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New Theory on CCSVI and MS Needs Further Study, Experts Say


doi: 10.1097/01.NT.0000383489.93815.43
News From the Aan Annual Meeting
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A controversial new theory suggests reduced blood flow in the azygous and internal jugular veins may be associated with MS, possibly by causing an iron overload in the brain and spinal cord.

TORONTO'The theory that chronic cerebrospinal venous insufficiency, or CCSVI, could be associated with multiple sclerosis (MS) remains largely unproven, doctors say.

The hypothesis, first proposed by Paulo Zamboni, MD, professor of vascular surgery at Italy's University of Ferrara, suggests reduced blood flow in the azygous and internal jugular veins may be associated with MS, possibly by causing an iron overload in the brain and spinal cord.

Neither the underlying hypothesis nor the suggested treatment — endovascular procedures to open lesions causing the insufficiency — have been proven, said Robert Zivadinov, MD, PhD, an associate professor of neurology at the State University of New York in Buffalo who is studying the approach.

“There are no data at this moment to determine whether this is useful,” he said.

As a result, MS patients should not undergo invasive procedures designed to correct venous blood flow outside of well-designed clinical trials, Dr. Zivadinov and other physicians said.

The research has fueled a surge of interest within the MS community, with patients blogging and flooding doctors' phone lines with requests for more information. Some have even traveled to clinics in Italy or Poland, spending thousands of dollars to undergo the unproven treatment.

More than 4,000 people called into a special Web seminar to hear the physicians speak during the AAN annual meeting here in April.

Dr. Zamboni and colleagues first reported in Current Neurovascular Research in 2007 that they had found significant hemodynamic alterations in veins anatomically related to plaque disposition in MS patients. Use of transcranial color-coded duplex sonography showed significantly increased reflux and/or bidirectional flow in the deep middle cerebral veins and the transverse sinus of 89 MS patients compared with 60 controls.

In a follow-up blinded study published in 2009 in the Journal of Neuropsychology, Neurosurgery & Psychiatry, the researchers looked at venous flow among 65 patients with clinically definite MS and 235 controls. They found what they called a “dramatic association” between MS and venous outflow abnormalities; MS patients were a significant 43 times more likely to have venous outflow anomalies on combined transcranial and extracranial color-Doppler high-resolution examination than controls. No conflicts of interests were reported in the study.

Moreover, “relapsing-remitting and secondary progressive courses were associated with CCSVI patterns significantly different from those of primary progressive courses,” Dr. Zamboni reported.

And last year Dr. Zamboni published in the Journal of Vascular Surgery of a pilot, open-label study of 65 patients who underwent percutaneous transluminal angioplasty to open stenoses in the internal jugular or azygos veins.



The researchers found patients improved with the treatment on some clinical outcome measures after the intervention, particularly the 35 patients with relapsing-remitting disease; 27 percent of them were relapse-free before surgery versus 50 percent afterwards. However, only 12 percent of patients benefited from treatment on the long-term.

Given the remitting, relapsing course, it's not known how many of these patients would have improved temporarily anyway, said Aaron E. Miller, MD, chief medical officer of the National MS Society and director of the MS Center at Mt. Sinai Medical Center in New York City, who was not involved with the studies.

“If one is contemplating that procedure, it should be done only in the context of a properly controlled trial,” he told participants of the Web seminar.

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Researchers are not dismissing the theory — just stressing that further study is needed. “This was somewhat of a surprising theory when I heard about it,” said John Corboy, MD, professor of neurology at the University of Colorado-Denver and co-director of the Rocky Mountain MS Center at Anschutz Medical Campus, who was not involved with the studies. “That said, concepts that seem out of the mainstream — such as peptic ulcers being caused by bacteria — can turn out to be accurate,” he said.

Dr. Zivadinov is trying to duplicate Dr. Zamboni's findings. At the AAN meeting, he presented data on the first 500 participants in the ongoing Combined Transcranial and Extracranial Venous Doppler Evaluation study designed to examine the prevalence of CCSVI among patients with MS vs. healthy controls.

All underwent transcranial and extracranial Doppler ultrasonography looking for five criteria for CCSVI originally established by Dr. Zamboni. The criteria are: reflux in the internal jugular and vertebral veins, reflux in the deep cerebral veins, high-resolution B-mode evidence of stenosis of the internal jugular, flow in the internal jugular or vertebral veins that could not be detected with Doppler, and reverted postural control of the main cerebral venous outflow pathways.

Participants who met two or more of the criteria were considered to have CCSVI. They were judged to be “borderline” if they met just one criterion, and not to have the condition if they met none.

Of the total, 56.4 percent of MS patients met CCSVI criteria compared with 22.4 percent of healthy controls. When 10.5 percent of MS patients with “borderline” narrowing were reclassified as having no venous insufficiency, the prevalence of CCSVI was 62.5 percent in MS patients, 25.9 percent in healthy controls, and 45 percent in people with other neurological disorders.

The conflicting results of the Zamboni and Zivadinov studies “raise a lot of questions,” Dr. Miller said.

Additionally, the association does not demonstrate causation, as the vascular findings could be the result rather than the cause of MS, Dr. Corboy said.

During a separate review lecture at the AAN meeting updating developments in MS, Dr. Corboy noted that Stanford University researchers who tried using stents to correct chronic venous insufficiency halted their work following two catastrophic complications.

In one case, a patient on warfarin to prevent stent-related thrombosis developed a fatal intracranial hemorrhage. In the second case, the stent dislodged and traveled to the right atrium, requiring cardiac procedures to remove it.

“Many of you are quite aware of this work and have been getting many phone calls from angiographers and other people about this procedure,” Dr. Corboy told colleagues attending the review lecture.

“I would not recommend it until we had a much better idea whether this approach has any merit whatsoever,” he said.

Asked about the Stanford experience during the Web seminar, Dr. Zamboni said stents should not be used to treat these patients.

He too acknowledged that CCSVI is best studied in clinical trial. But Dr. Zamboni said that MS patients who are “rapidly declining” and who have not responded to any other medications might want to appeal to physicians to receive the treatment “under compassionate grounds.”

“For these types of patients, the publication of our [research] generated a desperate need to find this type of treatment,” he said.

MS patients who do enter clinical trials should be told to continue taking other medications, the physicians at the Web seminar stressed.

“There is no reason to stop treatments,” Dr. Zivadinov said. “Clinical trials over the last 25 years have clearly shown the advantages of those treatments.”

Dr. Corboy said that for now, “it is absolutely premature to be doing any treatment trials outside of clinical trials — we don't even know that CCSVI is a cause of MS.”

The National MS Society and the Canadian MS Society intend to fund grants to further study whether CCSVI is truly associated with MS, Dr. Corboy said.

Dr. Zivadinov said he is awaiting funding for further study. In the meantime, he too urged neurologists not to treat MS patients for CCSVI outside of clinical trials. “I have to call in question all the people around the world who are providing open-label treatment,” he said.

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• Zamboni P, Menegatti E, Salvi F, et al. Intracranial venous haemodynamics in multiple sclerosis. Curr Neurovasc Res 2007;4:252–258.
    • Zamboni P, Galeotti R, Salvi F, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:392–399.
      • Zamboni P, Galeotti R, Salvi F, et al. Endovascular treatment of chronic cerebrospinal venous insufficiency: A prospective open-label study. J Vasc Surg 2009; 50:1348–1358.
        ©2010 American Academy of Neurology