CCSVI Update

Background Information on CCSVI and MS
Many questions still surround the possible connection between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS). CCSVI is a complex condition involving changes in blood flow from the brain back to the heart, which some researchers theorize could possibly lead to activation of the immune system, excess iron deposits, loss of myelin, and other nervous system damage.

With CCSVI, the veins located on the outside of the brain (extracranial cerebrospinal veins) – those designed to transport blood from the brain back to the heart – collapse and/or become blocked, a condition known as “stenosis.” This can be caused by issues or malformations such as twisted veins, flaps in the veins, inverted valves, and other changes that cause these veins to become narrowed. Studies have shown that when the normal blood flow is altered, especially when the flow of blood is reversed, the body may react with an inflammatory response.

Since the first description of MS by Charcot in the mid-1800s, MS lesions have been known to be “venocentric,” or occurring around blood vessels. More recent studies have also shown that with MS, iron stores may be found constantly encircling venous walls. Additionally, iron overload is found in MS lesions, although this is a feature also observed with other neurodegenerative diseases.

With CCSVI, reduced blood flow is seen in the internal jugular (IJV) veins and the azygous (AZY) veins. Reduced blood flow is observed in these veins to varying degrees in the head, neck, and spinal cord. This condition requires a combination of veins to be collapsed.

Two years ago, the results of a pilot study were published in an article written by Paolo Zamboni et al., “A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency,”Journal of Vascular Surgery , December 2009, vol.50(6), 1348-1358. In this article, lead investigator Dr. Zamboni describes an experimental endovascular procedure to widen the narrowed or blocked veins in a study of 65 MS patients (endovascular is defined as “within a blood vessel”). Some have referred to this as the “liberation procedure,” although this is misleading and no longer used to describe the endovascular treatment of venous obstructions. The purpose of this study was to evaluate the safety and clinical outcome of this procedure in the treatment of CCSVI with MS.

In this study, percutaneous transluminal angioplasty (PTA) was performed using a tiny balloon inserted into an affected vein. Each vein is accessed from a remote location in the groin, where a very thin catheter is threaded along a vein and through the heart (potentially causing a change in heart rhythm). After reaching the narrowed, blocked, or collapsed vein, the balloon is then inflated and deflated several times before it is removed. According to the article, no serious adverse events resulted from the procedure, although restenosis (where veins narrowed again) occurred in the IJV vein of 47 percent of the patients treated for IJV stenosis. Researchers state that a stent might be a logical solution, but stents of the correct size for IJVs are not readily available at this time.

The article also notes that in terms of results, individuals with relapsing-remitting MS (RRMS) showed a “highly statistical improvement at 18 months” on the Multiple Sclerosis Functional Composite (MSFC). Progressive patients – individuals with secondary-progressive MS (SPMS) or primary-progressive MS (PPMS) – showed a “significant but limited improvement” at six months, but no improvement with respect to baseline at 18 months. With regard to relapses in RRMS patients, 27 percent of these individuals were relapse-free during the year prior to the endovascular procedure. Postoperatively, 50 percent of the individuals with RRMS were relapse-free as of the 18-month follow-up time. However, the lack of an MS control (placebo) group limits interpretation, since many MS trials have shown that the placebo-treated group may also improve in certain outcomes. The practice effect of repeated testing may have influenced the positive outcomes as well.

Anecdotally, some individuals with MS who have undergone a procedure to widen narrowed or blocked veins (receiving either angioplasty or stents), and who did not have complications, feel that they are experiencing some improvement in certain symptoms. Typically, these might include improvements in fatigue, heat sensitivity, sleep, concentration, and balance. Over time, some even attribute improvements in bladder issues, mobility, flexibility, and other symptoms to the procedure. Conversely, some patients did not see any improvement following the procedure. This is why conducting clinical trials is so important – so the medical community may learn the facts about CCSVI and MS.

