November 17, 2010 (Göteborg, Sweden) — New data on the possible link between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS) have done little to clarify the relationship between these conditions, providing evidence both for and against the controversial hypothesis.
What does seem clear now, though, is that the relationship, if there is one, is not as simple as it may have first appeared. New findings suggest, for example, that venous lesions may be more common in later stages of disease and so may be a consequence or comorbidity rather than a cause of MS.
One of the issues appears to be differences in methods and imaging techniques in the cerebral venous system that mean researchers seem to be able to look at precisely the same images or data and settle on interpretations that are diametrically opposed.
Dr. Paolo Zamboni
Even Paolo Zamboni, MD, director of the Vascular Diseases Center at the University of Ferrara, Italy, who first proposed the link, is now considering the hypothesis that the vast majority, but perhaps not all, cases of MS may relate to CCSVI.
The state of knowledge on CCSVI, including new data from some of the leading researchers in this area, was the focus of a number of posters and presentations, as well as a symposium here at the recent 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
A Matter of Assessment?
The appealing idea that simple angioplasty of extracranial veins might cure or improve symptoms of this devastating disease caught the attention of highly educated and motivated MS patients late last year and has since engaged many in the unifying demand for access to what has been dubbed by some the "liberation procedure."
Dr. Zamboni — who denies having called it the liberation procedure — and colleagues presented new data here and addressed some of his critics. At the packed Charcot Symposium dedicated to discussion of the topic at the outset of the meeting, he first emphasized what these venous lesions are and what they are not.
"CCSVI is composed of several blockages in the main outflow routes, the jugular vein, azygous vein, but this is very important to understand," he said, displaying angiographic and high-resolution B-mode images along with a specimen, these blockages "are merely intraluminal defects; not problems in the wall, but intraluminal defects: webs, membranes, malformed valves."
One important issue in this debate on CCSVI, he said, is how venous outflow from the brain is assessed and how these lesions are imaged. Veins can be apparent or not on imaging based on a number of factors, including supine vs upright postures, respiration, or the imaging modality, and it does appear that this has some bearing in the interpretation of the contribution CCSVI may or may not be making to MS.
In his original article, Dr. Zamboni found 100% of MS patients had these abnormalities vs none of the controls (J Neurol Neurosurg Psychiatry. 2009;80:392-399). Since then, others have published prevalence studies, some suggesting a relationship and some not, but no other groups have found this complete separation between patients and controls on the basis of CCSVI.
Dr. Florian Doepp addresses the Charcot Symposium at ECTRIMS
In 2 particularly widely reported papers published in the Annals of Neurology last August, investigators found no relationship between CCSVI and MS. Lead author of one of those reports, Florian Doepp, MD, from University Hospital Charité, Humbolt University in Berlin, Germany, discussed his findings at the symposium here and extended their work to include more patients (Ann Neurol. 2010;68:173-183).
Using extra- and transcranial Doppler ultrasonography, he and colleagues analyzed extracranial blood volume flow, cross-sectional areas, flow in the internal jugular vein during the Valsalva maneuver, and CCSVI criteria in 56 patients with MS and 20 controls.
Except for 1 patient, blood flow direction in the internal jugular veins and the vertebral veins was normal in all of the subjects, and no stenosis was seen in the internal jugular vein of any of them.
Blood volume flow in both internal jugular and vertebral veins was equal between groups while subjects were in the supine position, they noted, but when subjects moved to the upright position, the decrease in total jugular blood volume flow was less pronounced in MS patients vs controls, leading to a significantly higher flow in that position.
No difference was seen in veins between groups during the Valsalva maneuver, and none of the patients to date have met more than 1 of Dr. Zamboni's 5 criteria for CCSVI, Dr. Doepp and colleagues reported.
However, others, including Dr. Zamboni, have interpreted these same findings by Dr. Doepp and colleagues as actually supporting the link between CCSVI and MS. An exchange of correspondence appeared recently in the Annals of Neurology, published online October 25, and some of these authors also took part in the Charcot Symposium here.
In his letter, Clive Beggs, PhD, from the Center for Infection Control and Biophysics at the University of Bradford, United Kingdom, says that although the findings by Doepp and colleagues challenge the previous findings by Dr. Zamboni and colleagues with regard to the detection of venous reflux in patients, he writes that he "cannot agree with the main conclusion of the article; namely that the cerebral venous characteristics of MS patients are essentially no different than healthy controls."
