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02/25/2012 02:14 AM

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Computers Boost Brain Power in MS, Mental Illness

By Nancy Walsh, Staff Writer, MedPage Today

Published: February 23, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

Action Points

Computer training showed promise in improving cognitive abilities in patients with schizophrenia.

In another study, a cohort of patients with MS who had 12 weeks of computer-based cognitive training showed increased activation of the prefrontal cortex and posterior cingulate cortex, areas of the brain involved in the performance of complex tasks.

Computer training is showing promise in improving cognitive abilities in patients with conditions as disparate as schizophrenia and multiple sclerosis (MS), researchers reported.

After 16 weeks of intensive targeted treatment, patients with schizophrenia were significantly better able to identify words they had generated themselves from those supplied by others (P=0.02), according to Karuna Subramaniam, PhD, and colleagues from the University of California San Francisco.

This ability to discern stimuli as originating from oneself versus from outside sources is a key deficit in schizophrenia, and the improvement seen in these patients "raises the exciting likelihood that the neural impairments in schizophrenia -- and undoubtedly other neuropsychiatric illnesses -- are not immutably fixed, but instead may be amenable to well-designed interventions that target restoration of neural system functioning," Subramaniam's group wrote online in Neuron.

In another study, a cohort of patients with MS who had 12 weeks of computer-based cognitive training showed increased activation of the prefrontal cortex and posterior cingulate cortex, areas of the brain involved in the performance of complex tasks, according to Massimo Filippi, MD, of Vita-Salute University in Milan, Italy, and colleagues.

"Most intriguingly, our study showed brain functional changes that were possibly induced by the treatment, which in turn might reflect the neurobiologic substrates of the improvement of the cognitive performance," the Italian researchers reported in the March Radiology.

The past two decades have seen major advances in neuroscience research, revealing much about the mechanisms involved in learning and the resulting changes in cortical plasticity.

To see if the neural abnormality known as reality monitoring in schizophrenia can be attenuated by cognitive training, the California researchers enrolled 31 patients with longstanding disease along with 15 healthy controls.

The patients were randomized to receive 80 hours of intensive computer training or an equivalent amount of time in the laboratory playing computer games.

The training consisted of exercises in visual, auditory, verbal, and social memory.

Reality monitoring was assessed by initially presenting the patients with a series of simple noun-verb-noun sentences, in which the tester either provided the second noun (the rabbit ate the carrot) or withheld it, so patients had to come up with a suitable word themselves.

Then, during functional MRI, patients attempted to recall for each word whether they provided it themselves or it was given to them by the tester.

In healthy participants, the researchers explained, recalling whether a word had been self-generated or provided by someone else is associated with greater functional MRI activity in the dorsal rostral area of the anterior cingulate cortex and medial prefrontal cortex.

Schizophrenic patients, in contrast, show no such activity.

However, after the computer training, the patients not only correctly identified the word source, with a large effect size (0.86), but also showed significantly more activity in the medial prefrontal cortex.

"After 16 weeks of intensive training of component cognitive processes, the schizophrenic patients began to 'normalize' their brain-behavior associations during performance of an untrained higher-order reality monitoring task such that they more closely resembled healthy subjects," Subramaniam and colleagues wrote.

Moreover, six months later the participants were showing improved social functioning.

"Thus, it is possible to significantly improve brain function in schizophrenia, even in patients who have been ill for an average of 20 years," they observed.

In the MS study, 20 women with relapsing-remitting disease were randomized to receive computer-based training focusing on information processing, attention, and executive function, or to act as controls.

The researchers tested for effects on these domains by using the Stroop test, which measures attention and flexibility, during functional MRI.

"Significant correlations were found between functional MR imaging changes in activation during the Stroop interference condition and improvements of performance on attention and executive neuropsychologic tests [r = &#8722;0.74 to 0.79, P<0.0001)," wrote Filippi and colleagues.

The researchers also found that treatment effects seen on MRI were maintained during a resting state, whereas deterioration occurred in controls.

There were no changes in volume of gray matter or white matter with the treatment, which was an unexpected finding and may be explained by a loss of plasticity caused by the MS process itself.

Limitations of the study included its small sample size, short follow-up, and the absence of a healthy control group.

"Clearly, a longer follow-up (which is currently ongoing) is required to determine whether the observed effects persist and if they are specific to the critical elements of the intervention," the Italian researchers concluded.

The schizophrenia study was supported by the National Institute of Mental Health.

One of the researchers in that study is an employee of Brain Plasticity Institute, which has a financial interest in computerized cognitive training programs, and another is a consultant to the company.

Some investigators in the MS study disclosed financial support from various companies including Merck-Serono, Teva, Biogen, Bayer-Schering, and sanofi-aventis.

Primary source: Neuron

Source reference:

Subramaniam K, et al "Computerized cognitive training restores neural activity within the reality monitoring network in schizophrenia" Neuron 2012; DOI: 10.1016/j.neuron.2011.12.024.

Additional source: Radiology

Source reference:

Filippi M, et al "Multiple sclerosis: Effects of cognitive rehabilitation on structural and functional MR imaging measures -- An explorative study" Radiology 2012; 262: 932-940. utm_content=&utm_medium=email&utm_campaign=DailyHeadlines& utm_source=

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03/05/2012 02:41 AM
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using DIET TO CURE HER MS, Dr. Terry Wahls learned how to properly fuel her body. Using the lessons she learned at the subcellular level, she used diet to cure her MS and get out of her wheelchair.

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03/13/2012 03:49 AM
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MRI Transforms MS Management, a Clinical Context Report

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This report is part of a 12-month Clinical Context series.

By John Gever, Senior Editor, MedPage Today

Published: March 11, 2012

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner



I'm John Gever with MedPage Today, and I'm here with Dr. Jerry Wolinsky of the University of Texas Health Science Center in Houston, and we're doing a clinical context expert commentary on multiple sclerosis.

Dr. Wolinsky is also the current president of ACTRIMS, the Americas Committee for Treatment in Research of Multiple Sclerosis, so he'll be a very good person to talk with on this topic. I think I'd like to start with prognostic factors for the clinician.

What is it that the clinician can pick up from your everyday free-range patient that can predict their outcomes and how can that be used to guide their treatment?


MD: Well, some of the things we actually very much look for is -- because this is so common in the most prominent form of the disease, the relapsing and remitting form -- is the number of attacks, the severity of attacks, locations of attacks, particularly over the last several years before the patient considers disease-modifying therapy.

Now, even as I say that, those pieces of information are not quite as practically useful as they once were.

And the reason for that is because I think patients, as well as physicians in general, are starting to understand that this is a disease which requires long-term management and that the armamentarium of drugs that we have to try to modify the natural history of the disease is maturing, and so often those decisions are really made when the individual is presenting with their very first clinical attack of MS.

When that happens, in a sense, we had some of our strongest predictive factors, but of course, we can't use the natural history kind of factors that we had before -- where we can say the number attacks in the first year, if they're greater than five, has a profound influence on the course of the patient's disease, because we should never wait that long anymore.

GEVER: Yeah.

WOLINSKY: These days where we have our biggest tool for that is really the use of MRI, so important both for diagnosis, but also important in terms of giving us some insight into prognosis so that the more lesion activity that we can deduce that a patient had up to the time of their first clinical attack, the more likely we are to know that that patient's on a trajectory that over the next five, 10, and 20 years will be one which could otherwise lead to a rather disabling state.

