Status of Research Projects Supported by a Collaborative Initiative by the National MS Society and the MS Society of Canada
In 2009, the National MS Society (USA) and the MS Society of Canada collaborated to commit over $2.4 million to support the following 7 research projects focusing on the role of chronic cerebrospinal venous insufficiency (CCSVI) in MS. To date, none of the published results support a relationship between CCSVI and MS.
Project Title: “CCSVI and its relationship to MS”
Jerry S. Wolinsky, MD
University of Texas Health Science Center at Houston
Using a comprehensive approach, this team first attempted to replicate the ultrasound methods used by Dr. Zamboni in people with all major clinical types of MS, compared with people in various non-MS control groups. Then, they sought to determine whether the findings could be validated by noninvasive imaging techniques, such as an MRI machine using a powerful magnet. The team included experts in MS, as well as experts from other fields such as vascular disease and venous imaging.
The team’s findings lend no support for altered venous outflow dynamics as common among MS patients, nor do they likely contribute to the disease process. They studied 276 people: 206 with MS and 70 non-MS. Overall, 82 subjects (29.7%) fulfilled 1 of 5 NS criteria proposed for CCSVI; 13 (4.7%) fulfilled 2 criteria required for diagnosis, and none fulfilled >2 criteria. CCSVI as defined by Zamboni criteria was present in 7.14% of non-MS and 3.88% of MS patients, a difference that is not statistically different. No significant differences emerged between MS and non-MS for extracranial or intracranial venous flow rate.
“Chronic cerebrospinal venous insufficiency: case-control neurosonography results.”
Andrew D. Barreto MD, Staley A. Brod MD, Thanh-Tung Bui MD, RVT, and others. ANN NEUROL 2013;73:721–728.
"Chronic cerebrospinal venous insufficiency: masked multimodal imaging assessment."
Brod SA1, Kramer LA, Cohen AM, Barreto AD, Bui TT, Jemelka JR, Ton K, Lindsey JW, Nelson F, Narayana PA, Wolinsky JS. Mult Scler. 2013 Oct;19(11):1499-507. doi: 10.1177/1352458513494493. Epub 2013 Jul 4.
Project Title: “A Multi-Modal Assessment of Chronic Cerebrospinal Venous Insufficiency”
Robert J. Fox, M.D.
Cleveland Clinic Foundation
The team concluded 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. Final results were published in 2015 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.
"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.
Project Title: “Study of CCSVI in MS using quantitative time-resolved 3D MRV”
Aaron Field MD, PhD
University of Wisconsin School of Medicine and Public Health
Dr. Field’s team is using alternative imaging methods, in addition to the ultrasound method used in Dr. Zamboni’s original reports, to conduct a controlled study of the CCSVI hypothesis in people with MS. This study uses an MRI scanner to generate highly detailed images of the head and neck veins in 112 people with early and later MS, 56 controls without MS, and 56 people with other neurological conditions. The team is also measuring the rate at which blood flows in the veins.
The team used three different imaging techniques in a large group of people with MS, people without MS, and people with other neurological diseases. This study tested the CCSVI hypothesis with three complementary imaging techniques (Doppler ultrasound, four-dimensional flow magnetic resonance imaging and contrast-enhanced magnetic resonance venography. They found no significant differences between test groups in terms of stenosis, and no link or causal relationship between internal jugular venous stenosis and MS.
“Four-dimensional flow magnetic resonance imaging and ultrasound assessment of cerebrospinal venous flow in multiple sclerosis patients and controls.”
Eric M Schrauben, Sarah Kohn, Jacob Macdonald, Kevin M Johnson, Mark Kliewer, Sam Frost, John O Fleming, Oliver Wieben and Aaron Field.
Journal of Cerebral Blood Flow & Metabolism. Published online before print June 30, 2016, doi: 10.1177/0271678X16657345
Project Title: “Cerebral Venous Hemodynamics in Pediatric MS”
Brenda Banwell, MD
Formerly at The Hospital for Sick Children
Dr. Banwell, a noted expert in pediatric MS, assembled a team to study CCSVI in pediatric MS patients – a population where the disease process is at a very early stage, and where advanced age and other health conditions that might affect blood flow did not exist.
