CCSVI – Part 1
A great deal has been written about CCSVI (chronic cerebrospinal venous insufficiency) since its initial appearance in 2009. An obscure article in an obscure medical journal became a worldwide phenomenon following a profile of the procedure and its originator, Dr. Paolo Zamboni, on the Canadian news program W5. (To view the broadcast go to (www.ctv.ca/servlet/ArticleNews/story/CTVNews/20091120/W5_liberation_091121/20091121?s_name=W5). CCSVI may have been conceived in Italy, but its medical tourism passport is Canadian.
This series will explore the ideas behind CCSVI and the research that has been done over the past three years to help people with MS address the question: Is it hope, or hype?
The CCSVI story begins in 2005 when Prof. Zamboni, a vascular surgeon in Bologna, Italy, published the finding that people with venous disease (affecting the veins) had high levels of iron in the tissues of their legs (Zamboni et al. Dermatol Surg 2005; 31: 644-649). These iron deposits were associated with elevated levels of an enzyme called MMP-9 (for matrix metalloproteinase-9), which contributed to the formation of leg ulcers. But MMP-9 also suggested to Prof. Zamboni that there was a connection with MS. MMP-9 is known to break down the blood-brain barrier, the layer of tightly packed cells that normally screens out harmful substances from passing from the blood into the central nervous system (CNS). Indeed, some MS therapies, such as the interferon-beta drugs, are known to reduce MMP-9 levels (Alexander and colleagues. Mult Scler 2010;16:801-809).
A year later, Prof. Zamboni proposed what he called The Big Idea in a lecture to the Royal Society of Medicine in London, UK (Zamboni P. J R Soc Med 2006; 99:589-593; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC2647682/pdf/JNN-80-04-0392.pdf). The idea was actually a concatenation of several ideas:
1) In some people with MS, the normal flow of blood in the veins runs backwards (refluxes) under certain conditions (such as coughing).
2) MS lesions tend to cluster around dilated blood vessels in the brain.
3) A breakdown in the blood-brain barrier leads to CNS inflammation. MMP-9 activated by iron deposits may promote this breakdown.
4) Some immune cells (macrophages) have high amounts of iron, which leads to an accumulation of iron in inflammatory MS lesions.
5) One of the mutations (HFE-C282Y) associated with a genetic iron overload condition (called hereditary hemochromatosis) is somewhat more common in people with MS of northern European ancestry (Rubio and colleagues. Hum Genet 2004;114:573-580). However, it’s important to note that this study concluded that this mutation is not an independent factor increasing a person’s susceptibility to MS. As for this aspect of the story, subsequent genetic and population studies have found that HFE mutations are not more common in people with MS, and these mutations do not influence the course of MS (Ramagopalan and colleagues. J Neuroimmunol 2008;203:104-107, Ristic and colleagues. Neurosci Lett 2005;383:301-304; Bettencourt and colleagues. Eur J Neurol 2011;18:663-666).
To pull all of these ideas together, Prof. Zamboni was suggesting that iron deposits in the CNS were the underlying cause of the inflammatory reaction that leads to the formation of MS lesions. The excess iron comes from macrophages (“big eaters”), which ingest foreign substances (such as bacteria) and debris in the body (such as old red blood cells, which contain iron) as part of the body’s immune response.
But iron soon became a side issue. For a vascular surgeon such as Prof. Zamboni, a more interesting idea was that the underlying problem of iron-induced inflammation in the CNS was due to abnormal flow of blood out of the brain caused by malformed veins.
In 2009, he investigated the problem of abnormal blood flow in people with MS (Zamboni and colleagues. J Neurol Neurosurg Psychiatry
2009;80:392-399; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC2647682/pdf/JNN-80-04-0392.pdf).
The term he coined in that paper to describe the problem – chronic cerebrospinal venous insufficiency (CCSVI) – would soon top a million hits on the Internet.
In Part 2 we’ll look at what researchers have learned about CCSVI.
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