If they have very limited disability, or limited findings on the MRI, then we have more time to be able to decide when and how to intervene.

GEVER: So if a patient comes to you with what appears to be a first MS attack or MS-like attack, you would send him to an MRI right away?


Right, so let's say we take an archetypal patient, a young woman who wakes up one morning, has a little bit of difficulty perhaps putting on the morning make up because the vision just doesn't seem to be right, and over the course of the day might be able to isolate that fairly well as something that's wrong with the vision out of the right eye,

maybe develops a little bit of pain, and perhaps ignores it for the first day, but by the next day the vision is falling and then is seen by an optometrist, or an ophthalmologist, or an emergency room physician, and usually they'll know that this is either optic neuritis or at least to get the appropriate consultation to figure it out.

In the past that might have been treated just as optic neuritis, but now, almost invariably, imaging will be done, and sometimes with the very first imaging, you can differentiate whether this is likely to be an isolated event or has a very high likelihood of being something associated with subsequent attacks, and what in the old days would have been a clinical diagnosis of MS, but now we can accelerate that process with confidence greatly.

GEVER: And are things like, you know, age of onset or the nature of the first attack --

WOLINSKY: Well, age of onset, location of the first attack, brain stem attacks, spinal cord attacks sometimes are a little bit more ominous in terms of the overall prognosis. Men, in general, tend to do less well with the disease over time than women. But again, these are not -- while they're useful, to me they're not as important as, is there a large lesion load on that initial MRI? If there is, then I know I need to be working with the patient so that they understand the importance of starting something for the long run early.

GEVER: Are there clinical practice guidelines that spell this out, provide an algorithm for what the --

WOLINSKY: Yeah, we actually have a pretty good algorithm for diagnosis at all stages of the disease. This is something that was, you know, has been evolving, I guess, over the decades, but particularly over the last about 10 years, so there was something called McDonald's criteria, which came out as a formal opinion paper, basically, by a group of experts to say, "This is what we think we need for a diagnosis, this is how we should integrate MRI in particular into our thinking process," and updating the older criteria that had been developed by Poser and others on a particular committee. That particular set of guidelines in part was best evidence and in part was expert opinion.

GEVER: Yeah.

WOLINSKY: And it certainly defined areas where it would be important to have more evidence on which to base that opinion. Those criteria were revised about five years later, based on a lot of additional information and fortunately, almost all of the criteria were just strengthened rather than modified.

GEVER: So, the experts were validated?

WOLINSKY: Yeah, it was a fairly educated guess, I guess is the best way to put it. And then most recently, the last year, we went through yet another revision of those criteria, again based upon additional data. So, there's very little in the current guidelines that isn't very well evidence-based about it. Perhaps we'll change some things sometime in the future but I think these will be very small refinements from this stage forward. One of the things is that that role of MRI both diagnostically -- and not part of that paper, but part of other observations made, especially in some of the clinical trials -- and about prognostic factors at onset, has been very well vetted.

GEVER: Yeah, and you mentioned earlier that the treatment armamentarium is now mature and really has expanded quite a bit in recent years and is continuing to do so. Could you talk a bit about the workhorse drugs that we have for MS?


GEVER: Glatiramer, interferon, natalizumab, and now we have fingolimod.

WOLINSKY: Yeah, so these are really, I'm not sure that I'm aware of another area of medicine where therapeutics have advanced quite as rapidly as they have here. Certainly, in the early days of my training, we had nothing but steroids for acute attacks and one of the great raging debates at that time was, do you even tell an individual they have MS because there's so little we can do for it? That began changing in the nineties, 1990s, when the first trials were well underway and eventually provided us with data that said, yes, we can reduce attacks, and, yes, we can reduce some of the activity that we see on MRI, and perhaps we even can modify the amount of accumulated disability, even in the relatively short two-year trials that have been the norm, more or less, to date. So, that led to the introduction of the interferons of which there are several different formulations, all of which are effective with different kinds of treatment regimes. And glatiramer acetate which came along fairly quickly as well. So, these are drugs that we now have the better part of two decades' worth of experience with. We know what they will do. We know about their relative equivalence and we know about their side-effect profiles and long-term issues and acceptance by patients.

Then the next, I guess, on the list, was the formal approval for a drug called mitoxantrone. Chemotherapy had been used from time to time in patients with extreme diseases, but this was really the first example where adequate trials were done to reach regulatory approval standards. It's a drug that I think most of us would prefer not to use because the side effects and the important consequences of use for some patients can be quite serious, so it's a reserved drug. Then natalizumab, which has a interesting history, both in terms of approval, brief retraction, and then reintroduced under relatively new guidelines that have been set by the FDA for side-effect minimization.

GEVER: Yeah, you can say the word PML.

WOLINSKY: Right, and we can talk especially about the PML, progressive multifocal leukoencephalopathy, but it's really the concept that one could do risk minimization.

GEVER: Yeah.

WOLINSKY: Which is something that I think we'll be seeing more and more, and not just with medications for multiple sclerosis, but in general, as one has to weigh risk benefits and sometimes the benefits look good enough that a certain amount of risk, if it can be managed or minimized for some individuals, may well be worth having in that balance.

GEVER: And you think that's worked out reasonably well?

WOLINSKY: Reasonably well. Now a perfect risk minimization for me is not one where you detect a disease that has substantial consequences early in the absence of any definite treatment that would reverse that disease, but rather where you could avoid that risk, if you can identify those at greatest risk for it. And perhaps there are some newer approaches that might be, that may eventually prove to be quite useful along those lines.

GEVER: Certainly, tests underway with the JC virus antibody test?

WOLINSKY: Right, and that's --

GEVER: That's what you're referring to?

WOLINSKY: That's the example, certainly, for a variety of reasons. There has been a considerable investment by the manufacturer to understand better what may lead to the risk, who might be at greatest risk for the use of the drug, and what durations of drug therapy might be associated with an increasing risk, and what kind of pre-treatment might have set the patient up for a greater risk. So, it looks like an individual who's never experienced an infection with JC virus is at substantially less risk than a patient who already has had that exposure and who is carrying the virus, as half of us do -- maybe both of us, at the moment -- and then are at risk, under the alteration of immune surveillance that occurs with the drug, and possibly, other factors, to have JC virus activate, become more neurotropic and potentially initiate a disease. So, this helps, I think, the physician and the patient know better, when they're starting the drug, what their short-term and longer term risks might be, in relationship to the benefit that can be had. And I think we're increasingly doing that with even the older drugs, that we have to understand what neutralizing antibodies mean for some drugs, to understand perhaps eventually better, in terms of which patients might not be able to respond to a drug, so you can just avoid having to wait and find out how well they're going to do --

GEVER: Yeah.

WOLINSKY: -- by predicting who the best responders will be. Subsequently to that, we've had fingolimod, which received approval about a year ago, and I suspect, that in the course of the next 18 to 24 months, perhaps a little bit sooner, I don't think any longer than that, we may see as many as four additional new drugs to add to our armamentarium and the remarkable thing is that each of these drugs would be representatives of new classes with entirely different mechanisms of action.

GEVER: And many of them or maybe all of them are oral, as well.

WOLINSKY: Or at least of the ones I'm thinking about, all but one are oral agents.

