Chronic Cerebrospinal Venous Insufficiency (CCSVI) and Multiple Sclerosis (MS)

Part I: Defining CCSVI and Its Possible Involvement with MS
A great deal of media attention has been given recently to 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.

Please note that all of these findings should still be considered preliminary at this time. Further studies are needed to confirm the theories given in this writing.

Studies with Altered Blood Flow and Its Potential Effects
A leader in the current CCSVI research is Paolo Zamboni, MD, director of the Vascular Diseases Center at the University of Ferrara in Milan, Italy. He and others have been studying blood flow, inflammation, and iron stores in MS for several years. The results of Dr. Zamboni’s pilot study in Italy were presented at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) held in September 2009.

More recently, Zamboni and colleagues have published their treatment data of 65 MS patients who underwent an angioplasty type of procedure to potentially improve blood flow from the brain to the heart. This experimental procedure and the initial outcome data are explained later in this article.

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." As a result, blood leaving the brain must be rerouted through smaller vessels around these primary veins, referred to as "substitute circles." These ancillary veins, however, cannot transport the blood as quickly or efficiently as those larger ones designed for this purpose. Not only does the blood flow slow down, but the blood may also flow backwards (referred to as "reflux"), and studies suggest that both the reflux of blood as well as a pulsing (back and forth) flow may be unique to individuals with MS.

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. Of particular importance is the activation of surface adhesion molecules, which enable damaging immune-system cells (such as macrophages and T-cells) to cross the blood-brain barrier, infiltrate the central nervous system (consisting of the brain and spinal cord), and potentially injure brain tissue, myelin (the protective covering of the nerves), and nerve cells.

The proposed damage from CCSVI also involves an iron overload for individuals with MS. As with certain other neurodegenerative conditions, unusually high levels of iron may be present. Iron levels may be particularly high in the brain and spinal cord of individuals with MS. With CCSVI, where blood flow out of the brain is slowed down and even reversed, extra iron is believed to be deposited and stored in sites near these vessels.

How Iron Affects the Body
Iron is needed by all living things. In addition to maintaining cellular balance and enabling nerve cells to perform routine functions, iron forms tissues and blood vessels; it transports oxygen through the body via blood circulation; it enables nerve impulses to be transmitted; and is essential to the development of myelin and oligodendrocytes (which produce and maintain healthy myelin). Iron is deposited in varying amounts to the different cells within the body, according to their specific need for proper functioning.

While the benefits of iron in normal levels are clear – and critical for bodily function – conversely, too much stored iron can cause problems. For instance, as people age, iron is more likely to accumulate in the brain. Conditions such as Alzheimer’s disease and Parkinson’s disease can occur in connection with iron stores. The processes associated with excess iron in the body are very complex, but it has been characterized as, "…one of the most dangerous catalytic elements responsible for the neurodegenerative process." (Levenson and Tassabehji, 2004)

MS Lesions, Blood Flow, and Advanced Technology
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.

The reason why CCSVI and iron overload in MS is presently under investigation is two-fold. First, studies in recent years have been able to demonstrate altered blood flow from the brain in the course of MS. Second, the development of more sensitive technology – such as advanced MRI and Doppler ultrasound techniques – has allowed researchers to better evaluate and measure the capacity of cerebrospinal veins as well as iron stores in the brain.

The CTEVD Study
As a follow-up to the small, pilot study conducted in Italy by Dr. Zamboni, a larger study is now underway. Titled, "Combined Transcranial and Extracranial Venous Doppler (CTEVD) Evaluation in MS and related Diseases," this larger study is being conducted at the University of Buffalo in New York.

According to the University, "The main goal of the CTEVD study is to investigate the prevalence (frequency) of CCSVI in patients with multiple sclerosis (MS) when compared to healthy controls (HC) and controls with other neurological disorders (OND). Another important aim of the CTEVD study is to investigate the relationship between CCSVI and clinical, magnetic resonance imaging (MRI) and environmental-genetic outcomes in MS patients, HC, and controls with OND."

For more information, readers may go to www.buffalo.edu/news/10562 to view a press release from the University of Buffalo. Readers may also go to www.bnac.net/?page_id=517 for specific information on study enrollment at the University of Buffalo. For more details on the study, readers may send an email to the University of Buffalo at ctevd@bnac.net.

The internet link to the study information includes the criteria to participate in the study. The University also states that,"Currently, enrollment will be closed until late January 2010 in order to evaluate initial study results on first 500 enrolled subjects." Instructions are then given for anyone who would like to be considered for this study or any future studies. Individuals without internet access may contact MSAA’s Helpline consultants for assistance, at (800) 532-7667.

Cautionary Note
As with all medical theories, information must be considered preliminary until rigorous clinical trials can confirm any findings. Next, more research is needed to determine if such findings are actually related to the condition, and if so, if it is a cause or an effect of a condition.