When the MS patients in the study were upright, he notes, the blood flow rate through the internal jugular veins was 2.5 times greater than controls, despite a similar cross-sectional area. Since blood flow through the vertebral veins was also "broadly similar, why then should a much greater proportion of the blood draining from the brain in the MS patients choose to flow through the [internal jugular veins] rather than through other extrajugular pathways?" Dr. Beggs writes.
"The only plausible answer to this question is that, for some unknown reason, the resistance of the other extrajugular venous pathways must have greatly increased in the MS patients," he added. In short, there is, "something abnormal in the MS patients," Dr. Beggs said during the Charcot Symposium.
In their response, Dr, Doepp and colleagues agreed that that particular finding requires further investigation. "Contrary to Dr. Begg's conclusions, however, we do not consider this finding to be suggestive of venous congestion," they write.
"What he didn't explain is why the volume flow in the vertebral veins is exactly the same between patients and controls," Dr. Doepp told Medscape Medical News. "We know very well when we compress the deep neck veins we have an increase in blood flow in the vertebral veins. Therefore, it's not really logical."
In addition, it is not clear why the blood volume flow was only different in the upright and not the supine position, "and you can't explain this by any flow disturbance in the neck veins," he said. "For this point we don’t have a clear explanation but at least our preliminary data from further patients say that this difference is not as high as it was presumed to be in our first study. So it's probably a side effect;... it's not really important."
In a letter of his own replying to Dr. Doepp's article, Dr. Zamboni published a high-resolution B-mode image of an intraluminal septum and noted that this is the most frequent stenosing lesion seen in CCSVI in their work. These lesions can only be imaged, he says, with high-resolution probes that are capable of exploring the jugular in the supraclavicular fossa.
Dr, Doepp's group, though, did not find frequent intraluminal jugular septation in their patients, Dr. Zamboni points out. "This underscores the urgency of establishing an internationally accepted protocol," he concludes. "In the attempt to achieve this cultural osmosis, my group is available to travel to Berlin and rescan with German colleagues the entire series by the means of the proposed methodology."
At the ECTRIMS meeting, another example of divergent interpretation of the same findings. Claudio Baracchini, MD, from the Department of Neurological Sciences at the University of Padua School of Medicine, Italy, presented a study looking at the prevalence of CCSVI in 50 patients with clinically isolated syndrome suggestive of MS and evidence of dissemination in space of lesions, called possible MS (pMS). Findings were compared with healthy controls and patients with transient global amnesia (TGA).
Abnormal findings on extracranial venous sonography were seen in 26 of the 50 pMS patients (52%) but also in 32% of healthy controls and 68% of TGA patients. Eight of the pMS patients met criteria for CCSVI, and 7 of these underwent venography that was found to be normal in 6; the last patient was found to have hypoplasia of the internal jugular vein.
"The results of our study do not support a cause-effect relationship between CCSVI and pMS," Dr. Baracchini told delegates here. "Importantly, any invasive endovascular therapeutic procedure, including angioplasty and stenting, is not only dangerous but presently unjustified in these patients."
To me it was a must to go see how he worked.
During the discussion, Dr. Baracchini noted that he went to Ferrara to view Dr, Zamboni's methods. "To me it was a must to go see how he worked," he said. Ultrasonography is not only operator dependent but is machine dependent, and Dr. Baracchini said he believes most of the discrepancies between Dr. Zamboni's findings and others' are due to the suboptimal machinery that Dr. Zamboni is using.
However, he was challenged himself during the discussion period by an audience member who retorted that the image Dr. Baracchini had shown during his presentation as an example absent of disease actually showed obvious obstruction. "Did you know what to look for, is my question?" he said.
Dr. Robert Zivadinov
Working initially with Dr. Zamboni on some of these papers, as well as a number of larger independent studies of CCSVI, is Robert Zivadinov MD, PhD, associate professor of neurology from the University of Buffalo, New York. The Buffalo group is currently pursuing a variety of different research directions, Dr. Zivadinov told Medscape Medical News, including prevalence studies, assessing which may be the best diagnostic tools, as well as associations with disease pathogenesis and clinical outcomes.
