CCSVI Study by the Fox Team - National Multiple Sclerosis Society

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CCSVI Study by the Fox Team


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Study on CCSVI in MS at Cleveland Clinic Foundation

In June 2010, the National MS Society (USA) and the MS Society of Canada committed over $2.4 million to support seven new research projects on the role of CCSVI (chronic cerebrospinal venous insufficiency) in MS, an abnormality of blood drainage from the brain and spinal cord in MS originally reported by Dr. Paolo Zamboni. The new projects take a comprehensive look at the structure and function of veins draining the brain and spinal cord in people representing a spectrum of MS types, severities and durations, and compare them to structure and function of veins in people with other diseases and healthy volunteers. The studies incorporate high standards of experimental blinding and controls designed to provide unbiased results.

Title: “A Multi-Modal Assessment of Chronic Cerebrospinal Venous Insufficiency”

Robert J. Fox, M.D.
Cleveland Clinic Foundation
Cleveland, OH
Term/Amount: 7/1/10-9/30/13 (extension granted); $571,261
  • A series of recent publications have suggested that some people with MS have obstructions in the veins that drain blood in the brain and spinal cord that may contribute to nervous system damage in MS.
  • Dr. Fox and a multi-disciplinary team are seeking to reproduce these findings in 90 people with MS and 80 control subjects without MS, using various tests, as well as examining vein tissues obtained via autopsy.
  • Data from these studies will provide a comprehensive foundation upon which to either design further longitudinal and intervention studies, or reject this hypothesis of MS pathogenesis.
About the Investigator: Dr. Robert J. Fox is an award-winning clinical researcher who is dedicated to finding better therapies for people with MS. He is currently Medical Director of the Mellen Center for Multiple Sclerosis Treatment and Research at Cleveland Clinic, where he conducts clinical trials in MS and serves as a peer reviewer and advisor to many agencies including the National MS Society’s headquarters and local Ohio Buckeye Chapter.

He graduated with a BA in neuroscience Summa cum laude from Amherst College and received his MD from Johns Hopkins University. He did his residency in neurology at the Hospital of the University of Pennsylvania. His National MS Society-supported Sylvia Lawry Physician Fellowship at Cleveland Clinic enabled him to gain hands-on experience conducting MS clinical trials and to pursue a Master’s in clinical research from Case Western Reserve University.

Dr. Fox’s multi-disciplinary team includes the medical director of the Cleveland Clinic’s neurovascular laboratory, an expert cardiologist in venous ultrasound, the section head of imaging sciences, and others with expertise in neuropathology, anatomy, biomedical engineering, and biostatistics. By assimilating such a diverse team of experts in their respective fields, a complete and accurate assessment of CCSVI will be performed.

Project Details: Recent preliminary studies have suggested that a phenomenon called Chronic Cerebrospinal Venous Insufficiency (CCSVI), a reported abnormality in blood drainage from the brain and spinal cord, may contribute to nervous system damage in MS. This hypothesis has been put forth by Dr. Paolo Zamboni from the University of Ferrara in Italy. This pilot study warrants a subsequent larger and better controlled studies to definitively evaluate the possible impact of CCSVI on the disease process in MS.

Dr. Fox and his team are seeking to reproduce these findings in 90 people with different forms of MS and 80 controls without MS. His team is conducting the same tests that were done in the original studies (ultrasound tests of the veins in the neck), an MRI test that looks specifically at veins, and neurological examinations. Most of these MS patients have been followed for the past 10 years in a longitudinal study using quantitative clinical and imaging measures, which will provide an opportunity to compare CCSVI findings to MS disease evolution. To distinguish whether vein abnormalities are from atrophy (brain tissue volume loss) and not specifically MS, they also are comparing the MS group to people with atrophy from Alzheimer's disease. Finally, they are examining the neck and spinal cord veins obtained via autopsy from people with MS and non-MS controls.

Data from these studies will shed light on the meaning of Dr. Zamboni’s original reports and how CCSVI relates to disease activity in MS.

Progress updates

July 2015: Dr. Fox’s team publishes final results of the clinical study to investigate differences in venous flow between people with MS and people without MS. The team studied 61 people with MS (4 with CIS; 28 with relapsing-remitting MS; 19 with secondary-progressive MS; 10 with primary progressive MS) and 20 people without MS (15 healthy and 5 with other neurological conditions). Ultrasounds were performed by trained technicians who were “blinded” as to whether the participants had MS or not. Using strict interpretations of CCSVI, the team found that 21% of the MS group met two or more criteria and 20% of the non-MS group met the criteria. This difference between groups was not statistically significant.