Research Challenges with CCSVI and MS
Since the results of Dr. Zamboni’s pilot study were published, the CCSVI theory in MS has received a great deal of attention from the MS community, the medical community, and the media. While a small number of universities and medical groups are planning or conducting initial studies on the diagnosis and potential treatment of CCSVI in MS, many MS patients are seeing vascular surgeons or interventional radiologists on their own to undergo speculative diagnostic and corrective procedures. Additionally, vascular specialists and neurologists are not always in complete agreement about the presence of this condition in patients with MS and the value of the potentially-risky invasive procedures used to treat this condition.

The problem faced by the medical community in researching the CCSVI theory is two-fold. First, researchers need to prove whether or not CCSVI occurs more often in individuals with MS versus the general population, and if so, how it may be related to the disease. For example, researchers would need to know if CCSVI is a result of a malformation with the veins and surrounding tissues from birth, or if it might develop later in life. Researchers would need to find out if this condition contributed to the development of MS, or if it occurs as a result of MS, or if it is even related in any way. Further complicating the issue is the fact that no single procedure or protocol has been identified for its diagnosis, and a wide range of results can occur (from 0 to 100 percent) when using different imaging equipment, techniques, and technicians to diagnose CCSVI.

The second problem in researching the CCSVI theory involves treating the condition, if it does in fact exist in individuals with MS. Dr. Zamboni and many others have used an angioplasty type of treatment for opening closed veins through a balloon that is inflated several times and then removed. This however poses the problem of veins closing in the months following the procedure. Other doctors are inserting stents into the closed veins. Anytime a stent is used to correct a problem in a vein, it poses more serious risks. These include the potential for excessive bleeding (a risk posed by the blood thinners used after surgery to avoid blood clots), as well as the stent dislodging and moving to another area of the body – possibly requiring immediate life-saving surgery. Even with the stents, scar tissue can sometimes form and clog the stent. Following the development of a safe procedure for correcting CCSVI, doctors would still need to determine if and to what extent patients may benefit from such a procedure, and if the benefits outweigh the risks.

While research into this theory may seem painstakingly slow, medical experts have been responding to the questions from the MS community and the news media. Several studies are being conducted in countries around the world in an attempt to find answers to the issues noted in the preceding paragraph.

More than 50 articles on the subject have been published in peer-reviewed magazines over the past two years, although many present conflicting results – with some finding significant proof of CCSVI in MS patients, and others finding no evidence – a problem often blamed on the lack of a protocol for specific diagnosis. Doctors are also looking at possible relationships between CCSVI and known risk factors for MS, including Epstein-Barr virus, genetic factors, Vitamin D deficiency, and cigarette smoking.

The first objective is to determine if CCSVI occurs in individuals with MS more frequently than in members of the general population. Small studies are looking into the success of diagnosing CCSVI through noninvasive imaging technology and procedures, such as Doppler sonography, magnetic resonance venography (MRV), and computerized tomography venography (CTV). Researchers are also testing invasive imaging technology and procedures, such as catheter venography and intraluminal sonography. While each of these procedures offers certain advantages and disadvantages, researchers also know that a wide range of results can occur from variations in how the operator performs such testing. Experts agree that: (1) a strict protocol for testing will need to be developed; (2) a combination of tests may be required for a confirmed diagnosis of CCSVI; and (3) the operators performing these tests will need specialized training for consistent results.

Another significant hurdle in these studies is the issue of blinding. The researchers, doctors, and operators performing the diagnostic tests need to be blinded as to who has MS and who is a member of the control group, or the results could be biased. In an effort to address these problems, study participants are instructed not to disclose any information about their health to those administering the diagnostic tests. The operator must then leave the room, while other personnel is brought in to assist individuals when changing positions, so the operator does not know if the study participant has any mobility issues.

After a positive diagnosis is made, blinding is also involved in the studies where corrective procedures are performed. This means that a portion of the study participants – those in the control group – will go through a sham procedure, where they will have a catheter with a balloon or stent threaded through the groin to the affected vein in the head or neck, but no changes will be made to the vein. Following the procedure, those evaluating the results will be blinded as to who received the real procedure and who did not.