Among their findings presented here are the following:
The researchers compared Doppler sonography and 2 magnetic resonance venography (MRV) techniques to the gold standard, catheter venography, in 10 subjects with MS and 10 healthy controls. They found "much better specificity and positive predictive value of Doppler to detect venous anomalies with respect to MRV," Dr. Zivadinov noted. "Our conclusion is Doppler is a better noninvasive tool than MRV."
They suspect that power may be a key factor in explaining divergent findings from different data sets, he noted. In a previous report from the large Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study, presented at the American Academy of Neurology meeting in April and now in press, 56% of MS patients were found to have CCSVI vs 22% of controls, a statistically significant difference.
In a new paper also in press, where they included only 57 patients and 21 controls studied with MRV, "we're finding only a trend toward a difference, and actually we are writing in that study that it's probably underpowered to detect it," Dr. Zivadinov said.
Most of the other published studies, including that by Dr. Doepp and colleagues, for example, had 50 patients or fewer, he added. "So if we are really talking about a phenomenon that's not 100% to zero anymore [as Dr. Zamboni originally reported], then...most of the studies that have been published are probably underpowered."
Also using the CTEVD data set, the Buffalo researchers presented 3-T magnetic resonance imaging (MRI) results from 351 of the 499 subjects, showing the presence of CCSVI was associated with more advanced disease subtypes, seen in 89.5% of secondary progressive patients vs 49.2% of relapsing-remitting and 38.1% of clinically isolated syndrome (CIS) patients. The presence of CCSVI was also associated with higher lesion burden and brain atrophy in all study subjects but not in the individual study subgroups.
In 268 MS patients and 150 healthy controls again from CTEVD, they compared the association of CCSVI with an established genetic risk factor for MS, HLA DR*1501. They found for those with CCSVI, the odds ratio for MS patients vs controls was 4.5 vs 2.3 for the genetic risk factor.
Using susceptibility-weighted MRI, they found in 59 MS patients vs 33 healthy controls that patients with increasingly severe CCSVI had fewer veins in the brain parenchyma. "There are a number of different hypotheses, but probably the most important one is that the areas more distant from the occlusion are those getting most affected and we see less veins in the deep white matter and in the deep gray matter structures where most of the lesions are," he noted.
Finally, they showed that the more severe the CCSVI, the higher the iron deposition in the brain, thought to be the result in part of poorer venous drainage. In other studies not related to CCSVI, the Buffalo group has shown regions of higher iron accumulation in the brain were associated with loss of brain volume and higher clinical disability, he added, making measurement of iron concentration a potentially interesting biomarker in MS for new clinical trials.
"So there is definitely an association of CCSVI with MS, at least in our datasets," Dr. Zivadinov said. "Our findings are consistent with an increased prevalence of CCSVI in MS but with modest sensitivity/specificity. Our findings point against CCSVI having a primary causative role in the development of MS," he added. "We are showing that CCSVI is connected to the progression of disease, but whether it is a cause of the progression or a consequence, we don't know at this time."
A Contentious Issue
Jeffrey Cohen, MD, from the Cleveland Clinic Foundation summed up the data presented here at ECTRIMS during his review of the meeting highlights at the end of the conference.
"CCSVI, which continues to be a contentious issue, remained contentious at this congress, mostly because of the very conflicting results that are being presented," he said.
If there is in fact an association, it's a modifying factor; maybe a comorbidity or perhaps just reflects a normal aging phenomenon.
"My read on the data from the Zamboni and Zivadinov groups is that it appears the incidence of venous abnormalities in fact increases over time; thus, patients with progressive MS have a higher incidence than those with relapsing-remitting MS, who have a higher incidence than those with CIS — so that already suggests that this is not a causative condition," Dr. Cohen said. "If there is in fact an association, it's a modifying factor; maybe a comorbidity or perhaps just reflects a normal aging phenomenon."
Dr. Zamboni speculates that there may exist different types of MS that have slightly different origins leading to the similar disease outcome, of which only a proportion, although a large proportion in his view, may stem from these intraluminal abnormalities.
During the last year, the CCSVI hypothesis has been the focus of worldwide attention and controversy. On one side are MS patients, many of whom have high and perhaps unrealistic expectations of what is a highly experimental and still singularly unstudied procedure, but who nevertheless have direct access to centers offering endovascular treatment for CCSVI via the Internet.