Using more broad interpretations of CCSVI, the team found that 36% of the MS group met CCSVI criteria and 40% of the non-MS group met the criteria. The difference between the groups was not statistically significant. The team concludes that its observations do not support an increased prevalence of CCSVI in MS and do not support a role of CCSVI in the MS disease process. They also suggest that differences in published findings likely relate to how ultrasound assessments are conducted and interpreted. ("No Association of Chronic Cerebrospinal Venous Insufficiency with Multiple Sclerosis" Robert J Fox, Claudiu Diaconu, Leasa Baus, Alia Grattan, Irene Katzan, Jar-Chi Lee, Larry Raber, Alexander Rae-Grant, Sneha Ramesh, Mei Lu, Esther SH Kim. Can J Neurol Sci. 2015; published in Early View on July 21, 2015.) Read the open-access paper.  

October 2013: Team publishes results from a small study related to hydration levels and CCSVI assessments.

June 2013: Dr. Fox requested an extension to this grant to finish analyzing scans and prepare results for publication in scientific journals. He has presented preliminary results at several medical conferences.

September 2012: Researchers continue with their progress in the seven Society-funded CCSVI studies in MS. Read about the most recent progress.

January 2012: Dr. Fox’s team continues to use MR venography, ultrasound, MRI and clinical measures in people with MS or who are at risk for MS (CIS) and comparison groups to evaluate vein drainage. The ultrasound team, which underwent training in the technique originally used by Dr. Zamboni, found several aspects of the published methodology ambiguous, and they have standardized the protocol and analysis to achieve consistent results.

Early on they identified physiological and technical factors that can complicate screening for vein blockages using ultrasound, including that heartbeat irregularities, stages of breathing, head position and pressure applied by the operator could alter results; and that the state of hydration of the subject (whether they drank adequate amounts of fluids) might impact results of several of the criteria used to determine CCSVI.

The team reported at the international ECTRIMS/ACTRIMS congress in October 2011 preliminary results of ultrasound assessments. Pooling the results of the ongoing, blinded study of CCSVI in MS and non-MS controls, they reported results from the first 20 subjects, finding that 6 (30%) met criteria for CCSVI, four subjects met no criteria, and none met criteria for reverted postural control of cerebral venous outflow. Nine subjects (45%) had a flap and/or septum/abnormal valve. Identifi¬cation of deep cerebral vein reflux depended upon the ultrasound technique. They noted that this finding highlights the importance of ultrasound methodology in performing and interpreting deep cerebral vein assessments. (P1104 – “Ultrasound assessment of chronic cerebrospinal venous insufficiency.” R. Fox, L. Baus, C. Diaconu, A. Grattan, I. Katzan, S. Kim, M. Lu, L. Raber, A. Rae-Grant)

At the same ECTRIMS/ACTRIMS meeting, the team shared preliminary results from an ongoing study of vein structure in autopsy specimens from seven people who had MS in their lifetimes, compared to six people who did not have MS. In this unblinded study, they identified abnormalities inside the vein tubes (lumen) that drain the brain and found a variety of structural abnormalities and anatomic variations in both groups. However, they reported higher frequency of abnormalities in those who had MS (2 abnormalities in 2 out of 6 controls versus 9 abnormalities in 6 out of 7 MS patients). They noted that MR venography may be less effective than ultrasound for identifying these venous abnormalities, and that ultrasound that examines only vein wall circumference may miss some intraluminal abnormalities. (Abstract 134 – “Anatomical and histological analysis of venous structures associated with chronic cerebro-spinal venous insufficiency.” C. Diaconu, S. Staugaitis, J. McBride, C. Schwanger, A. Rae-Grant, R. Fox)

Quotes from Dr. Robert Fox

  • “A series of recent publications have indicated that some patients with MS have abnormal veins in the neck and chest. The same authors have also suggested that these abnormal veins could cause some or all of the symptoms of MS. To date this work has not been independently reproduced by other researchers, a step which is key in any new scientific discovery.”
  • “We will study a group of patients with MS and see if we find the same vein abnormalities. At the conclusion of these studies, we will have a clear understanding of the relevance of CCSVI to multiple sclerosis.”