GEVER: Of course, we've been talking about drugs here, surely there must be nonpharmacological things that have some kind of evidence base that you can recommend to patients to at least improve their quality of life. Would not be disease-modifying, of course, but --

WOLINSKY: Right, and many of the things that are best for my patients are things that are best for every man, or woman. So, healthy lifestyles, eating habits, smoking is clearly not good for anyone, but there are increasing data to suggest that the risk of multiple sclerosis increases among smokers and there are very good data that suggest that patients with more progressive forms of the disease are more likely to be smokers. Now, whether that's cause and effect or not is always a little bit hard to know epidemiologically, but avoiding smoking is a great idea. We're increasingly attracted to the notion that vitamin D has some role to play in MS, and while it may take quite a while to have class A evidence for that, I think a lot of physicians who take care of patients with MS are being careful to be sure that their vitamin D levels are appropriate and if not, that they're taking supplementation at an appropriate level.

GEVER: Now, do practice guidelines yet talk about vitamin D measurement?

WOLINSKY: There has been discussion about this, and for example, on the National MS Society's website, I think there's a fair amount of information about it. In terms of putting it out to a practice guideline, it's a little bit premature to say, "You have to look for this, and you have to replace this." Because that level of evidence really isn't there. But it's a little bit hard to ignore the building association.

GEVER: And there are also a number of symptoms of MS that are not the classical things that people think about, with the muscle weakness and the tingling and those sorts of things, but there's bladder control issues and spasticity, and what do we do about those?

WOLINSKY: Well, I -- you know, there are a myriad of things that can go wrong when the conductive pathways in your central nervous system are not working properly. So, we can go through a litany of symptoms and signs that are certainly helpful diagnostically -- helpful for us to think the patient might have the disease -- but that's almost a course in neurology. So let me just take a few of the common symptoms and what kinds of approaches might be taken for symptom management. So, a major issue for many patients with MS is a problem with fatigue. Of course, we all have problems with fatigue from time to time, but usually we understand why, and when we get tired, we may not function so well. But when we're not worried that if we become tired, fatigued, that it will be so profound in terms of its manifestations that maybe, while we could walk unassisted, if we had MS, as that fatigue sets in, we require a cane. Or it takes us twice as long to walk distances it might when we're fresh in the morning, or we can't get through an entire workday.

And fortunately, there are medications which now, they're not perfect, but often help combat some of that fatigue in a very effective way.

GEVER: Now, are these things that we haven't talked about already or --

WOLINSKY: No, these -- so I think we, what we've been talking about so far have been what I would call disease-modifying drugs, where we're saying, "We understand if we have a patient on this, that there will be fewer attacks, that there will be fewer new lesions on their MRI, that there will be less accumulated disability and increasingly we can expect that their lives will be more normal." Now, we're talking about, when there are problems that have been caused by the disease, what can we do symptomatically, to improve those difficulties that they're experiencing on a day-to-day basis? So, I'm no longer in that setting, talking about something to prevent what otherwise could be the future for that individual for the disease. I'm talking about something that we can expect to see an improvement. And we can then measure, is that improvement worth having? Are the side effects too great for that improvement?

And usually the physician with a patient over a relatively short period of time can understand if, is that drug working? If not, do we move to another approach that might be very useful for that same set of symptoms?

GEVER: And fatigue, especially, is a difficult thing, not only for MS patients, but for many diseases. And, you know, it can compromise therapy, not just be a lifestyle problem for the patient. So, this really seems like an important thing to get a grip on.

WOLINSKY: Yeah, very much so, and then understanding exactly there are some words which we use, all of us, where I know what I mean, and you may know what you mean when you use the word, but we may use the word entirely differently. And this is one of those areas where it's very important for the physician to work with the patient to understand exactly the nature of that symptom. Sometimes a drug like amantadine hydrochloride, or related drugs in that class, will be very useful in a global kind of fatigue that patients with MS have. Occasionally, a drug like modafinil (Nuvigil) will be useful, even though those drugs are primarily thought about as being useful for shift workers who have more of a sleepiness than fatigue. And occasionally, a drug like dalfampridine -- I always fall back on the older form, you know, pyridine, in my mind, takes me a minute to get caught around -- which probably is affecting conduction in delineated pathways within the central nervous system, can really be remarkable for improving endurance for selected patients, as a different kind of fatigue, if you will. Unfortunately, every one of these drugs, like a lot of symptomatic medicine, don't always work 100% of the time for 100% of patients, so there really is a greater tailoring that has to be done. It's really the art and practicing of medicine, somewhat more even than the disease-modifying drugs.

GEVER: Thank you so much.

WOLINSKY: Sure thing. Enjoy it.

GEVER: I'm John Gever, MedPage Today.

Wolinsky has disclosed the following relevant financial relationships:

Salary/Honoraria: Over the past 12 months, has served on advisory boards or data monitoring committees, has consulting agreements or received speaker honoraria from: Astellas, Bayer HealthCare, Biogen Idec, Celgene, Consortium of Multiple Sclerosis Centers, Eli Lilly, Hoffman La Roche, National Institutes of Health, National MS Society, Novartis, sanofi-aventis, Serono Symposia International Foundation, Teva Pharmaceuticals and Teva Neurosciences, and Ohio State University.

Royalty: Royalties are received for outlicensed monoclonal antibodies through the UTHSCH to Millipore (Chemicon Internation) Corporation since 1993.

Contracted Research (including PI): Has research or contractual support from the Clayton Foundation for Research, the HIH [2 U01 NS045719-06 (PI of the subcontract to UTHSCH for image analysis) and 2ROI-EB002095-06AI (Co-I)], the NMSS (RC-1019 A5) and sanofi-aventis. MultipleSclerosis/31399?utm_content=&utm_medium=email& utm_campaign=DailyHeadlines&utm_source=

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03/31/2012 04:25 PM
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Angioplasty Helps in MS, Studies Find

This report is part of a 12-month Clinical Context series.

By Kristina Fiore, Staff Writer, MedPage Today

Published: March 27, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, Nurse Planner

5 comment(s)

action Points

These studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Performing angioplasty to remove blockages in neck and chest veins improved symptoms of multiple sclerosis.

The studies lend support to the controversial theory that MS is linked to chronic cerebrospinal venous insufficiency (CCSVI).


Performing angioplasty to remove blockages in neck and chest veins appeared to improve symptoms of multiple sclerosis, according to two small studies presented here.

Although they were retrospective and neither included a placebo group, both studies concluded that angioplasty of the jugular and/or azygos veins was associated with significantly improved quality of life for MS patients, researchers reported at the Society of Interventional Radiology meeting.

"We're encouraged to know that patients are clearly getting better," Kenneth Mandato, MD, of Albany Medical Center in Albany, N.Y., told MedPage Today. "These results can serve as a springboard to a larger study where both the patient and a neurologist are blinded."

The studies lend support to the controversial theory that MS is linked to chronic cerebrospinal venous insufficiency (CCSVI).

The idea of CCSVI comes from the work of Paolo Zamboni, MD, a vascular surgeon at the University of Ferrara in Italy. In 2009, Zamboni reported a study that found MS patients were more likely to have narrowed jugular or azygos veins than healthy patients.

These blockages cause high pressures, which adversely impact inflammation in the brain and may contribute to the formation of characteristic MS plaques. Treating these veins in the neck and chest could help treat the disease, Zamboni suggested.