On the other are highly sceptical neurologists who have seen quick-fix hypotheses for MS come and go and are concerned for their patients, an unknown number of whom are shelling out thousands of dollars of their own money for procedures at hospitals in India, Mexico, or Bulgaria with no formal neurologic follow-up.
Some patients in their turn have suggested that neurologists are resisting this simple treatment because they are protecting their turf as prescribers of expensive drugs.
The problem is that between them, these factions may obscure the potential of a hypothesis that, given the proper study, might at least provide some insight into MS mechanisms.
"When I began this story I was aware that something like this might happen," Dr. Zamboni told Medscape Medical News. "I'm really determined to root this in science, or at least do my best."
Simply, he said, he wants "to scientifically proceed with a rigorous randomized controlled trial in order to rapidly understand the value of the angioplasty in MS treatment, rather [than] perform treatments on patients out of any scientific and ethical control."
Among the "disasters," he says, has been the rush for private practitioners to offer angioplasty procedures for gain and the lack of cooperation between specialties so that neurologists are involved in follow-up of these patients. Dr. Zamboni is clear — as he has in fairness been from the beginning — that the procedure should only be done in the context of randomized clinical trials with neurologic follow-up.
Endovascular Treatment Results
At this meeting, Dr. Zamboni and Dr. Zivadinov and colleagues presented results of a small pilot safety trial of endovascular treatment of venous lesions in patients with MS. A first small pilot study was published in December 2009 and reported by Medscape Medical News at that time (J Vasc Surg. 2009;50:1348-1358).
In the current trial, called the EVTMS study, 15 patients with relapsing-remitting MS and evidence of CCSVI were enrolled and randomized to receive either immediate endovascular treatment (8 patients) or treatment delayed for 6 months (7 patients), and these were compared with 8 healthy controls.
Treatment of significant stenosis was with angioplasty alone, and patients were prospectively followed up at 3, 6, 9, and 12 months with sonography, MRI (at 6 and 12 months), and clinical examination.
No serious adverse events were seen, with the exception of 1 transitory vasovagal syndrome 1 hour after the intervention, they report.
"No significant clinical or MRI differences have been seen, although there were less relapses in the immediate treatment group, 1 vs 4, and a decrease in T2 lesion volume in the immediate group, about 10%," Dr. Zivadinov noted. Restenosis did not occur in any of the azygous veins treated but was seen in 29% in the internal jugular veins.
I think based on this study that we can't say more than there is no deterioration of the patients who are getting this type of treatment...
"I think based on this study that we can't say more than there is no deterioration of the patients who are getting this type of treatment, and we need to do more specific placebo-controlled trials to understand whether this treatment is useful or not, but I would add that no remarkable differences have been seen in this first study," he said.
A second group, led by Marian Simka, PhD, from the Department of Vascular and Endovascular Surgery at EUROMEDIC Specialist Clinics in Katowice, Poland, also presented interventional data on a total of 587 endovascular procedures — 414 balloon angioplasties and 173 stent placements — in 347 MS patients, looking specifically at safety.
They found no life-threatening complications, including no deaths, no major hemorrhage or cerebral stroke, and no instance of stent migration, as well as no injury to nerves. There were 2 stent thromboses, although they point out that because these occurred in a jugular vein that was not patent before the procedures, there was no likely clinical consequence.
Other complications included 2 cases of postoperative false aneurysm successfully treated with thrombin injection, 1 surgery to open the femoral vein to remove a balloon, transient cardiac arrhythmia in 2 patients, 2 cases of minor bleeding from the groin, 1 minor gastrointestinal bleed, 1 postprocedure lymphatic cyst, and problems with removal or delivery of the catheter.
"Regardless of the actual impact of the endovascular treatments for venous pathology on the clinical course of multiple sclerosis, which warrants more clinical studies and long term follow-up, these procedures appeared to be safe and well tolerated by the patients," Dr. Simka and colleagues concluded.
In his highlights talk, Dr. Cohen mentioned both of these interventional studies, noting he was "gratified" to hear that all of these researchers agreed that endovascular procedures should only be done in the context of studies. "And I would add that those need to be legitimate studies," he stressed.
However, Giancarlo Comi, MD, from Vita-Salute San Raffaele University in Milan, Italy, who acted as moderator for the Charcot Symposium, told Dr. Zamboni that in his view, it is still too early even for clinical trials until more is known about the link between these conditions.
