Chronic cerebrospinal venous insufficiency (CCSVI)
Chronic cerebrospinal venous insufficiency (CCSVI) is a term coined by Dr. Paolo Zamboni of the University of Ferrara in Italy. CCSVI describes a theory in which the veins in the head and neck are narrowed or blocked, and therefore unable to efficiently remove blood from the central nervous system. More specifically, the pressure caused by the build-up of blood in turn causes reflux of blood back into the central nervous system through new blood vessels which develop when the others are not working properly. Dr. Zamboni suggested that because these compensatory blood vessels don't have the same structural integrity as larger veins, they tend to leak blood into the surrounding tissue, depositing iron in the central nervous system and thereby triggering an immune response associated with multiple sclerosis.
In 2009, Dr. Zamboni went on to describe a list of criteria that a person had to meet in order to have CCSVI. He also published results from a study which demonstrated that CCSVI was present in all the individuals with MS that he examined. Following the release of Dr. Zamboni’s findings, additional studies have been conducted world-wide, the results of which have led to conflicting conclusions. Some researchers have shown an association between vein abnormalities and MS while others have not. Overall research suggests that there is no association between CCSVI and MS.
The proposed treatment for CCSVI, sometimes referred to as “liberation therapy”, is an angioplasty procedure, which involves opening blocked or narrowed veins by inflating a small balloon or inserting a stent to allow for better blood flow and improve drainage of blood from the brain. The procedure is not approved in Canada.
MS Society of Canada funds research on CCSVI and MS
In June 2010, the MS Society of Canada and the National MS Society (U.S.) jointly contributed over $2.4 million to support 7 research projects focused on the relationship between CCSVI and MS. All applications were reviewed by an international panel that included experts in interventional radiology, vascular surgery and neurology. The MS Society of Canada worked collaboratively with their American counterparts to assemble the reviewers, who assessed the scientific merit and feasibility of the proposed research, as well as the experience of the applicant teams.
At the same time, in 2010 the MS Society in conjunction with
the Canadian Institutes of Health Research (CIHR) established a working
group comprised of neurologists, imaging and vascular
specialists, ethicists and scientists who were tasked with
monitoring and identifying priorities around research related
to CCSVI and MS. The Scientific Expert Working Group
participated in a series of meetings, the last of which took
place on March 8, 2017. The purpose of the final meeting was to
discuss the preliminary results of the pan-Canadian phase I/II
clinical trial led by Dr. Anthony Traboulsee. A communication was
issued by the MS Society and CIHR on this meeting.
Using advanced imaging techniques and experimental design, those studies which were approved for funding evaluated the structure and function of veins draining the brain and spinal cord in people living with MS, and compared them to the structure and function of veins in healthy volunteers as well as people affected by other neurological diseases.
Researchers who led this work have reported data at major scientific conferences and in various peer-reviewed journals:
Dr. Fiona Costello and team at the Hotchkiss Brain Institute at the University of Calgary recently published a study in June 2014 exploring the validity of the CCSVI hypothesis by comparing venous anatomy and blood flow in people with MS compared to healthy individuals. The team used ultrasound and magnetic resonance venography, a procedure that generates detailed images and observes blood flow in the head and neck veins, to assess the proportion of venous abnormalities between individuals with MS and healthy controls. No differences in the proportion of abnormalities in venous blood flow between the two groups were found. The study showed no association between CCSVI and MS.
Costello F et al. Validity of the diagnostic criteria for chronic cerebrospinal venous insufficiency and association with multiple sclerosis. Canadian Medical Association Journal 2014 June 2 [Epub ahead of print]
Dr. Anthony Traboulsee and team at the University of British Columbia, Vancouver Coastal Health, and University of Saskatchewan published a study reporting on the prevalence of CCSVI in people with MS, their unaffected siblings and healthy control volunteers. Ultrasound and catheter venography were used to identify signs of CCSVI. Analyses revealed no association between CCSVI and MS.
Traboulsee AL et al. Prevalence of extracranial venous narrowing on catheter venography is similar in people with MS, their siblings, and unrelated healthy controls: a blinded case-control study. The Lancet; 2014 383(9912): 138-145.
Dr. Brenda Banwell, former Director of the Pediatric MS Clinic at the Hospital for Sick Children in Toronto and currently Chief of Neurology at the Children’s Hospital of Philadelphia, and colleagues examined whether pediatric MS patients displayed vein abnormalities at an early age. This group of researchers used ultrasound and MRI technology to examine signs of CCSVI in children with MS and controls of the same age. Findings indicated that venous outflow was intact in children with MS and CCSVI was not found to be associated with MS. The findings published by Dr. Banwell and colleagues argue against CCSVI as a causative factor of MS.
Laughlin S et al. No Evidence for Impairment of Venous Hemodynamics in Children or Young Adults with Pediatric-Onset Multiple Sclerosis. American Journal of Neuroradiology; 2013 34(12):2366-2372.
Dr. Jerry Wolinsky and colleagues at the University of Texas Health Science Center , used a number of imaging techniques to examine signs of CCSVI in MS patients and healthy controls. Results from their study did not show altered venous flow in people with MS, suggesting venous outflow likely does not contribute to MS.
Brod SA et al. Chronic cerebrospinal venous insufficiency: makes multimodal imaging assessment. Multiple Sclerosis Journal; 2013 19(11): 1499-507.
Dr. Robert Fox and his team at the Cleveland Clinic used ultrasound, venography and MRI techniques along with clinical measures to evaluate vein drainage in those with MS, those at risk for MS and control groups. Recently published in The Canadian Journal of Neurological Sciences, the study reported no association between CCSVI and MS. The researchers emphasize that the use of different imaging tools and variation in the interpretation of data may explain conflicting results in CCSVI-related studies.
