Apr 09, 2010
Updated November 19, 2010
Summary: 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. Based on the results of his initial preliminary findings published in June 2009 from a study of approximately 65 patients, Dr. Zamboni and colleagues who have begun investigating CCSVI state that this pilot study warrants a subsequent larger and better controlled study to definitively evaluate the possible impact of CCSVI on the disease process in MS. On June 11, 2010, the US National MS Society and MS Society of Canada announced a commitment of over $2.4 million to support 7 initial CCSVI grants to determine the role of CCSVI in the MS disease process. Further studies are also taking place at centers including University at Buffalo Medical Center and the Center for Vascular Awareness in Albany, NY.
Dr. Zamboni and others have also recommended larger scale studies, described below, to determine if CCSVI may be treated through an endovascular surgical procedure, which involves inserting a tiny balloon or stent into blocked veins in order to improve the flow of blood out of the brain and spinal cord.
The National MS Society shares the public’s sense of urgency to expeditiously advance any lead that has the potential of stopping, repairing or preventing MS. Accordingly, the Society is pursuing this new and potentially promising research direction by committing to fund expanded research on CCSVI in MS. In December 2009, the Society invited investigators worldwide to apply for grants on this topic. In response, research proposals were received from investigators internationally. In June 2010, the US National MS Society and MS Society of Canada announced their commitment of over $2.4 million to support 7 new research projects focusing on the role of CCSVI in the MS disease process.
National MS Society research leaders also met with Dr. Zamboni in February in advance of his invited lecture at New York University’s Society-funded MS Center of Excellence. In meetings and during his presentation, Dr. Zamboni suggested that if further evidence supports the link between MS and CCSVI, that its treatment may ultimately add to the arsenal of therapies available for MS. He emphasized the need for more research on his hypothesis, and noted that it is still not proven whether CCSVI is a cause of MS or related to MS in some other manner. Dr. Zamboni also noted that people with MS should remain on their immunomodulatory therapies as has his wife after her endovascular surgical procedure.
CCSVI Research Funding Timeline
December 16, 2009 – Expedited Request for Proposal distributed worldwide.
February 9, 2010 – Numerous international CCSVI research proposals for grant funding received.
May 2010 – International panel of MS and vascular experts conducts an expedited review of all applications received through this special request for applications.
June 2010 – Funding decisions announced.
July 1, 2010 – Anticipated start date for funding of any successful research applications.
Taking advantage of the organizations' international scope, the applications underwent an accelerated review process by an international panel being convened in cooperation with other MS Societies to ensure an expedited, coordinated response. If this hypothesis is confirmed, it could open up new research avenues into the underlying pathology of MS and new approaches to therapy.
Background: In a recent study by Dr. Zamboni and colleagues, the team evaluated abnormalities of blood outflow in major veins draining from the brain and spinal cord to the heart in 65 people with different types of MS, compared with 235 people who were either healthy or who had other neurological disorders. They used advanced ultrasound techniques to detect abnormalities of venous drainage. The investigators reported evidence of slowed and obstructed drainage in the veins draining the brain and spinal cord in the majority of those with MS. They also reported evidence of the opening of “substitute circles” – where the flow is deviated to smaller vessels to bypass obstructions, and these were often found to have reverse flow (reflux) of blood back into the brain.
The investigators call this venous obstruction “chronic cerebrospinal venous insufficiency,” or CCSVI. The treatment status of the people with MS (i.e., whether or not they were on an MS disease modifying drug) did not appear to influence whether they showed signs of CCSVI. The authors speculated that the reverse flow of blood back into the brain might set off the inflammation and immune-mediated damage that has been well described in MS. This study was published in June 2009 (J Neurol Neurosurg Psychiatry 2009; 80:392-399).
It is proposed that CCSVI may be treated through an endovascular surgical procedure. One such study was described at an international MS research conference last September. It involves a collaboration between researchers in Italy, Buffalo (NY) and Birmingham (AL) who are attempting to treat venous obstruction in 16 individuals using balloon dilation such as has been used for many years to treat blocked arteries.