Dr. Zamboni told Medscape Medical News he disagrees that it is too soon for any such trials, arguing that there is no reason that investigation into the link between CCSVI and MS and clinical trials should not proceed as a "parallel process."
Dr. Zivadinov compared it to any other novel treatment strategy. "If you have a molecule that's interesting, you test it in a clinical trial, right?" he says. "You don't know if it's going to work or not, so what we need to do is exactly what we are doing, which is to test the efficacy and safety in very small pilot studies and then, if there is something positive there, we should extend it to the bigger clinical trials. If it is not, we need to close the argument that endovascular treatment should be studied in MS."
A solid answer on this question is needed by both the patient and physician community, Dr, Zivadinov added. "The currently ongoing placebo-controlled study in Buffalo, in collaboration with Department of Neurosurgery at the University of Buffalo, is aiming to answer this question and data should be available by the second part of 2011," he said. "We are against performing open-label endovascular treatment in patients with MS."
Dr. Zamboni is also critical of those who would offer this procedure without evidence and in an effort to make money. "It is unethical to charge for an experimental procedure," he says bluntly.
It is unethical to charge for an experimental procedure.
Still, the reality is that the potential pool of interventions to correct CCSVI in MS patients would be a large market, and the patients themselves are pushing hard for it.
In the recent Annals of Neurology correspondence, Dr. Simka and colleague Marek Kazibudzki, PhD, responded to a previously published commentary by Omar Khan, MD, from Wayne State University School of Medicine in Detroit, Michigan, in which Dr. Khan and colleagues warned that stenting veins can result in serious injury and called for such "invasive and potentially dangerous interventions to be discouraged until further evidence of the connection between CCSVI and MS could be established" (Ann Neurol. 2010;67:286-290).
In their reply, Dr. Simka and Dr. Kazibudzki point out that the Consensus Document of the International uni0n of Phlebology on Diagnosis and Treatment of Venous Malformations recommends that, for veins draining the brain and spinal cord, patients receive diagnostic testing, including duplex scanning and MRV, and treatment with angioplasty and stenting for proven obstructive lesions (Int Angiol. 2009;28:434-451).
They also point to several lines of evidence supporting a link between venous abnormalities and MS.
Dr. Khan and colleagues in turn respond that they find the letter by Dr. Simka and Kazibudzki to be "an attempt to legitimize the treatment of [CCSVI] with potentially dangerous endovascular procedures."
They point out that the Polish group has "publicized CCSVI stenting for several thousand Euros per procedure," and they "question the ethics of such commercialization for a condition yet to be established, that is, CCSVI in MS, and exposing patients to a potentially dangerous procedure without any randomized, controlled studies."
They add that "more recognized societies representing interventional radiology and neuroradiology," including the Society for Interventional Radiology (SIR), the American Society of Neuroradiology, and others, have not yet issued consensus statements on this topic.
In the meantime, though, the SIR recently published a statement in the September issue of the Journal of Vascular Interventional Radiology, endorsed by the Canadian Interventional Radiology Association (J Vasc Interv Radiol. 2010;21:1335-1337). In it, the SIR recognizes what they call the "challenge and potential opportunity presented by promising early studies of an interventional approach to the treatment of MS."
The society is moving rapidly to "catalyze" the studies needed, but currently considers the published literature "inconclusive on whether CCSVI is a clinically important factor in the development and/or the progression of MS and on whether balloon angioplasty and/or stent placement are clinically effective in patients with MS."
These venous procedures, although they've been performed for years by interventional radiologists, are not without risk, the statement notes, and the durability of the procedure, or any impact of the placebo effect — that might be expected to be quite "robust" in MS patients — are presently unknown.
...when conclusive evidence is lacking, SIR believes these often difficult decisions are best made by individual patients, their families and physicians.
Nevertheless, the position statement notes that, "when conclusive evidence is lacking, SIR believes these often difficult decisions are best made by individual patients, their families and physicians," a position that apparently leaves the door open for elective procedures.
In a press release that accompanied the position statement, the SIR refers readers to their Website for more information about the society and "to find those interventional radiologists who provide endovascular treatment for CCSVI."