Fox RJ et al. No Association of Chronic Cerebrospinal Venous Insufficiency with Multiple Sclerosis. The Canadian Journal of Neurological Sciences Inc. 2015 August 2 [Epub ahead of print]
Dr. Carlos Torres and group at the Ottawa Hospital have employed ultrasound and powerful MRI technology to examine vein anatomy and assess iron deposits in MS patients and healthy controls. The research team is trying to provide a better understanding of normal variations in vein anatomy and examine the possible role of iron pooling in patients with blocked veins.
In a recently published study in the journal European Radiology, Dr. Torres and his team found that variations in vein anatomy, such as asymmetry and narrowing of the internal jugular veins, were quite common in people living without MS. These findings suggest that variations in vein anatomy are not unique to people living with MS and do not support the theory that CCSVI is associated with MS.
Torres C et al. Extracranial Venous abnormalities: A true
pathological finding in patients with multiple sclerosis or an
anatomical variant? Eur Radiol. 2016 Mar 24. [Epub ahead of
Dr. Aaron Field and team at the University of Wisconsin School of Medicine and Public Health have used ultrasound techniques as well as alternative imaging methods to generate detailed images of head and neck veins in 112 people with both early and late stages of MS, as well as 56 healthy controls and 56 controls with other neurological conditions.
The team used three different imaging techniques (Doppler ultrasound, four-dimensional flow magnetic resonance imaging, and contrast-enhanced magnetic resonance venography) to test whether narrowing of the head and neck veins was associated with MS. None of the techniques uncovered a significant difference in vein narrowing between the MS and control groups, providing additional evidence that CCSVI is likely unrelated to MS.
Schrauben EM et al. Four-dimensional flow magnetic resonance imaging and ultrasound assessment of cerebrospinal venous flow in multiple sclerosis patients and controls. J Cereb Blood Flow Metab. 2016. [Epub ahead of print].
Other published studies on CCSVI and MS
- Findings published in July 2014 from a two-phase clinical trial led by Drs. Adnan H. Siddiqui, Robert Zivadinov and Ralph H.B. Benedict indicate that while venous angioplasty is relatively safe, it is not an effective treatment for MS and may worsen underlying disease activity.
- A Canadian study published by Dr. Rodger et al. in 2013 examined the relative prevalence of venous abnormalities in MS and control patients using ultrasound and MRI techniques. Results revealed no evidence for CCSVI and no abnormalities in venous structure and blood flow in people with MS. The results from this study provide compelling evidence against the involvement of CCSVI in MS.
- A multi-centre Italian study, referred to as CoSMo, is one of the largest studies to date exploring CCSVI in people with MS. Results of the study, published in September 2013, reported no differences in the prevalence of CCSVI between people living with MS and those without MS or affected by other neurological diseases. The study was conducted in 35 MS centers across Italy and included 1767 participants.
- In April, 2011, Dr. Zivadinov published a study in Neurology, which reported an increased prevalence of CCSVI in Mhere S, but was considerably lower than the prevalence reported by Dr. Zamboni in 2009. The study points against CCSVI having a primary causative role in the development of MS
- For a complete list of CCSVI study findings, visit MS Society of Canada updates
Pan-Canadian CCSVI Clinical Trial
The placebo-controlled, double-blind phase I/IIpan-Canadian CCSVI clinical trial launched in 2012 has released preliminary unpublished results.
The primary purpose of the clinical trial was to evaluate the safety of venoplasty (a procedure that involves inserting a balloon that widens the veins and improve blood flow) versus placebo in people with multiple sclerosis who displayed signs of chronic cerebrospinal venous insufficiency (CCSVI). A secondary outcome of the study was to establish the efficacy of this procedure in treating MS both in the short and long term.
A total of 104 participants from Vancouver, Winnipeg, Montreal and Quebec City, with signs of CCSVI as established from ultrasound and venography, were randomized: 49 participants received venoplasty and 55 received the placebo. Participants crossed over to the treatment or placebo arm at 48 weeks, for an additional 48-week treatment period. Preliminary results at 48 weeks showed no statistical difference in outcomes between the two study groups in terms of MRI measures, clinical assessments of MS symptoms and patient self-assessments. The research team concluded that venoplasty is ineffective as a treatment for people living with multiple sclerosis.
What has been learned?
Research findings to date indicate that treating vein narrowing is not effective in treating MS.
A growing body of evidence on the prevalence of CCSVI among people living with MS suggest that CCSVI is not associated with MS, and based on recent preliminary findings, venoplasty was shown to be ineffective as a treatment for MS. Researchers suggest that continued discrepancies in results between studies may be attributed to inconsistencies in imaging techniques, training of personnel, and interpretation of results. As well, some studies challenge the validity of the proposed diagnostic criteria for CCSVI.
There are potential complications associated with CCSVI-related procedures.
As with any invasive procedure, there is risk. There is general agreement that balloon angioplasty has less risk than the treatment of CCSVI involving stents. Please read our Risks and Safety section for more detailed information.
Individuals who have obtained CCSVI-related procedures are self-reporting quality of life benefits (e.g., less fatigue, warmer limbs, better balance).
These self-reported benefits are often of limited duration.
The MS Society acknowledges people living with MS will want more information about the results of the Canadian CCSVI clinical trial.
Results of the pan-Canadian CCSVI trial are currently being prepared for publication in a peer-reviewed journal and will provide a better understanding of the effects of venoplasty in MS. Although the timeframe for the publication is unknown, the MS Society will provide detailed findings once the study has been published. More information about the clinical trial can be found here.