In a small, open-label study by Dr. Zamboni and colleagues published in December 2009, the team evaluated the safety and preliminary outcomes of vascular surgery (percutaneous transluminal angioplasty) in 35 individuals with relapsing-remitting MS, 20 with secondary-progressive MS, and 10 with primary-progressive MS. (J Vasc Surg 2009; 50:1348-1358) They reported some positive effects, primarily in those with relapsing-remitting MS, and suggested that controlled trials were necessary to better determine potential safety and benefits of this procedure. In controlled trials, “blinding” of participants and researchers as well as the use of a comparative control group are considered essential to ensure that the hopes and expectations of the participants and the researchers do not bias the trial outcomes or the interpretation of those outcomes. So far, none of the procedures conducted to correct CCSVI have been done in the context of a controlled trial.
Following the publication of Dr. Zamboni’s study, the National MS Society prompted communications between MS Societies worldwide through the MS International Federation (www.msif.org) and leveraged resources to ensure an open exchange of information and a coordinated and expedited approach to conducting and evaluating additional research on CCSVI. The Society then released a worldwide Request for Applications to the scientific community to explore CCSVI, and is collaborating with the MS Society of Canada and other societies to convene an international panel of experts to conduct an accelerated review of proposals. Through an internationally coordinated and expedited review process, new CCSVI research projects are expected to begin July 1, 2010. (See Research Funding Timeline above for more details.)
On February 10, 2010, the University at Buffalo Medical Center released a press release describing preliminary results from an ongoing Combined Transcranial and Extracranial Venus Doppler Evaluation study. Using Doppler criteria developed by Dr. Zamboni, it is designed to evaluate the prevalence of venous obstruction, with a planned enrollment of 1700 consecutively recruited people who have possible and/or definite MS, other neurological conditions, and healthy controls. They are also using MRI of the brain, and in a subgroup, MRI of the veins of the neck to help verify the Doppler results. The results reported are based on the first 500 participants enrolled. Of those, 499 were eligible for statistical analysis: 289 people had MS, most with the relapsing-remitting form. There were 163 healthy controls, 21 with CIS (first neurological episode, at risk for developing MS0 and 26 with other neurological disease. Doppler scan results were reported on five specific criteria that affect venous blood flow. Patients who met at least two of the criteria were considered to have CCSVI.
The preliminary results, which were expanded upon in a poster presentation at the American Academy of Neurology (AAN) meeting in early April 2010, were interesting but somewhat mixed. At least 56.1 percent of the MS cohort met the criteria for CCSVI. This was also true for at least 22.7 percent of the healthy controls, and at least 42.5 percent of people with other neurological conditions. They concluded that further blinded studies are needed to determine the prevalence of CCSVI in MS.
This study is one of several CCSVI-related presentations given at the American Academy of Neurology (AAN) during its annual meeting in Toronto on April 10-17, 2010. Some of this data was shared at Web forum about CCSVI that was co-hosted by the AAN and National MS Society on April 14. View a recording of the Web forum.
In order to understand the long term benefits and risks of procedures related to CCSVI for all people with MS, it is important that those who conduct such procedures balance the need to move forward with all due speed with the need for controlled trials that will provide us with the best information. People with MS must have the tools and information they need to make well-informed choices.
Prospective candidates for CCSVI treatment should know that there have been reports of CCSVI surgical procedures resulting in adverse events, including deaths. According to the Annals of Neurology and the Wall Street Journal, a person died of a hemorrhage in the brain while taking a blood thinner (anti-coagulant), which is commonly prescribed when stents are inserted into blood vessels. In another instance, a Canadian man is reported to have died from complications during follow-up surgery after having a stent inserted in Costa Rica. In another individual, a stent dislodged and moved to the heart, requiring emergency open heart surgery to remove the device.
Many questions remain about how, when and whether this phenomenon plays a role in nervous system damage seen in MS. Only through diligent tracking, communication and re-testing will these questions be ultimately answered.