But the neurological community has remained highly skeptical of the theory. Questions remain about how to properly measure what a 'normal' jugular or azygos vein looks like, and techniques for assessing these parameters need to be standardized.

In the first study, Mandato and colleagues conducted a retrospective study of 213 MS patients who were treated at their center during a four-month period; 192 responded to follow-up surveys on quality of life using the MSQOL-54.

Most (96) had relapsing-remitting disease, 66 had secondary progressive MS, and 30 had primary progressive disease.

A total of 189 had angioplasty and another three also had a stent placed.

Mandato and colleagues found that patients reported significant improvements in both physical and mental health scores (P<0.05 for both).

Physical health scores improved by 77% for both relapsing-remitting and primary progressive patients, and by 59% for those with secondary progressive disease (P<0.05 for all).

Mental health scores were also similarly improved, but Mandato noted that those with secondary progressive disease were significantly less likely to benefit than those with the other two disease types (P<0.05).

They also found that those who'd been diagnosed more than 10 years ago had the least improvements, but in further analyses, years since diagnosis weren't associated with changes in physical or mental health scores.

In a second study, Hector Ferral, MD, of NorthShore University Healthcare System in Evanston, Ill., and colleagues also conducted a retrospective review of 107 procedures in 95 patients with MS who were evaluated at their facility from June 2010 to September 2011.

Half of patients had relapsing-remitting disease, 39% had secondary progressive MS, 6.4% had primary progressive MS, and disease was unclassified in 4.2%.

Clinicians assessed patients' jugular and azygos veins and conducted an angioplasty in those who needed it; some were also stented. All patients were given anticoagulants for six weeks following treatment.

Overall, Ferral and colleagues reported seeing stenosis in 94.9% of patients, and angioplasty was associated with a sustained improvement (more than four weeks) in 55.5% of patients.

On the other hand, 38.8% of patients reported no improvement at all.

The greatest improvements in symptoms were reported in relapsing-remitting patients, the researchers said.

Only 7.7% of patients reported any complications, and most were minor, such as bleeding at the puncture site.

Major complications, including clot formation in the treated veins, occurred in 3.3% of patients, which was a relatively low rate, Ferral and colleagues said.

They concluded that venous abnormalities are common in MS patients and angioplasty appears to be associated with some improvement.

Timothy Coetzee, MD, chief research officer for the National MS Society, said in an email to MedPage Today that even though these studies lacked a placebo group and were retrospective, they add to the literature on CCSVI.

"To truly understand the CCSVI hypothesis and what it means for people with MS requires conducting well-designed studies," he said. He added that the society has teamed with a Canadian MS society to support CCSVI research using rigorous controls and standardized assessment techniques and technologies.

Mandato agreed that prospective, double-blind randomized controlled trials are needed to further evaluate the role of endovascular therapies in MS, and encouraged more collaboration between interventionalists and neurologists.

"The medical community needs to take a multidisciplinary approach to this procedure before it can be validated," he said, adding that skepticism of the hypothesis is "healthy" and is necessary to drive further research.

The researchers reported no conflicts of interest.

Primary source: Society of Interventional Radiology

Source reference:

Sekhar KP, et al "Short-term outcomes after endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) in patients with MS" SIR 2012; Abstract 48.

Additional source: Society of Interventional Radiology

Source reference:

Ferral H, et al "Clinical experience in the management of CCSVI" SIR 2012; Abstract 49.

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04/02/2012 10:04 PM
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MS and Quality of Life, a Clinical Context Report

Download Complimentary Slide Presentation This report is part of a 12-month Clinical Context series.

By John Gever, Senior Editor, MedPage Today

Published: April 01, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, Nurse Planner

Action Points

Up to 50% of patients with multiple sclerosis have a cognitive problem which can often be difficult to diagnose.

Depression also is increased among MS patients and is best treated by a combination of psychological counseling plus antidepressants.


JOHN GEVER: I'm John Gever with MedPage Today. I'm here to do a Clinical Context interview with Dr. Jack Burks, who is the Chief Medical Officer of the Multiple Sclerosis Association of America and a practicing neurologist, and we are here in Amsterdam at the ECTRIMS/ACTRIMS Annual Meeting, where we're hearing a lot of new research about multiple sclerosis.

What happens when a patient with MS sees the doctor is, very frequently, you know, the doctor has a treatment algorithm -- you do this, this, and this for a patient with multiple sclerosis, and okay, we're done, get out of here -- and I'm sure that's not satisfying to the patient and is really not treating what the patient needs.

What do clinicians need to know about the patient experience with MS? I mean what are some of the things that they may not be getting from their neurologist or from their family physician?

JACK BURKS, MD: Well, I think the important part is we now have treatments for multiple sclerosis which we didn't have 20 years ago and so there's a lot of excitement.

There are new drugs being developed every year, there are oral medicines coming, there are very powerful medicines coming, and it's an exciting time. And therefore the focus is really on how can we stop your MS, which is an appropriate focus, and we're making great progress.

What gets second-line consideration -- I'll call it that way, I'll be nice -- is the quality-of-life issues.

Now, what happens to the patients' other problems, their bladder problems, their bowel problems, their sexual dysfunction, their thinking problems, their being tired all the time?

Because the conversation is focused at what's the best medication for you, which is a very important conversation.

But we don't spend as much time, I think, with the other issues that are very important to the patients, because if we have a treatment for MS, a disease-modifying therapy, you may not see any difference for years.

But if you have a treatment for the bladder, for example, that can work in two days and they've had this problem for 15 years, that's also -- that's an important issue that we also need to discuss.

I think that we don't spend as much time talking about it, and the patients tend not to bring it up either. So part of it is my fault, maybe, because I don't delve into it.

And the other part is the patients don't say much about it and it's sort of like don't ask, don't tell. If they don't ask, you know, I tend not to talk about that as a neurologist.

And we need to change that because we have a number of new treatment modalities for these symptomatic managements that help quality of life, frankly, and that is also very exciting to me.

GEVER: And, I guess, how does the clinician get this conversation going? I mean, should the clinician have a checklist of symptoms? You know,

"Are you having bladder problems, are you having bowel problems, are you having trouble swallowing?"

BURKS: Well, almost all physicians who take care of MS patients have a checklist. And we ask the patients to fill out a form, and they check everything, because MS affects so many different things.

But we really spend our time focusing on the disease-modifying therapies, and we don't really go into much depth, because they literally may have 10 or 15 issues. So we sort of leave it up to the patient to say what things are really bothering you.

And then the patients get so focused on disease-modifying therapies, too, then they don't want to mention it.

Or they say, "Well, you know, it's just part of having MS and I'll live with it," not realizing there are actually treatments that could be very helpful for them.

And so the way to change that, I think, is to make patients more aware that there are ways to treat these other issues and have physicians knowledgeable enough to know what those methods of treatment are and address them.

And that's true for the primary care doc as well as the neurologist, because a lot of these patients spend a lot more time in a primary care doctor's office than they do at a neurologist's office.

GEVER: And I guess we'll start with neurologists anyway. Are they generally aware of the treatments for some of these other non-disease -- not the symptoms that are modified by disease-modifying therapies -- the other symptoms?

Do clinicians know about treating the bladder issues and the cognitive deficits and so forth?

BURKS: Yes, I think they do. They just don't talk about them very much. I mean if you gave doctors a quiz, they would say, "Oh, yes, you can treat the bladder by such and such, and the bowels, you can try to relieve constipation.

