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Neurology Now:
doi: 10.1097/01.NNN.0000387765.20876.4c
Departments: The Waiting Room

This Way In: CCSVI and Multiple Sclerosis

Phillips, Lisa A.

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Research into a possible connection between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS) is sparking intense interest in the MS community. People with MS are calling for more access to a controversial treatment to correct CCSVI. Some have even traveled to clinics in India and Poland to undergo the unproven treatment, which can cost thousands of dollars.

More than 2,400 people tuned in to a live Web forum on April 14, sponsored by the National Multiple Sclerosis Society and the American Academy of Neurology (AAN), called “What Do We Know About CCSVI?” The forum gave people an opportunity to hear about the research directly from the doctors who developed the theory and conducted initial research into the MS-CCSVI link. These frequently asked questions provide an overview of the issues discussed in the Webinar.

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What is CCSVI?

Figure. The message ...
Figure. The message ...
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Chronic cerebrospinal venous insufficiency is an abnormality in how blood drains from the brain and the spinal cord, as reported in research published in 2009 by Paulo Zamboni, M.D., and colleagues in the Journal of Neurology, Neurosurgery & Psychiatry. Dr. Zamboni is professor of vascular surgery at Italy's University of Ferrara. His theory is that stenosis (narrowing of the blood vessels) and/or blockages reverse blood flow in the azygous vein, which carries blood from the lower spine, and internal jugular veins, which carry blood from the brain and neck—and that this causes an overload of iron in the brain and spinal cord.

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What does it have to do with MS?

The proposed link between CCSVI and MS is that the increased deposition of iron triggers inflammation and lesions in the brain, leading to the degeneration of the myelin sheath surrounding nerves. The degeneration of myelin is considered the cause of MS.

Dr. Zamboni's study showed what he and his colleagues called a “dramatic association” between MS and blood flow abnormalities in major veins draining from the brain and spinal cord. The 65 people with different types of MS in the study were 43 times more likely to have blockages or stenosis of the veins than the 235 controls, as shown by Doppler high-resolution brain scans. The study was blinded, meaning that the ultrasound technicians and physicians interpreting the scans did not know whether the patients had MS or were in the control group, which was comprised of healthy subjects and subjects with other neurologic diseases.

However, the hypothesis that CCSVI is associated with MS is not proven, says Dr. Robert Zivadinov, M.D., Ph.D., associate professor of neurology at the State University of New York at Buffalo. The treatment for correcting CCSVI, which involves inserting a tiny balloon or stent into narrow or blocked veins in order to improve blood flow, is still being tested. “There are no data at this moment to determine whether this is useful,” says Dr. Zivadinov, who is studying the approach, known in the MS community as the “liberation treatment.”

Furthermore, uncovering an association between people with CCSVI and MS is not the same as discovering that CCSVI causes MS, emphasizes John Corboy, M.D., professor of neurology at the University of Colorado-Denver and co-director of the Rocky Mountain MS Center at Anschutz Medical Campus. Dr. Corboy says the vascular abnormalities, even if replicated by others with similar and different techniques, could be the result rather than the cause of MS.

Dr. Zivadinov says, “Several studies will be needed to prove the real prevalence of CCSVI in MS. The link has to be proven also by correlating MRI, genetic, and clinical characteristics with CCSVI, which is exactly what we are doing.”

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I've heard that people with MS have gotten much better after venoplasty surgery to correct CCSVI. Is that true?

A small, open-label study by Dr. Zamboni, published last year in the Journal of Vascular Surgery, evaluated 65 people with various stages of MS who underwent vascular surgery. (In an open-label study, the participants and researchers know which treatment is being administered, which can bias the results.) They reported some positive outcomes, in particular for people with relapsing-remitting MS, the most common form of the disease. People with this form experience unpredictable attacks, in which MS symptoms worsen, followed by periods of time when they return to normal or near-normal functioning.

Twenty-seven percent of the study participants were relapse-free before surgery, versus 50 percent at 18 months. But restenosis of the jugular veins—associated with later relapse—occurred in nearly half the patients within 18 months.

It's possible, given the nature of relapsing-remitting MS, that some of the patients might have improved temporarily without the treatment, says Aaron E. Miller, M.D., chief medical officer of the National MS Society and director of the MS Center at Mt. Sinai Medical Center.

Dr. Corboy points out that Dr. Zamboni's study did not have a control group and that patients remained on their disease-modifying drug regimen. “Claims of improvement are based only on comparison to patients themselves prior to the procedures,” he says. “No one would accept this as evidence of a treatment effect in MS.” Indeed, experts emphasize that patients should not stop their current therapies.

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Are larger trials underway?

Dr. Zivadinov is trying to duplicate Dr. Zamboni's findings in a larger study designed to examine how prevalent CCSVI is among people with MS versus healthy controls. In preliminary results on the first 500 participants, presented at the annual meeting of the AAN in April, Dr. Zivadinov has found less prevalence of CCSVI among MS patients than did Dr. Zamboni. All of the participants in the Combined Transcranial and Extracranial Venous Doppler (CTEVD) Evaluation study underwent Doppler ultrasound scans to determine if they met the criteria for CCSVI. Out of the total, 56.4 percent of the participants with MS were found to have CCSVI, versus 22.4 percent of healthy controls. In Dr. Zamboni's 2009 study, 95 percent of the people with MS had some form of vein blockage or insufficiency. The conflicting results “raise a lot of questions,” Dr. Miller says.

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Even if the findings are mixed, I feel like anything that might help me is worth a try. I saw on the Web that I could go to Europe or India for vascular surgery to correct CCSVI. Is this a good idea?

The message from most of the participants in the Webinar was clear: Do not undergo invasive procedures designed to correct blood flow unless they are part of a well-designed clinical trial.

“These vascular procedures are associated with several potential, real, and serious complications—and need to be done by a qualified practitioner in a setting where we can learn whether the procedure has any beneficial impact on the disease process,” says Dr. Corboy. “Only then will we learn if the procedure should be more generally used.”

He points out that two Stanford University researchers who tried to use stents to correct CCSVI stopped their work after one patient developed a fatal hemorrhage and another suffered a complication in which the stent dislodged and required cardiac procedures to remove it.

Dr. Zamboni says that stents should not be used to treat CCSVI and agrees that the condition is best studied in clinical trials. But he adds that people with MS who are “rapidly declining” and have not responded to other treatment might want to ask their doctors for the treatment “on compassionate grounds.”

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How can I get information about participating in a clinical trial?

Dr. Zivadinov and his colleagues are proceeding with phase II of the CTEVD study. To find out more, contact the Buffalo Neuroimaging Analysis Center at 716-859-7040 or email ccsvi@bnac.net.

Lisa A. Phillips

©2010 American Academy of Neurology

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