Frequently Asked Questions about CCSVI and MS
Q: What is the National MS Society’s view of CCSVI?
A: The Society is committed to pursuing all promising avenues of research that can lead to improved treatments and ultimately, a cure for MS. It is important for researchers to think outside the box and we believe Dr. Zamboni has done this. His hypothesis on CCSVI and its corrective treatment is a path that must be more fully explored and one that we are supporting with research funding.
Q: Will the National MS Society fund research into CCSVI in MS?
A: Yes. The National MS Society, the MS Society of Canada and the Italian MS Society are pursuing follow-up research into how CCSVI might be involved in the MS process. Investigators from around the world applied for grants to explore this lead. These applications underwent an accelerated review process by a panel of international experts in both MS and vascular diseases and an announcement about a commitment of $2.4 million for new CCSVI grants was made in June 2010, with work expected to begin July 1, 2010.
Q: How were research proposals that have been received by the Societies reviewed?
A: All research applications underwent a rigorous expedited review process by an international review panel that included experts drawn from all key relevant disciplines including: neuroradiology, neurovascular imaging, MS imaging, vascular surgery, biostatistics, interventional radiology, interventional neuroradiology, and MS clinical neurology. The U.S. National MS Society and the MS Society of Canada worked collaboratively to assemble the reviewers who considered scientific merit, responsiveness to the international Request for Applications, experimental design, likelihood of producing definitive data, and the experience of the applicant teams. The leadership of the US and Canadian MS Societies followed the panel’s recommendations and undertook the funding of these studies.
Q: Do the reports of a possible association between insufficient vein drainage and MS mean that MS is caused by venous insufficiency?
A: Based on results published about these findings to date, there is not yet enough evidence to conclude that obstruction of veins causes MS, or to determine when this obstruction may occur in the course of disease.
Q: I have MS. Should I be tested for signs of CCSVI?
A: This is a personal decision to be discussed with your health care provider. At this point, no connection has been confirmed between CCSVI and multiple sclerosis, in fact, CCSVI appears to occur in many people who don’t have MS. In talking with your doctor, here are some of the questions you may want to ask: How is the testing done; Are there any risks associated with the testing procedure itself; how much will the testing cost; what would I learn by having this test done; do technicians need special skills to evaluate the test results; how accurate and reliable are the test results; if the test indicates that I have signs of CCSVI, does that mean I should have vascular surgery?
Q: Should I get surgical treatment for CCSVI?
A: Like all important medical decisions, the question of whether individuals should undergo any procedure is a personal one that should be discussed with their health care providers. There is urgency for more effective MS treatments, particularly for more progressive forms of MS. Each of us varies in our ability to tolerate risks; an intervention that may seem far too risky to one who is doing relatively well with his or her current treatment strategy may not feel very risky at all to someone whose MS is obviously progressing in spite of everyone’s best efforts. Each individual must make this decision in conjunction with a trusted health care provider.
Endovascular surgery, like any surgical procedure, carries some risks. This does not mean that it would not be considered as a potential treatment in the future if further research provides evidence of its possible benefit. We need to determine if treating CCSVI improves symptoms or changes the course of the disease in any way. That is why the Society is leading research efforts to determine how CCSVI may be involved in the MS disease process. To get the quickest answers and most reliable results about benefits and risks of any surgical procedure that might attempt to address blood flow in or out of the brain, it is prudent that such surgery be performed as part of controlled trials, especially in light of adverse events reported to date.
Prospective candidates should know that there have been reports of CCSVI surgical procedures resulting in adverse events, including deaths. According to the Annals of Neurology and the Wall Street Journal, a person died of a hemorrhage in the brain while taking a blood thinner (anti-coagulant), which is commonly prescribed when stents are inserted into blood vessels. In another individual, a stent dislodged and moved to the heart, requiring emergency open heart surgery to remove the device. MS endovascular surgery was halted at Stanford University after these two adverse effects occurred. In another instance, a Canadian man is reported to have died from complications during follow-up surgery after having a stent inserted in Costa Rica. Other possible risks include: infection at the puncture site; damage to the blood vessel, which could lead to the formation of clots; and internal or external bleeding if anti-coagulants are used.