And, you know, if they have sexual dysfunction for men, you can try Viagra. For women,

if they're dry, you'll use lubricants. I think that's general knowledge; it just doesn't get discussed much.

GEVER: So, these aren't really anything special for MS patients. If any patient coming in complaining of a bladder issue, you would use it -- basically go through the same sorts of treatments with them?

BURKS: If we had the discussion, yes, and especially true with the bladder issues, since you brought that up first, because there are treatments that can really stop incontinence, and incontinence is a huge issue for patients.

And we've had treatments for many, many years, anticholinergic treatments, but they have side effects.

The patients get tired of the side effects, and they don't think they were really that great. And now the FDA has approved botulinum toxin for the treatment of incontinence, which is a shot, a bladder shot.

You have catheterization; takes only a few minutes, but it will last, you know, eight to twelve months. So that's a big deal for the patients. So why don't the patients talk to the doctors about that?

Because they have other things on their mind and they think, "Well, I'll just have to live with it. It's a burden of having multiple sclerosis and I'm not going to bother anybody else about it," or "I'm embarrassed to talk about it."

But it's interesting. I had a conversation with a patient the other day and I was asking her. She had primary-progressive MS and so she had a lot of symptoms. And so I was asking her, "What's bothering you?" and she went through about 10 different things.

And then I just said, "Well, what about your bladder?" And she said, "Doctor, I don't want to go there. This is such a terrible problem for me. I don't even want to discuss it with you." So that gives you some idea of how people look at it.

And so now that we're aware of more treatments, better treatments, we need to bring it to the front with the patients and say, "Let's talk about this."


BURKS: "Maybe we can help you with this." And the patients need to know about it, too, so they can ask the doctor about it. Because if a patient comes to me and asks me about their bladder problems, you know, I'll take the time to talk to them.

But if they don't mention it and I've got 14 things on my list of problems that they have that I'm dealing with, it may not come up, or it may come up very superficially.

GEVER: Yes. And while we're talking about bladder, the nonpharmacologic interventions -- I know that pelvic floor exercises are not, you know, there's some controversy about how effective they really are. But I wonder, in an MS patient, might they be even less likely to be effective because of the motor issues that come with MS?

BURKS: Not that they shouldn't be tried, but they're not so effective.

The problem with the bladder in multiple sclerosis is neurogenic, and that means the innervation to the bladder wall and the sphincter of the bladder are disrupted because of demyelination in the spinal cord and above.

So, therefore, it's not so much a mechanical issue, it's a more of a neurologic issue.

But that doesn't mean you can't work with the mechanical issues as well, because most people with incontinence don't have neurologic problems that have been diagnosed. I would say 90% of the people with urinary incontinence are not multiple sclerosis patients.


BURKS: But if you look at MS patients, 80% of them have that problem and we're just not discussing it very much.

GEVER: Yes. And you mentioned the botulinum toxin and anticholinergics. Are there other medications, classes of medication that one can --

BURKS: There are. There are some alpha-blockers. Depending on that -- there are problems with failure to store in the bladder and failure to empty in the bladder.

What I'm talking about is failure to store. They have to go to the bathroom a lot; they can't store the urine. But then there's another factor that in some patients -- and not all patients, of course -- is failure to empty.

They have these big, flaccid bladders and they have to do intermittent catheterization to empty the bladder or they'll get infections from the urine that collects there.

So it is different ways of looking at it, and one of the big issues is there's what we call dyssynergia.

So you have the bladder wall, and then you have the external sphincter, and the bladder wall contracts, external sphincter relaxes, and people urinate.

Well, in MS, the bladder wall contracts at the same time the sphincter contracts, so where does the urine go?

It goes up into the ureters towards the kidneys; you get reflux, which can be a serious problem.

So not only are you talking about bladder problems, you might have kidney problems as well, so dyssynergia is another issue that we deal with very differently.

GEVER: And I would assume bowel problems would go along with this as well. And is it a constipation issue or an incontinence issue, or both?

BURKS: Mostly constipation, sometimes diarrhea, and we have to be careful.

Like if I treat a patient with bladder problems, which most people have, with an anticholinergic drug, their side effects include constipation; dry eyes, dry mouth, and constipation and fuzzy thinking.

So, therefore, you have to be very careful, because people with bladder problems don't want to drink. If they don't drink, they don't have to go to the bathroom so much.

So if you don't drink and you're on anticholinergic drugs, your constipation becomes a huge issue.

So you really have to institute a bowel program very early in MS, and good bowel hygiene can minimize the discomfort and increase the quality of life dramatically in people who are having constipation.

GEVER: And does this include medications, and are we talking about your basic over-the-counter type of laxatives? Is that what you would recommend or --

BURKS: No, I don't like laxatives, but stool softeners might be used, but fiber, bulk-forming agents. There's typical ways we treat constipation and anyone else, and they're not prescription drugs, for the most part.

And laxatives, people get accustomed to laxatives, and then they don't work so well, and so I try to stay away from laxatives unless I have to.

GEVER: And so I guess while we're looking at that part of the body, there's sexual dysfunction as well. You know --

BURKS: Well, we don't talk about that. It's amazing; people don't talk about it. Men will talk about it because they have Viagra.


BURKS: They have the erectile dysfunction medications. I won't talk about the specifics, because they all work and that's helpful to them.

But it's amazing, most women have sexual dysfunction, too, but we don't hear about that so much.

They have pain on intercourse. They have dryness. They have -- less likely to have an orgasm.

All these things can be helped if we just talk to the patients about it.

There are ways to deal with this, like lubrication. I mean the simplest thing in the world is an over-the-counter lubricant that can reduce the friction, can reduce the pain.

But there are a variety of ways to deal with it. Some people get muscle spasms when they have sexual intercourse and their legs tighten up. Well, there are treatments for muscle spasms that we can use.

We can treat the pain directly, at times, so there's a lot of things to it, but we don't get to use any of those in many patients because we don't talk about them.

GEVER: Yes. And are there other unique things about sexual dysfunction in MS where a treatment that you might recommend for another type of patient that you would not expect to work in an MS patient?

BURKS: No. I think the lubrication, the erectile dysfunction drugs, the talking about it, you know, and there's a psychological part of sexual dysfunction that is huge.

So we don't want to just focus on the physical side, but also the mental side.

And so it's amazing how well we can deal with sexual dysfunction if we talk about it.

GEVER: Yes. And I understand swallowing issues are a factor in MS as well, and honestly I don't know anything about that. Tell me about it.

BURKS: They can be, they can. That's a really good question, John. The swallowing is especially important, because if you don't swallow properly you might get aspiration pneumonia.

And so therefore it's really important to talk about "Do you have swallowing problems?" "Well, no, I don't have swallowing problems." "Well, do you cough when you take a glass of water?" "Oh, yeah, I do that all the time." You know, so you have to bring it out.

And then you can do testing on the swallowing, and then the rehabilitation therapist actually can work with the swallowing.

The speech language pathologists actually do a lot of work with swallowing as well, teaching them how to eat properly, where to put the neck.

I won't go into the details, but the key is that speech language pathologists are very good at helping people with swallowing problems, and swallowing problems that lead to pneumonia are a serious issue.

GEVER: Okay. And so what else, what else might the MS patient experience that they don't talk about enough with their doctor?