At this point in time, CCSVI with iron overload is one of many theories which may help explain the MS process if confirmed. Until a confirmed, new treatment effect on MS is verified scientifically, MS patients should not change their treatment regimen without consulting their physician. The established disease-modifying therapies have been proven to slow disease activity, reduce exacerbations, and delay disability for many patients. Also, individuals should not reduce their iron intake – as iron deficiencies can cause more serious complications.

Part II: Experimental Treatment of CCSVI and Interpretation of Study Results
An Experimental Treatment Trial with Endovascular Widening of Narrowed and Blocked Veins

The Procedure
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. According to the study results presented in the December 2009 issue of the Journal of Vascular Surgery, "CCSVI is strongly associated with multiple sclerosis."

An experimental endovascular procedure was used to widen the narrowed or blocked veins in a study of 65 MS patients (endovascular is defined as "within a blood vessel"). Lead investigator Dr. Zamboni refers to this as the "liberation procedure." The purpose of this study was to evaluate the safety and clinical outcome of this procedure in the treatment of CCSVI with MS.

The 65 participants included 35 individuals with relapsing-remitting MS (RRMS), 20 with secondary-progressive MS (SPMS), and 10 with primary-progressive MS (PPMS). A number of criteria were used to select the patients, including a confirmed diagnosis of MS as well as CCSVI, normal kidney function, and RRMS patients who were taking FDA-approved disease-modifying treatments.

In this study, percutaneous transluminal angioplasty (PTA) was performed on the 65 MS patients by using a tiny balloon inserted into an affected vein. The veins were accessed from a remote location in the groin, and the balloon was threaded through a vein until reaching the affected areas. The balloon was first inflated, held for 30 to 60 seconds, and then deflated. This process was repeated several times in each affected vein before the balloon was removed.

The procedure was done as day surgery using a local anesthetic, and patients were released after four hours of postoperative observation. Other physicians at other institutions have used stents to open collapsed veins. Patients were given a preventative dose of heparin for three weeks following the procedure to reduce the risk of blood clots.

Safety and Vascular Study Results
According to investigators, the procedure was well tolerated, with no serious operative or postoperative complications. Six of the 65 patients reported postoperative headache that was temporary and went away on its own.

The theory contends that collapsed veins cause venous hypertension. Interestingly, prior to the procedure, venous pressure was not significantly higher than those without CCSVI blockages. Postoperatively, pressure was reduced.

A major issue in the months following the procedure was that restenosis (where veins narrowed again) occurred in the IJV vein of 47 percent of the patients treated for IJV senosis. This disappointing outcome occurred in the IJVs 16-times more frequently than in the AZY, and most often occurred at the eight-to-nine-month point following the procedure. Researchers state that a stent might be a logical solution, although dedicated devices of the correct size for IJVs are not readily available at this time. In other words, technical improvements may be needed in the future.

Four patterns of stenosis were observed, and researchers note that certain patterns appeared to be associated with the different types of MS. According to the published results, in 90 percent of the PPMS patients (9 of the 10), the stenoses were limited to the veins which drain blood from the spinal cord. The reduced blood flow in the spinal cord, which occurred in several locations, may explain why the patients with PPMS experienced less benefit from the procedure than those with RRMS.

Neurologic Study Results

According to the published report, RRMS patients showed a "highly statistical improvement at 18 months" on the Multiple Sclerosis Functional Composite (MSFC). Progressive patients (individuals with SPMS and PPMS), showed a "significant but limited improvement" at six months, but no improvement with respect to baseline at 18 months. The MSFC measures: leg function and ambulation through the Timed 25-Foot Walk; arm function and dexterity through the Nine-Hold Peg Test; and cognitive function through the Paced Auditory Serial Addition Test (PASAT). Specific subscale results were not reported.

With regards 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, which is a significant increase in the number of patients who did not experience a relapse (also referred to as an exacerbation, attack, or flare-up of symptoms).

However, the lack of an MS control 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.

All of the RRMS patients whose veins remained open were relapse-free following the procedure. However, the numbers are small and the overall annual relapse rate (ARR) for the entire RRMS group was not significantly affected, since this included those RRMS patients who had a restenosis of the IJVs. Nonetheless, this is encouraging preliminary data.

In terms of MRI results, the percentage of patients with active gadolinium-enhanced lesions at MRI was significantly reduced from 50 percent to 12 percent. However, the authors note that different MRI equipment was used, and this lack of consistency could have an effect on the actual outcome. Also, without an MS control group, regression to the mean may be a partial explanation for improvement.

Mental and physical quality of life measures, as determined by a 54-item questionnaire (the Multiple Sclerosis Quality of Life-54 Instrument), was significantly improved in the RRMS patients. For the individuals with progressive types of MS (SPMS and PPMS), a limited improvement was reported after the first six months, but not at the 18-month point. The RRMS patients were early in their disease course and were required to remain on disease-modifying therapies, which may also partially explain the improvement in the RRMS group.