In 2013 the team published results of its study which found no difference in arterial and venous blood flow rate between 26 adolescents with MS and 26 age-matched controls without MS. Additional findings with similar conclusions were published in 2014.
“No evidence for impairment of venous hemodynamics in children or young adults with pediatric-onset multiple sclerosis.” Laughlin S, Macgowan CK, Traubici J, Chan K, Khan S, Arnold DL, Marrie RA, Banwell B.
AJNR Am J Neuroradiol. 2013 Dec;34(12):2366-72. doi: 10.3174/ajnr.A3661. Epub 2013 Jul 18.
“Cerebral arterial and venous blood flow in adolescent multiple sclerosis patients and age-matched controls using phase contrast MRI.”
Macgowan CK, Chan KY, Laughlin S, Marrie RA, Banwell B.
J Magn Reson Imaging. 2014 Aug;40(2):341-7. doi: 10.1002/jmri.24388. Epub 2013 Sep 30.
Project Title: “Determining the relationship between CCSVI and MS”
Fiona Evanne Costello, MD, FRCP
Hotchkiss Brain Institute
Faculty of Medicine, University of Calgary
Dr. Costello’s team examined a cross-section of 120 people with MS compared to 60 healthy controls, seeking linkages between vein abnormalities and different aspects of MS activity and tissue damage.
The team published results in 2014. They detected no differences in the proportion of venous outflow abnormalities -- as measured by ultrasonography or gadolinium-enhanced magnetic resonance venography -- between 120 people with MS and 60 controls without MS. This study also revealed significant methodologic concerns in the proposed diagnostic criteria for CCSVI.
“Validity of the diagnostic criteria for chronic cerebrospinal venous insufficiency and association with multiple sclerosis.”
The prevalence of incidental findings in multiple sclerosis patients.
Trufyn J, Hill MD, Scott JN, Modi J, Ciura V, and others. Can J Neurol Sci. 2014 Jan;41(1):49-52.
Project Title: “Chronic Cerebrospinal Venous Insufficiency in relation to Multiple Sclerosis”
Carlos Torres, MD
The Ottawa Hospital
Dr. Carlos Torres led a team employing powerful MRI and Doppler ultrasound technology to explore vein anatomy and look for iron deposits in the brains of 50 people who have MS and 50 age-matched healthy volunteers.
The team published results in 2016, finding that asymmetry of internal jugular veins (IJVs) appeared in 75% of the people they studied, regardless of whether they had MS or not. They found that stenosis (narrowing) and asymmetry of the IJVs was present in people without MS. Overall, they determined that their findings do not support the theory of CCSVI.
Extracranial Venous abnormalities: A true pathological finding in patients with multiple sclerosis or an anatomical variant?
Carlos Torres , Matthew Hogan, Satya Patro, Santanu Chakraborty, Thanh Nguyen, Rebecca Thornhill, Mark Freedman, Miguel Bussiere, Hamid Dabirzadeh and others. Eur Radiol. 2016 Mar 24. [Epub ahead of print]
Project Title: “Investigation into Venous Insufficiency in Multiple Sclerosis”
Anthony Traboulsee, MD
Medical Director, MS Clinic at UBC Hospital, Vancouver Coastal Health and University of BC
Katherine Knox, MD
Saskatoon MS Clinic, University of Saskatchewan
The team studied the prevalence of CCSVI in 200 people including those with MS and controls without MS, using catheter venography, ultrasound, and magnetic resonance venography. Unique to this study is the inclusion of family members, such as identical twins of MS patients who have not developed MS, in control groups.
The team published findings in 2013 suggesting no association between CCSVI and MS. They found that CCSVI occurs rarely in both people with MS and in people without MS. They also reported that extracranial venous narrowing of greater than 50% was a frequent finding in people with MS, unaffected siblings, and unrelated healthy controls.
Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study.
Traboulsee AL, Knox KB, Machan L, Zhao Y, and others. Lancet. 2014 Jan 11;383(9912):138-45. Epub 2013 Oct 9.
CCSVI Theory: Latest Findings Show No Association to Multiple Sclerosis