BURKS: I would think cognitive dysfunction; that's another thing that we don't talk about very much. That's because MS patients are not like Alzheimer's patients.

You know, if you talk to an Alzheimer's patient for five minutes, you know they have cognitive impairment; MS patients, no. They look good, they talk good. They make sense.

But 50% of them have a cognitive problem, and the cognitive problems are many, but they're hard to pick up sometimes. Like, they have problems with executive function.

When they start something, when they stop something, they have trouble understanding the consequences. But actually, you don't pick that up in a regular mental status examination.

Or they have trouble with, like, working memory. Working memory is that you're working on task A, you go to task B, and then you go back to task A, you can't remember where you were; that's called working memory, where you can't retain it to come back.

Again, we don't pick that up on our regular testing, but it's incredibly important.

If you're a middle-level manager with multiple sclerosis and you're sitting in a cubicle with a hundred other cubicles in the same room and you're being interrupted constantly, your performance is really terrible because you cannot go from one task to another.

However, if you can get a corner office with a wall and a door that shuts and you work on one project at a time, your performance rating goes up dramatically.

So these are not just esoteric academic issues, these are things about family, jobs, living in the real world. There are ways to, like, adapt to the cognitive road, so cognitive rehabilitation is actually very important.

And the medication side of it has not gotten as much emphasis as the medication side of Alzheimer's, for example.


BURKS: People are trying various drugs, but there's no consensus right now.


BURKS: But helping people adapt to their cognitive issues, something that can be done. But most physicians I think don't really understand cognitive rehabilitation.


BURKS: And for MS patients, that's really important.

GEVER: And how does the clinician pick this up? And I would imagine it's that the patient probably is not even aware of it him or herself much of the time.

BURKS: They probably are; they just deny it. The families are aware of it, so if you talk to the families you're more likely to get the stories. Or when we do -- there are special neuropsychology tests that we do for cognizance.

GEVER: Okay.

BURKS: And when we do those, you'd be surprised the number of times that the patients, for the first time in their life, realized they have cognitive problems and they're devastated.

GEVER: Good. You can name names here. What are the specific tests that one would use?

BURKS: Well, there are a number of batteries; they're named after people.

GEVER: Okay.

BURKS: And the key is if you're interested in that as a physician, send them to a neuropsychologist.

The neuropsychologist knows the specific test that can be used, and there are a number of choices for that. And some neuropsychologists like one set of tests, another like another set of tests, but this should be a neuropsychology decision, not a neurologist's or a primary care doctor's decision, I think. We just need to get them to these people.

It's like the bladder issues. We need to get them to a urologist to get botulinum toxin, but if we don't talk about it, we're not -- they're missing the opportunity at least to explore another treatment, because the urologist has to do that.

GEVER: And I've seen depression also being on the list of common but often unrecognized symptoms in MS patients. And it would seem logical that somebody with a chronic disease, a scary chronic disease like MS, is going to be depressed about it. So, you know, what's the appropriate approach to that?

BURKS: Well, there are two issues with depression in MS.

One is if you have a chronic illness and your spouse walks out and you lose your job, you know, you're going to be depressed.

But MS by itself can cause neurochemical changes that can precipitate depression as well, so we have both.

We have the situational depression, and then we have the MS-related depression, and, again, we're talking about half the patients have had major depressive issues in their life.

When they get a major depressive issue, you can tell it; it's actually pretty easy and you put the people on antidepressants.

But the fact is psychological counseling plus antidepressants are much better than either one alone, so, therefore, you have to have -- it's a team approach to MS, you know, and I'm talking about teams.

I'm talking about the psychologists, and I'm talking about rehabilitation people. I'm talking about the urologist.

I'm talking about all sorts of different people that are involved in quality-of-life issues that if the neurologist becomes the captain, and making sure everybody does their job and they coordinate it, that's great, and that's what we're trying to get at, the team approach to multiple sclerosis, because one doctor can't do everything.

And the primary care doctors are spending more and more time with the MS patients as well.

So it's important for primary care doctors to also understand this, because they may have more of a sense of the patients than even the neurologists who are really focusing on disease-modifying therapies; that's where they're the specialists.

Because some of the disease-modifying therapies have adverse events that are significant and we really have to pay attention. What are we concerned about with this drug, this drug, and this drug?

Are we making sure we're checking for all these adverse events? And by the time we get all that stuff, we don't talk much about bladders or sexual dysfunction, things like that.

GEVER: So I guess it's time to sum up here. What would really be the most important message that you would want a clinician to take away from this topic?

BURKS: It's to have a list of issues that are common, the ones we've talked about, and there are others.

But the ones we've talked about are a good start, and make sure that the patients are actually asked questions about those.

"How is your bladder? Are your sexual relationships satisfactory? Do you have constipation?"

And then, "Tell me more about it," and then most of us know how to do something about it once we talk about it. So I think the key is recognition, taking the time to talk to the patients about things other than their lymphocytes.

GEVER: And I would imagine it's going to be helpful, too, if the doctor says to the patient, "And I can help you with that."

BURKS: Absolutely, and that's what we're seeing. We're seeing more and more treatments. Like, for example, one of the biggest fears MS patients have is "I'm going to be in a wheelchair."

Well, there's a new FDA drug approved for walking; it helps them walk better. Not everybody, but worth a try, but they need to be given that option.

There is a condition where people cry inappropriately; it's called pseudobulbar affect. Sometimes they laugh inappropriately, too, but it's usually crying. And they say, well, they're just depressed. No.

There's a medication out, approved by the FDA, for pseudobulbar affect now, so we're talking about some pretty exciting things.

And muscle spasms; you know, well, there's medications for that now. Again, Botox can be used; botulinum toxin can be used for spasticity.

It's approved for upper limb spasticity, but most people don't know that yet.

So we need to be aware of what the treatments are and ask the right question, because now we have treatments that we didn't have before.


BURKS: And it's important to get that information.

GEVER: Great. Well, thank you so much, Dr. Burks. I know it's been extremely informative for me, certainly, and I think for our audience as well, so thank you very much.

BURKS: It's a pleasure to be here. Thank you.

GEVER: In Amsterdam, I'm John Gever, MedPage Today.

Burks has disclosed the following relevant financial relationships:

Received salary/honoraria and consulting fees from Avanir Pharmaceuticals, Allergan, Acorda Therapeutics, Bayer HealthCare, Novartis Pharmaceuticals, and Serono MultipleSclerosis/31780?utm_content=&utm_medium=email& utm_campaign=DailyHeadlines&utm_source=

© 2012 Everyday Health, Inc. All rights reserved.

Post edited by: Bettyg, at: 04/02/2012 10:11 PM

Post edited by: Bettyg, at: 04/02/2012 10:22 PM

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Basic Science Improving MS Care, a Clinical Context Report

Download Complimentary Slide Presentation

This report is part of a 12-month Clinical Context series.

By John Gever, Senior Editor, MedPage Today

Published: April 03, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, Nurse Planner

Action Points

The reason for the strong female predominance of multiple sclerosis (MS) is not known, but at least in mice may be related to the peroxisome proliferator-activated receptors (PPARs), a group of proteins that function as genes.

Note that the drug natalizumab, an alpha-4 integrin blocker used for MS patients, has the rare side effect (occurring in approximately in one of a few hundred patients) of a devastating viral infection called progressive multifocal leukoencephalopathy (PML), caused by the JC virus.


