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a) a gene variant // b) a virus // c) an immune disorder // d) environment // e) all of the above, in combinations we don’t yet understand.

MS: Multiple Complications

By Meera Lee Sethi // Illustrations by Brian Rea // Fall 2010
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multiple sclerosis

Brian Rea

During the 142 years since French physician Jean-Martin Charcot first described multiple sclerosis, the disease has resisted easy classification. It’s characterized by patchy lesions—scleroses—that develop in the central nervous system when the myelin sheaths meant to protect nerve fibers (and sometimes the fibers themselves) deteriorate. The lesions disrupt signals traveling through the brain, spinal cord and nerves. But MS may progress quite differently in different patients, with some experiencing clearly defined attacks followed by partial or complete remissions and others getting steadily worse as neurological symptoms—numbness, weakness, poor motor control, vision problems—increase. In still others, there is a slow deterioration punctuated by bouts of heightened symptoms.

Although almost all scientists agree that, at bottom, this chronic, disabling condition is an autoimmune disorder, in which the body attacks its own tissues, there appears to be an elaborate mosaic of contributing factors. “There’s evidence of roles for genetics, environmental factors, infections, geography, vitamin D, diet.... It goes on and on,” says neurologist T. Jock Murray, professor emeritus at Canada’s Dalhousie University and author of a 580-page history of the scientific struggle to figure out MS. “It’s far more complex than most diseases, and it’s very difficult to conceptualize in a simple way.”

Yet in 2009, a physician named Paolo Zamboni, affiliated with Italy’s University of Ferrara, put forth a radically straightforward hypothesis to explain the disorder. Zamboni thinks the characteristic lesions of MS are caused by physical obstructions in veins leading out of the brain and spinal cord—a vascular condition known as chronic cerebrospinal venous insufficiency (CCSVI). These blockages, Zamboni says, cause blood refluxes and inflammatory injuries that end up as lesions. “It’s a plumbing analogy,” says Murray. “You have an obstruction that’s causing a problem, so you remove the obstruction and the problem goes away.”

In the studies that underpin this theory, Zamboni used transcranial and extracranial color Doppler sonography—a sophisticated ultrasound imaging technique—to diagnose impaired blood flow in every MS patient he tested. The method found no such blockages in the healthy controls. He found that treating the blockages with a surgical procedure that widens the vessels increased the number of patients who were relapse-free and reduced the rate at which additional lesions formed.

But other research isn’t so black-and-white, and so far most neurologists and hospitals in the United States have been cautious or even skeptical. Preliminary results from one ongoing study show CCSVI in only 56% of MS patients, as well as in 23% of healthy controls and in 43% of patients who have other neurological conditions, suggesting that blocked veins aren’t directly related to MS, even though they may be present in many patients. There have yet to be double-blind studies that confirm a causal link, or placebo-controlled studies to prove the efficacy of removing venous obstructions in MS patients.

Still, Zamboni’s work has attracted considerable attention, particularly among patients and their families. “The simplicity of this idea makes it compelling,” says Murray. Last summer the National Multiple Sclerosis Society and its sister organization in Canada committed more than $2.4 million to seven North American CCSVI research projects.

Recently, though, a surge of research on multiple fronts has begun to produce, if not yet a clear view of exactly what causes the disease, then at least a better understanding of many of the pieces of the mosaic. With advanced neuroimaging, microscopy and genomic sequencing tools facilitating more detailed examination of the characteristics of MS, these are boom times for MS investigations. But with the exception of the work on CCSVI, most of the research isn’t distilling the complexity associated with MS so much as elucidating it.

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Multiple Sclerosis Treatments: New Routes to Relief

A number of new therapies are on the horizon to treat patients with MS.


1. Multiple Sclerosis: The History of a Disease, by T.J. Murray (New York: Demos Medical Publishing, 2005). In this gracefully written history, Murray reflects on how our continually shifting understanding of the disease has tended to reflect the rise and fall of various research trends, such as an increased interest in immunology during the 1980s.

2. “From Genes to Function: The Next Challenge to Understanding Multiple Sclerosis,” by Lars Fugger, Manuel A. Friese and John I. Bell, Nature Reviews Immunology, June 2009. The authors call for research that goes beyond identifying genes that increase susceptibility to MS by deconstructing the role these genes play in its development.

3. “Chronic Cerebrospinal Venous Insufficiency in Patients With Multiple Sclerosis,” by P. Zamboni et al., Journal of Neurology, Neurosurgery & Psychiatry, April 2009. Zamboni presents a study of 300 MS patients and control group participants in which he finds CCSVI to be strongly associated with the disease.

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