used to recommend an expensive and invasive procedure to treat CCSVI.

Proposed Mechanisms

Even Dr. Zamboni recognizes the relationship might be more complex than some of his supporters. Whereas Zamboni theorized that the venous abnormalities might spark a cascade involving an autoimmune response, some supporters trumpet CCSVI as an alternative to the more accepted theory that MS results from the immune system attacking itself. The immune system isn't the problem, they say, which is conventional medications don't work in MS. The problem with this argument is that good science has shown that conventional medications do work, and even Zamboni doesn't actually argue that point. His theory works with the autoimmune hypothesis, not against it.

If the vein malformations are the problem, you could predict that other venous problems should also lead to MS. There are no known relationships, though, between venous disease and known MS risk factors such as geographic location, date of birth, parental ancestry, and more. Usually, venous disease leads to other problems such as ischemic injury and edema, which usually occur after the age of 50-- these rarely occur with MS, which usually comes on at a younger age. Genetic studies have found no relationship between CCSVI and consistent link to MS, HLA DRB1*1501.

The original thought was that CCSVI may cause MS through an autoimmune response triggered by iron. First, there's no clear relationship between CCSVI and iron deposition. Furthermore, brain diseases associated with increased brain iron, such as pantothenate kinase-associated neurodegeneration (PKAN) do not lead to symptoms of MS, and are not related to CCSVI.

This is not to say that veins aren't involved with MS--they are, and this relationship has been recognized for over a century. That inflammation primarily exists surrounding the veins in MS is uncontested. But there are many reasons why that might be. For example, maybe it's easier for inflammatory cells to cross the relatively thin walled veins as opposed to thick walls of arteries.

In short, rather than CCSVI being a firmly established diagnosis, there remains a great deal of contention about how it should be defined, and even more about whether it has any relationship whatsoever to multiple sclerosis, much less a causative one. This hasn't stopped people from paying thousands of dollars, though, in an attempt to treat or cure their multiple sclerosis. Moreover, many of these people feel a direct benefit from the procedure. Why would that be if the procedure didn't actually do what it's supposed to? More on that in the next article.

Sources:

Dake MD. Chronic cerebrospinal venous insufficiency and multiple sclerosis: history and background. Techniques in vascular and interventional radiology 2012;15:94-100.

Ghezzi, A; Comi, G; Federico, A (2011 Feb). "Chronic cerebro-spinal venous insufficiency (CCSVI) and multiple sclerosis.". Neurological sciences 32 (1): 17-21.

Rodger IW, Dilar D, Dwyer J, Bienenstock J, Coret A, et al. (2013) Evidence against the Involvement of Chronic Cerebrospinal Venous Abnormalities in Multiple Sclerosis. A Case-Control Study. PLoS ONE 8(8): e72495.

Valdueza JM, Doepp F, Schreiber SJ, et al. What went wrong? The flawed concept of cerebrospinal venous insufficiency. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 2013;33:657-668.

Zamboni P, Galeotti R, Menegatti E, et al. (April 2009)."Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis". J. Neurol. Neurosurg. Psychiatr. 80 (4): 392-9

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