JOHN GEVER: I'm John Gever with MedPage Today, here to do a clinical context expert commentary on multiple sclerosis with Dr. Lawrence Steinman of Stanford University, a preeminent neuroimmunologist.

Dr. Steinman, there are a number of questions that, you know, really have been with us as long as we have known about MS. Some of them may have become more prominent recently.

I think one of the most puzzling is the female predominance of the disease.

I mean because we don't really know what the triggers of MS are, it seemed like it would be a window into the disease. And yet really it hasn't worked out that way too well so far.

And of course the female predominance has increased over the last decades. So talk a little bit about that, if you would.

LAWRENCE STEINMAN, MD: Yes. Well, one of the most striking things about MS is that over the past 20 years the ratio of females to males has increased from about 2 to 1 to over 3 to 1.

So I don't think that females have evolved that quickly. There must be something going on in the environment that has changed the situation.

Alternatively, one could argue that maybe we are reporting the disease better or that females are more vocal and are being ascertained in a more prevalent way. But this isn't happening, as best we can tell. The ratio really is increasing dramatically.

So we set out in the laboratory to attempt to begin to answer the question about what might be differences between males and females. And the work I am describing was done first at my lab at Stanford by a very brilliant postdoc, Dr. Shannon Dunn, who moved to the University of Toronto after finishing her postdoc with me.

So, what she found: first of all, beginning in mice, we have an animal model of multiple sclerosis in mice. It's a model that was first described about 80 years ago called, for want of a better term, EAE, experimental autoimmune encephalomyelitis. And in that model, females are much more susceptible [than] males.

So we were looking at various gene families that are under the control of androgens and estrogens. And one of the genes that was of most interest to us are a group of genes called the PPARs [peroxisome proliferator-activated receptors].

And they come in various varieties, and they are very sensitive to steroid hormones.

So when we knocked out a particular member of the PPAR family -- PPAR-alpha -- it turned out that the susceptibility in males shot way up.

So what we learned from her studies in mice -- and they are very elaborate, and they were published in top journals -- was that PPAR, particularly PPAR-alpha and also PPAR-delta and -gamma, serve as brakes on the immune system.

So is it the case, at least in a mouse, that female mouse have, say, a smaller amount of the brake, if you will, than a male mouse? And the answer is yes.

And it turns out that in the liver and on their T cells and in other places we look, that the males have much more of PPAR-alpha than females. If we castrate the males -- and that's a horrible experiment -- the PPAR level drops.

We also noticed that in a cage, the alpha male, the dominant male, has the highest level of PPAR. So it's exquisitely sensitive to testosterone. If we give testosterone to females, they'll grow a moustache in a mouse -- I'm saying that facetiously -- but they will also increase their level of PPARs.

And then we can treat mice with some of the standard drugs that are PPAR agonists. So for instance, gemfibrozil, a drug approved for lowering triglycerides, is very effective at treating EAE.

So she, Dr. Shannon Dunn, began the translation of this work to humans while she was still at Stanford. And she sought out to ask, "Is what we saw in the mouse also happening in humans?"

And she carried on the work since arriving at the University of Toronto and really has elegant results, which generally confirm what she saw in the mouse.

And the results are fairly astonishing. Females are much stronger immunologically than males. There is probably abundant reason in evolution for this to happen.

But if I immunize a female, they are going to mount a much stronger response to tetanus toxoid or to common vaccines. They have higher levels of cytokines in their blood.

The studies she did were absolutely meticulous and difficult to carry out. She had to know what stage of the menstrual cycle females were in, and she had to know -- she had to have, for each female, a matched male buddy so that over time, and when they came in at different times of the month and different periods of the year, that there was always a control.

But the take-home message is very dramatic. And this work is on the cusp of getting published, so that's very exciting.

So one of the things that may be happening is that there may be changes in the way women's steroid hormones are being produced.

Of course, birth control pills impact on that. But we have also seen, over the past few hundred years, that the age of onset of menstruation -- menarche -- is coming down, down, down.

So females, for environmental reasons, are undergoing rapid changes. And I think that -- I don't have an answer on why the female ratio is changing, but I have some very big clues.

The clues are also very useful because they could lead to treatment with drugs that are already approved and for which we have experience in millions of individuals. So that could be one of the really satisfying benefits of this research.

But I think Shannon Dunn's research is really at the center of beginning to understand why females are more susceptible and why the ratio is increasing.

GEVER: Yes. And much-mentioned treatments. Another thing that's changed in recent years is really an explosion of new therapies for multiple sclerosis -- certainly the disease-modifying therapies -- which of course then raises the question for clinicians of,

"How do we choose among these, and how do we, you know, have rational decisions about what to give patients?"

So, again, where would we stand with this? What kind of progress have we been making?

STEINMAN: Well this is an area of exceptional interest. The other day we were trying to use sports metaphors to understand what we are supposed to do with the wealth of opportunities and medications that have been approved and are about to be approved for the treatment of MS.

Can we make decisions based on predictive biomarkers, for instance? Or must we have to depend on more traditional marketing?

So somebody -- you know, getting back to the sports metaphor -- was talking about Wayne Gretzky. And his big secret in hockey was that he didn't care about where the puck was today or at this moment. He would skate to the puck.

And then somebody threw out the problem, "What if -- Wayne Gretzky, when he was playing hockey, as brilliant as he is, there is only one puck on the ice at any time. What if somebody threw out half a dozen pucks? How could he skate to the right one?"

And that's the situation that we find ourselves in, in contemporary neurology and trying to treat MS patients. There is a wealth of things to do.

So one of the tests that is now available -- it's approved in Europe -- is helping us to understand when we might want to use the drug natalizumab, the alpha-4 integrin blocker.

And one of the problems with natalizumab is this Achilles' heel that it has, that in one of a few hundred people who get the drug develop a devastating viral infection called PML.

The PML is caused by a virus called the JC virus. And it turns out that if you do not have antibodies to the JC virus, you are pretty much free of the risk of developing PML. Whereas if you do have antibodies, the risk of developing PML is about one in a few hundred people if you take more than two years of the monthly injections of natalizumab.

So we have an approved test that is helping us mitigate the risk. So this is a very big breakthrough, and it's quite successful.

Now another area that we are very interested in: a postdoctoral fellow of mine, Robert Axtell, began the work at the University of Alabama-Birmingham with Chander Raman.

And in April of 2010, we published a study showing that some of the individuals who are nonresponders to beta interferons have a very high level of a cytokine called IL-17F in their blood.

So over the last year and a half, we have engaged in two big studies -- one with a pharmaceutical company, Biogen, looking at their beta interferon product, and the other with Bayer. We have come to the conclusion, based on these studies, that above certain levels of IL-17F there is a very strong chance that you will be a nonresponder to beta interferon. And above higher levels you will most definitely be a nonresponder.

Now that's the good news. The bad news is that this covers only about 10% of patients. Now you could ask yourself, if you were a patient and there was a test available, a simple blood test, for measuring a cytokine, would you want to know whether you were likely to be a nonresponder? And I think the answer is yes. I think we will become better as we understand the biomarker field, that making the test more extensive, it will involve other markers.

We published this summer on a second marker, IL-7, that may aid us in combination with IL-17F. But this is another example of a work in progress, where we are definitely heading down a path where we will be able to make predictions.