Current Studies and CCSVI Registry
Clearly, researchers have a great deal of work ahead to find answers to these many questions relating to CCSVI and MS. However, the work has begun. To follow is a list of some of the current studies in CCSVI and MS. All of these studies may be found by visiting www.clinicaltrials.gov and searching for “CCSVI AND multiple sclerosis.” Some of the studies are listed as still recruiting participants, but interested individuals should check with the contact person listed for the most current information on recruitment.

Community Care Physicians, P.C. is sponsoring a study titled, “Evaluation of Angioplasty in the Treatment of Chronic Cerebrospinal Venous Insufficiency ( CCSVI ) in Multiple Sclerosis” to determine if venous angioplasty is an effective treatment for CCSVI in MS. The study is enrolling 130 participants and is scheduled from August 2010 to August 2013 (with final data for the primary outcome collected in August 2012). The studies are being conducted at two locations: Albany , New York and Latham , New York .

The “Observational Study of the Prevalence of CCSVI in Multiple Sclerosis and in Other Neurodegenerative Diseases (COSMO)” is being conducted at more than 40 Universities and medical centers in Italy . Sponsored by Fondazione Italiana Sclerosi Multipla in collaboration with Opera Srl, the study is scheduled from December 2010 to February 2012 (with final data for the primary outcome collected in November 2011). The study will evaluate the prevalence of CCSVI and of other malformations of the veins in different forms of MS and in other neurological conditions. Researchers plan to enroll at least 1,200 adults with MS in the study, as well as 400 healthy subjects and 400 subjects with other neurodegenerative diseases.

Genetic Disease Investigators in collaboration with Optos plc is still recruiting patients for its study titled, “Vascular Fundus Changes in Patients With High Probability of Chronic Cerebrospinal Venous Insufficiency ( CCSVI ).”The study is taking place at Total Eye Care in Colleyville , Texas and expects to recruit 60 patients for its study running from May through November 2011 ( with final data for the primary outcome collected at that time). The study description notes, “In the small subset of EDS [Ehlers-Danlos Syndrome, a disorder of connective tissue] and multiple sclerosis patients seen at Total Eye Care, the investigators have noticed a vascular irregularity (using the optomap® and examining the results under high magnification) which offers credence to the theory of CCSVI.”

The Vascular Group, PLLC in collaboration with Center for Vascular Awareness is sponsoring a study titled, “Study To Evaluate Treating Chronic Cerebrospinal Venous Insufficiency ( CCSVI ) in Multiple Sclerosis Patients.”Held at a single location in Albany , New York , it planned to enroll 600 participants for its study running from August 2010 through October 2011 ( with final data for the primary outcome collected at that time). The purpose is stated as ” to evaluate the safety, feasibility and efficacy of percutaneous transluminal angioplasty in treating extracranial venous obstructive lesions, and its influence on the clinical outcomes of Multiple Sclerosis (MS) patients that have been found to have chronic cerebrospinal venous insufficiency ( CCSVI ).”

Euromedic Specialist Clinics is sponsoring the study, “Endovascular Treatment for Chronic Cerebrospinal Venous Insufficiency ( CCSVI ),” enrolling 1,000 participants and running from March 2010 to October 2011 (with final data for the primary outcome collected in October 2011). Taking place at a clinic in Poland , the description states, “The aim of this study is to assess the efficacy of endovascular treatment (balloon angioplasty and/or stenting) for the improvement of clinical symptoms in multiple sclerosis patients measured by Expanded Disability Severity Score (EDSS), Multiple Sclerosis Impact Scale-29 (MSIS-29), Fatigue Severity Scale (FSS) and heat intolerance.”

One of the studies listed is sponsored by the Hubbard Foundation, titled, “Multi -center Registry for CCSVI Testing and Treatment.” Located in San Diego , California , the purpose is to develop a registry of patients evaluated and treated for CCSVI, looking at changes in quality of life. The study has an estimated enrollment of 1,000 participants and will run from September 2010 through September 2015 . The Hubbard Foundation is looking for doctors and medical facilities that perform CCSVI testing and treatment to register under their IRB (Institutional Review Board) approval to conduct research and provide the outcome of those tested and treated for CCSVI.