Interpretation of Study Results from MSAA’s Chief Medical Officer

MSAA Chief Medical Officer Jack Burks, MD, points out the value of putting forth a new hypothesis such as this, which is both creative and encouraging. He also explains that "thinking out of the box" may be needed to develop future treatments. Dr. Burks adds, "Finding interesting data to support this hypothesis is intriguing. These mixed results in a small pilot study are not surprising and may lead to more precise findings in larger, scientific trials in the future.

"Over the past century, more than 100 proposed treatments for MS have reached this stage of development," Dr. Burks continues. "From here, scientifically valid, multi-center studies are needed to demonstrate efficacy without significant adverse effects. The CCSVI scientists recognize the need for these additional studies and are not recommending this procedure, except as part of future clinical trials."

Specifically, in an article from Medscape Medical News (dated December 3, 2009 and written by Susan Jeffrey), Dr. Zamboni emphasizes that "…the current report should be viewed as an interesting finding that urgently requires replication by other groups."

Dr. Burks explains, "Dr. Zamboni is not advising patients to rush out and have this procedure. I agree with his perspective. Additionally, in non-experienced hands, surgery may not be as safe as demonstrated by Dr. Zamboni. Changes in the surgical approach may be forthcoming (such as stents versus balloon catheterization). Future trial results may be better, with fewer incidences of restenosis.

"Many variables exist with most pilot studies. However, these studies often generate more specific hypotheses. Delineating patients who experienced restenosis versus those with continued venous patency (open veins) may prove very interesting. Adding an MS control group will add credibility to future studies.

"This procedure cannot be considered a cure at this time. Fifty percent of RRMS patients still had relapses after surgery. The specific relationship to relapses and restenosis is important. The researchers are planning the right steps. However, the results from future studies are needed before relevant conclusions and recommendations can be established."

Dr. Burks comments, "As with much of the research with MS, this study raises more questions than answers. While the surgery is aimed at opening blocked veins and returning normal blood flow, the resultant immunologic and chemical changes will need to be addressed in the future. Can returning normal blood flow from the brain stop the attack on myelin and nerve cells? Will it also remove excess iron stores from the central nervous system, or will another type of treatment be developed? Do iron deposits in the brain differ in areas affected by CCSVI versus areas with normal venous flow? Such questions present many exciting areas for further research."

The authors state the need for further scientific data, and they point out the shortcomings of this pilot study, which include:

• failure to maintain open blood vessels in about half of the patients with IJV stenosis
• a small number of patients
• lack of an MS control group
• mixed results
• open label design, which may inadvertently lead to bias
• the study was conducted at only one MS Center
• patients were required to stay on FDA-approved, disease-modifying therapies
• lack of consistency in MRI protocol

"In addition," Dr. Burks continues, "there appears to be less of an effect on people with progressive disease, who lack effective treatment options. This trial is also complicated by the fact that most of the positive results were demonstrated in RRMS patients, with minimal disease and on current DMTs. These medical treatments may have of themselves created dramatic positive results, with or without the venous insufficiency intervention.

"In light of these shortcomings, I would encourage MS patients to wait for scientific results before considering this unproven procedure as part of their own treatment. The current data does not justify the use of this procedure outside of clinical trials. I hear that some people with long standing MS are considering taking a loan to have this procedure done immediately. Some are even thinking of selling their homes to get the needed funds, which have been estimated at more than $80,000. If this hypothesis does not eventually end with a positive treatment effect, these patients will be left with their MS – and no home. Obviously, the investigators and I do not recommend this drastic action at this time."

Dr. Burk concludes, "We need to let the science proceed as planned and to wish the researchers much success. MSAA will continue to provide balanced updates as the research work progresses."

Written by Jack Burks, MD, MSAA’s Chief Medical Officer and
Susan Wells Courtney, MSAA’s Senior Writer and Creative Director

All media inquires should be addressed to Amanda Bednar, MSAA Public Relations Manager, at (800) 532-7667, extension 122 or via email: abednar@mymsaa.org

Resources:
Ajay vikram Singh and Paolo Zamboni, "Anomalous venous blood flow and iron deposition in multiple sclerosis,"Journal of Cerebral Blood flow & Metabolism (2009) 29, 1867-1878, doi:10.1038; published online September 2, 2009.

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.

Susan Jeffrey, "Endovascular Treatment of Cerebrospinal Venous Insufficiency Safe, May Provide Benefit in MS," Medscape Medical News, December 3, 2009.

University of Buffalo ‘s press release, "Buffalo neurologists investigate possible new underlying cause of MS," available at www.buffalo.edu/news/10562 .