Virtually all FDA approved disease-modifying MS therapies have their own risk/benefit profiles. The difference is that these therapies have been shown, through large-scale, controlled clinical trials, to significantly reduce MS disease activity in certain individuals. Dr. Zamboni, who originated the CCSVI hypothesis, has emphasized the need for carefully controlled research on CCSVI, and has noted that people with MS should remain on their disease-modifying therapies, as has his wife after her endovascular surgical procedure.
Q: How can I get involved in research on CCSVI in MS?
A: A larger-scale clinical study is getting underway in Buffalo, New York and is now recruiting participants nationwide with the aim of evaluating the prevalence of venous obstruction in people with MS. This study does not involve treatment of venous obstructions. If there is a broad call for recruitment for participants of the seven newly funded CCSVI research studies, the information will be posted on www.nationalmssociety.org/ccsvi when it becomes available.
Q: If CCSVI turns out to be important in MS, can it be treated?
A: Surgical procedures for CCSVI in MS are still experimental. It is prudent that such procedures be undertaken in conjunction with formal clinical trials in order to assure that rigorous safety safeguards and long-term monitoring standards are followed.
Q: Does CCSVI make the standard treatments of MS meaningless?
A: No. There is ample evidence that the FDA-approved therapies for MS provide benefit to a significant percentage of people with the most common form of MS.
Q: How is the Society supporting the work of Dr. Zamboni and others regarding CCSVI?
A: Dr. Zamboni has called for more research to move his preliminary CCSVI research forward and the Society is leading the way in advancing that effort. As in all early research, Dr. Zamboni’s work has raised as many questions as it has potentially answered. The Society’s role is to ensure that whether someone is diagnosed with MS today or ten years from today there will be safe and effective treatment options available. On June 11, 2010, the US National MS Society and the MS Society of Canada announced funding of 7 projects investigating CCSVI in MS, valued at a total of over $2.4 million. In addition, the U.S. and Canadian MS Societies are in discussion with the Multiple Sclerosis International Federation to establish an international CCSVI Research Coordinating Committee to consider CCSVI research that is underway around the world.
Q: What are some of the questions raised in Dr. Zamboni and others’ research that need to be explored?
A: Why has venous obstruction recurred in such a large percentage of patients who underwent the endovascular surgery and what does that mean to the disease process for these individuals? Is there abnormal venous obstruction in all people with MS? How do we determine who, if anyone, might best benefit from endovascular surgery? Are such benefits long-lasting or temporary? Can Dr. Zamboni’s results be replicated in larger controlled and blinded studies of MS patients? If so, when does CCSVI occur in the course of the disease – is it a cause or effect of the disease process? How can we address the known risks associated with endovascular surgery? Acknowledging the questions that Dr. Zamboni himself has raised only helps in designing the necessary research to secure the needed answers.
Q: Is it true, as some people have suggested, that the Society’s dependence on money from the pharmaceutical industry is impeding its support of Dr. Zamboni’s research?
A: No. Last year, nearly 95% of our funding came from individual contributions. The vast majority of our gifts are less than $100. However, we partner with all those who want to do something about MS NOW, including pharmaceutical company support (4%), and direct and pro-bono Corporate support (1%+).
Q: How can I contribute to the CCSVI research efforts?
A: The National MS Society has established a Rapid Response Fund to pursue new and unexpected research opportunities when they arise, such as expedited funding of these CCSVI grants. To support the Society’s Rapid Response Fund please have individuals email their full name and contact information to email@example.com. An event participant cannot make that request on behalf of their donors.
Q: How can I keep up to date on CCSVI and MS?
A: As new information becomes available about CCSVI, it will be posted on the National MS Society’s Web site, www.nationalMSsociety.org/CCSVI