The S. Anna Hospital (at the University of Ferrara , in Ferrara , Italy ) is conducting a study titled, “BRAVE-DREAMS (BRAin VEnous DRainage Exploited Against Multiple Sclerosis ).” It plans “To assess in a double-blinded randomized-control trial (RCT) study design safety and effectiveness of balloon angioplasty of the main extracranial and extravertebral veins in multiple sclerosis (MS) associated to chronic cerebrospinal venous insufficiency ( CCSVI ).” The study plans to enroll 679 participants and is scheduled from July 2011 to July 2013 (with final data for the primary outcome collected in April 2013).

In June 2010, the National MS Society and the MS Society of Canada committed more than $2.4 million to support seven new research projects focusing on the role of CCSVI in MS. These include the following research teams and leaders:

• Dr. Brenda Banwell, The Hospital for Sick Children, Toronto, Ontario : studying vein abnormalities in children and teenagers who have MS, and healthy controls of the same age
• Dr. Fiona Costello, Hotchkiss Brain Institute, University of Calgary, Calgary , Alberta : examining a cross-section of people with MS compared to other neurological diseases and healthy volunteers
• Dr. Aaron Field, University of Wisconsin School of Medicine and Public Health, Madison: using magnetic resonance (MRI) scans to generate detailed images of the head and neck veins in people with early and later MS, healthy volunteers, and controls with other neurological conditions
• Dr. Robert Fox Cleveland Clinic, Cleveland: studying people with MS or who are at risk for MS (CIS) and comparison groups including healthy volunteers and people with brain atrophy (shrinkage) from Alzheimer’s disease
• Dr. Carlos Torres, The Ottawa Hospital, University of Ottawa, Ontario: employing powerful MRI technology to explore vein anatomy and assessing for iron deposits in the brains of people with MS and in age-matched healthy volunteers
• Dr. Anthony Traboulsee, UBC Hospital MS Clinic, UBC Faculty of Medicine and Dr. Katherine Knox, Saskatoon MS Clinic, University of Saskatchewan : studying the prevalence of CCSVI in people with MS and controls without MS, using catheter venography, ultrasound, and magnetic resonance venography
• Dr. Jerry Wolinsky, University of Texas Health Science Center at Houston : replicating the ultrasound methods used by Dr. Zamboni to investigate the association of CCSVI with major clinical types of MS and in non-MS control groups

Closing Remarks
As with any unproven theory and treatment, interested patients are strongly encouraged to first talk with their doctor. If appropriate, individuals may choose to seek potential diagnosis and treatment by participating in an approved clinical trial. Without a tested and proven protocol for the diagnosis and treatment of CCSVI, individuals could be putting themselves at risk. In July 2011, news arrived of a second individual with MS from Canada who sought treatment outside of the country and died due to complications. Although such tragic results are not common, individuals considering this type of procedure should be aware of the risks involved.

MSAA enthusiastically but cautiously supports the investigation of any plausible causes and treatments for MS, striving to communicate such research to the MS community as soon as any information becomes available. However, at the same time, MSAA’s policy is to consider patient safety as the top priority – recognizing that all prospective theories and experimental treatments need to be thoroughly studied through rigorous clinical trials.

For information on the specifics of CCSVI, and to learn about patient experiences, readers may visit the CCSVI Alliance’s website at www.ccsvi.org.

Additional resource for this article:

Robert Zivadinov, et al., “Chronic cerebrospinal venous insufficiency in multiple sclerosis: diagnostic, pathogenetic, clinical and treatment perspectives,” Expert Review of Neurotherapeutics , 11(9), 1277-1294 (2011)

Written by Susan Wells Courtney, MSAA Senior Writer
Reviewed by Jack Burks, MD, MSAA Chief Medical Officer