CCSVI May Be the Result, Not the Cause of MS

Susan Jeffrey

May 06, 2011

May 6, 2011 — Results of a cohort study examining the prevalence of chronic cerebrospinal venous insufficiency (CCSVI) suggest that the condition appears to be elevated in patients with multiple sclerosis (MS) but probably does not take a causative role in the disease.

Researchers from the University of Buffalo found an increased prevalence in MS over other neurologic conditions and healthy controls but with only "modest" sensitivity and specificity, they note.

"Based on our findings, we don't think CCSVI could be a cause of MS," lead study author Robert Zivadinov, MD, PhD, from the Buffalo Neuroimaging Analysis Center and the Jacobs Neurological Institute at the University of Buffalo, New York, told Medscape Medical News.

Within MS patients, the prevalence of CCSVI actually appears to increase with disease severity, from 38% in those with first clinical onset to up to 90% in those with progressive disease, he added. "So clearly, at this time we cannot exclude completely that CCSVI is playing a role in the first clinical attack...but as a unique factor to be the cause of this disease, I don't think that's the case."

The paper, first released last year, was published online April 13 and will appear in the July 12 issue of Neurology.

CTEVD Study

The possible link between impaired venous drainage from the brain and MS was first postulated by Paolo Zamboni, MD, director of the Vascular Diseases Center at the University of Ferrara, Italy. Since then, a number of studies have focused on trying to elucidate the possible relationship between lesions in the extracranial veins and MS symptoms.

Dr. Robert Zivadinov

In the meantime, many patients are undergoing elective angioplasty and stenting procedures to open these venous lesions, paying privately with clinical results that are not necessarily followed or recorded, making it imperative to find out whether and how CCSVI may contribute to the development of MS.

The present study, called the Combined Transcranial and Extracranial Venous ECD (echo-color Doppler) Evaluation study (CTEVD), was a single-center, cross-sectional investigation looking at the prevalence of CCSVI in a large cohort of patients with MS, clinically isolated syndrome (CIS), other neurologic diseases, and healthy controls. In all, 499 subjects were enrolled: 289 with MS, 163 healthy controls, 26 with other neurologic diseases, and 21 with CIS.

To define CCSVI, they used venous hemodynamic parameters proposed by Dr. Zamboni, with 2 or more criteria required to make a diagnosis of CCSVI.

Prevalence rates were calculated 3 ways, first using only those subjects with a definitive diagnosis of CCSVI and excluding the borderline cases, next including borderline cases in the "no CCSVI" group, and third by including any subject with any 1 of the 5 criteria for CCSVI in the CCSVI group.

They report that the prevalence of CCSVI was highest among MS patients for each of these calculations but with "modest sensitivity/specificity," they write.

Table. CTEVD: CCSVI Prevalence (Percentages)

Calculation MS Patients Clinically Isolated Syndrome Other Neurologic Diseases Healthy Controls P Value
Prevalence (borderline cases considered "no CCSVI") 56.1 38.1 42.3 22.7 <.001
Prevalence (borderline cases excluded) 62.5 42.1 45.8 25.5 <.001
Prevalence of ≥1 VH criteria 81.3 76.2 65.4 55.2 <.001

CCSVI = chronic cerebrospinal venous insufficiency; CTEVD = Combined Transcranial and Extracranial Venous ECD (echo-color Doppler) Evaluation study; MS = multiple sclerosis; VH = venous hemodynamic

They also found that CCSVI prevalence was higher among those with progressive vs nonprogressive MS (P = .004).

Follow Inquiry to Its End

In an editorial accompanying the publication, Robert J. Fox, MD, and Alex Rae-Grant, MD, from the Cleveland Clinic Foundation, Ohio, agree with the researchers' conclusions that these findings suggest CCSVI "is not likely to be a primary causal process in MS.

"An increased prevalence in progressive as compared to relapsing disease leaves open the possibility that CCSVI may be playing a contributory role in, or be a consequence of, the disease or may be age-related," they write.

The response of the MS patient community to the possibility that clinical improvement might result from treating CCSVI was "profound," the editorialists write, with many social media Web site and blogs promoting the CCSVI theory "as salvation for patients with MS." As many others have done, these authors advocate that procedures to address CCSVI be limited to clinical trials.

Dr. Fox was the recipient of 1 of 7 research awards totaling $2.4 million from the US and Canadian MS societies that will together evaluate more than 500 patients and 600 controls using ultrasonography, magnetic resonance angiography, catheter-based venography, and pathologic studies of autopsy tissue.

...we should neither jump on the bandwagon as it passes through town nor assiduously miss the parade.

"It behooves the clinical research community to carefully pursue CCSVI to its end; we should neither jump on the bandwagon as it passes through town nor assiduously miss the parade," they write. "If CCSVI is a useful clinical or research endeavor for some proportion of the MS population, we should acknowledge its importance.

"If CCSVI is not found to be linked to MS, efficient and definitive studies will let us redirect precious resources toward research efforts more likely to advance the understanding and treatment of this disease."

'Enormous Variability' in Interpretation

Asked for his comment on the new publication, Dr. Zamboni pointed out that there has been "enormous variability" in interpretation of the Doppler epidemiologic studies published to date looking at the relationship of CCSVI to MS.

Even so, together the 9 studies published to this point have scanned more than 1300 MS patients and 500 controls and showed an overall prevalence of CCSVI of 71% in patients and 8% in controls, Dr. Zamboni told Medscape Medical News. "There is no denying that CCSVI belongs to the complexity of MS," he said.

As for the present findings by Dr. Zivadinov and colleagues, he said, "it seems to me that the conclusions are not very cautious. The Buffalo study has shown that the prevalence of MS in pediatric CCSVI is 4 times higher than that of the healthy adult population," he said. "This cannot support that CCSVI is caused by MS."

The study was funded by internal resources of the Buffalo Neuroimaging Analysis Center and Baird MS Center, the Jacobs Neurological Institute, University of Buffalo, the Direct MS Foundation, the Jacquemin Family Foundation, and smaller donors. Dr. Zivadinov serves as a section editor for BMC Neurology and serves on speakers' bureaus for Biogen Idec, Teva Neuroscience, and Sanofi-Aventis. Disclosures for coauthors appear in the paper. Dr. Fox has received speaker honoraria from Biogen Idec and Teva Pharmaceutical Industries Ltd; has served as a consultant for Biogen Idec, Genentech Inc, and Novartis; has served on clinical trial advisory committees for Biogen Idec; has received/receives research support from the National Multiple Sclerosis Society, which includes funding to study CCSVI; and serves on the editorial boards of Neurology and Multiple Sclerosis. Dr. Rae-Grant has received speaker honoraria from Biogen Idec, EMD Serono Inc, and Teva Pharmaceutical Industries Ltd; receives publishing royalties for Handbook of Multiple Sclerosis (Springer Healthcare, 2010); serves on the speakers' bureau of Biogen Idec; and has received research support from the National Multiple Sclerosis Society.

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