Dr. Zamboni told Medscape Medical News he has been invited to participate in SIR's upcoming annual meeting and hopes to convince this group to collaborate with neurologists on multicenter trials. He feels the best role for SIR would be to refine the procedure. "I'd like them to improve this procedure because our results are not very good," he added, referring to the restenosis rates. "Their contribution could be more technical."
Controversy in Canada
In Canada, where the incidence of MS is among the highest in the world, the call for access to the procedure, or at least to trials of the procedure, has been at a fever pitch for months. Even small-town newspapers have run stories about local MS patients taking matters into their own hands, paying to get the procedure done, sometimes fundraising for themselves, and reporting various levels of symptomatic relief, such as reduced fatigue or less tingling in hands and feet.
In online blogs and commentary, some patients seem to view this as a proven therapy that they are being denied, but others simply feel they should be allowed to have the procedure on a compassionate access basis given that so little is otherwise available to those with advanced disease.
Recently, reports have begun to surface of patients developing complications after receiving intervention abroad. CBC News reported November 16 the case of an Alberta man who developed thrombosis near the stent after a procedure performed in Poland and reports he is having difficulty getting physicians to treat it because of the experimental nature of the procedure. The case is sparking discussion of who should pay to fix the complications from these elective procedures done abroad.
After the Canadian federal government declined to fund trials in August, some provincial governments have now decided to do so. Saskatchewan, for example, announced October 19 some $5 million in funding for clinical trials. The Canadian MS Society also announced in September it has earmarked a further $1 million for therapeutic trials of angioplasty for these venous abnormalities once the evidence is sufficiently strong to support them.
In July, 7 studies funded by $2.4 million from the National Multiple Sclerosis Society (NMSS) and the Canadian MS Society with the aim of establishing the prevalence of CCSVI in MS got under way at institutions across Canada and the United States. The 2-year grants went to the following:
Brenda Banwell, MD, at the Hospital for Sick Children, Toronto, Ontario, Canada, who is looking at the occurrence of CCSVI in children and teenagers with MS vs health controls.
Fiona Costello, MD, at the University of Calgary's Hotchkiss Brain Institute, Alberta, Canada, is using ultrasonography and MRV to look at the prevalence of CCSVI in MS patients and controls.
Aaron Field, MD, at the University of Wisconsin School of Medicine and Public Health in Madison will use MRV in patients with early and advanced disease, as well as ultrasonography, to determine the prevalence of CCSVI.
Robert Fox, MD, from the Cleveland Clinic in Ohio, will also use MRV and ultrasonography, as well as MRI, to compare those with MS or CIS to healthy controls and patients with brain atrophy from Alzheimer's disease. They are also obtaining neck and brain tissue at autopsy to evaluate CCSVI.
Carlos Torres, MD, from Ottawa Hospital at the University of Ottawa, Ontario, Canada, is using 3-T MRI and Doppler ultrasonography to assess venous anatomy and iron deposits in 50 patients and 50 healthy controls.
Anthony Traboulsee MD from the University of British Columbia (UBC) Hospital MS Clinic, UBC Faculty of Medicine, and Katherine Knox, MD, from the Saskatoon MS Clinic at the University of Saskatchewan, Canada, are studying the prevalence of CCSVI in those with MS and controls, comparing results using catheter venography, ultrasonography, and MRV. Included in the control group will be family members, including identical unaffected twins of those with MS. And finally,
Jerry Wolinksy, MD, from the University of Texas Health Science Center in Houston, will also attempt to replicate Dr. Zamboni's ultrasonography methods, looking at the association of CCSVI in the major clinical types of MS as well as non-MS controls.
"These studies are going to look in a variety of different ways both at the anatomy and function of the venous system," said NMSS Chief Medical Officer Aaron Miller, MD, professor of neurology and medical director of the MS Center at Mount Sinai Medical Center in New York City. "So they will not only use the same kind of technology that Dr. Zamboni used, but if they should find that that observation holds up, they will have additional information to tell us whether it's really physiologically meaningful; whether (CCSVI) actually alters venous flow."
The Charcot Symposium was sponsored by the European Charcot Foundation, a nonprofit, independent organization in Europe sponsored by private organizations, MS societies, and industry.
26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS): Abstracts P-318, P-265, P-508, 81, 82, P-914, P-773, P-653, P-641, P-663, P-774, and P-579. Presented October 13 – 16, 2010.