Now there are other individuals -- Richard Ransohoff in Cleveland, Manel Comabella in Barcelona -- that have slightly more complicated tests that are telling us the same story -- that if you have a certain signature at baseline, it will tell us that you are probably unlikely to benefit from beta interferon.

Now this is going to be very good for the patient, because there is no sense in taking a medication that isn't going to help you. It delays taking the medicine that could help you. And the other thing is we spend a lot of money on these medicines, so we may as well eliminate a group of patients who are not going to benefit from all this money that's being spent and, again, put them on a more optimal medicine.

So I see an intensification of efforts to try to understand who will be a responder and who will not be a responder, and an intensification of efforts to know who will suffer some of the bad side effects of these drugs so that we can put them on different drugs.

GEVER: Yes, so it's really -- it's making personalized medicine a reality for MS.

STEINMAN: That's right.

GEVER: Yes. And there must be neuroprotective molecules out there, because not everybody gets MS. You know, presumably the genetic factors and the environmental factors that predispose toward it, they don't affect everybody the same way. And similarly, people who do have MS, they don't progress the same -- in the same way or the same speed.

Do we know what any of these are yet? And can we make them work for us?

STEINMAN: Yes. There are a few molecules that we and others have identified that turn out to be imbued with real guardian functions. And one of the molecules is known as alpha B-crystallin. And it was first discovered by Johannes van Noort in Leiden in the Netherlands, where he showed that it's the most intensely immunogenic molecule that is found in the white matter of the brain. And about 12 years later, we published a paper that showed that this very same molecule could actually protect animals from EAE, and it's produced in copious amounts in MS brain lesions.

So we have been working on the alpha B-crystallin molecule, and it turns out that it has the capacity to protect oligodendrocytes from dying after they have received immunological stresses. And we are beginning to understand the mechanism of how it works. So this particular molecule could be exploited to treat multiple sclerosis. It works very well in EAE. Van Noort has already taken this forward into humans. And we are planning our own trials in humans with this molecule.

Now one of the beauties of this molecule is that in the MS brain it's produced, although in insufficient quantities to be of the help that we can obtain from it if we give actually pharmaceutical levels of the alpha B-crystallin.

In the lens of the eye, the composition of the lens is almost wall-to-wall alpha A- and alpha B-crystallin. And the lens of the eye is associated with this concept of immune privilege. It's very hard to get an immune response started. So the beauty of these proteins called the crystallins is that they co-evolved, at least in the lens, to refract light and to give the lens immune privilege.

And what's happening in the MS brain is that, in response to the inflammation, the brain is making alpha B-crystallin, and we are beginning to learn how to develop therapies based on these remarkable molecules that are produced within the body.

There are a few other molecules that have come to our attention. The molecules involved in high blood pressure are also involved in the inflammation seen in MS. And we have a number of common drugs that we use to treat high blood pressure -- the angiotensin converting enzyme inhibitors, the ACE inhibitors -- that we are looking to bring into the clinical trials in multiple sclerosis.

So I think that there are or will be a wealth of protective molecules that we'll begin to pay attention to and will allow us to develop novel therapies.

GEVER: How long it's been since we have known that myelin was the autoimmune target in MS. But, you know, however long that's been, it hasn't helped us develop a therapy that targets the actual source of disease. What kind of progress have we been making on an antigen-specific therapy?

STEINMAN: Well, progress has been slow on an antigen-specific therapy. Some of the most attractive approved drugs target a wide swath of the immune system. They are aiming at taking down all the B cells or taking down all the T cells and B cells. So wouldn't it be nice, instead of using a big hammer, to have a surgical scalpel? And if only the procedure was simple, that we could use a scalpel.

First, we have to identify what is really being targeted in multiple sclerosis. So it's, it turns out, it's multiple components of the myelin sheath, and not only the proteinaceous components, but the lipid components. So the response is very complex.

And yet we and others are attempting strategies to try to treat MS patients with antigen-specific therapies targeting some of these myelin products. We reported about a year ago a Phase 2 trial with an experimental drug that showed promise, and we hope to take that forward.

But there is a small component of demyelinating disease called neuromyelitis optica, where the immune target may be much more restricted to a single molecule. And in this case, it's the water channel known as aquaporin 4. And that discovery was made by Vanda Lennon and her coworkers at the Mayo Clinic.

So recently Jeff Bennett at the University of Colorado and Alan Verkman at the University of California San Francisco have made an antibody to aquaporin 4. But the antibody has been disarmed so that it cannot cause immunological damage to the water pore. So the strategy is to use that monoclonal antibody as a decoy.

So this is a very exciting approach that we hope can be taken forward into humans with neuromyelitis optica [NMO] and provide the first proof that an antigen-specific therapy will work.

And I like the idea to go after the small orphan disease and build on that, and ultimately -- based on favorable outcomes and the experience we gather -- to actually put this to work for a more complicated situation in multiple sclerosis.

GEVER: Yes. And of course that's also going to be frustrating for patients who don't have NMO but who do have MS to see you working in that field. But it is, of course, completely understandable.

STEINMAN: Well I think there is a lot for patients to be happy about. We do have many more therapies, and there is an intense amount of research activity. But I have too many patients writing to me, "Dr. Steinman, I wish I could be one of your experimental mice. They seem to be doing so well." And I have tremendous sympathy with that comment, because we really need to get what we can do so well in an experimental animal to actually come into play and work in humans with MS and related diseases.

GEVER: Well thank you Dr. Steinman. This has been really informative.

STEINMAN: My pleasure.

GEVER: I'm John Gever for MedPage Today.

Lawrence Steinman, MD, has disclosed that he has no real or apparent conflicts of interest to report. MultipleSclerosis/31923?utm_content=&utm_medium=email& utm_campaign=DailyHeadlines&utm_source=

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04/08/2012 03:59 AM
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2000 (Poland): Lyme borreliosis and Multiple sclerosis: Any Connection?

A Seroepidemic study. Ann Agric Environ Med. issue 7, 141-143


10 out of 26 MS patients tested positive for Lyme borreliosis.

Notes how it is virtually impossible to make a distinction between late stage Lyme disease and Multiple sclerosis, not even with MRI.

Diagnosis of MS vs. late stage neuroborreliosis are guesswork – there are no reliable tests for either.


Multiple sclerosis may often be associated with Borrelia infection.

Ann Agric Environ Med. 2000;7(2):141-3.

Lyme borreliosis and multiple sclerosis: any connection? A seroepidemic study.

Chmielewska-Badora J, Cisak E, Dutkiewicz J.

SourceDepartment of Occupational Biohazards, Institute of Agricultural Medicine, Jaczewskiego 2, 20-090 Lublin, Poland.


A total of 769 adult neurological patients hospitalised in clinics and hospitals situated in the Lublin region (eastern Poland) were examined during the years 1997-2000 with ELISA test for the presence of anti-Borrelia burgdorferi sensu lato antibodies.

A statististically significant (p=0.0422) relationship was found between the clinically confirmed diagnosis of multiple sclerosis and the positive serologic reaction with Borrelia antigen.

Ten out 26 patients with multiple sclerosis (38.5%) showed positive serologic reaction to Borrelia, whereas among the total number of examined neurological patients the frequency of positive findings was twice as low (19.4%).

The result suggests that multiple sclerosis may be often associated with Borrelia infection

PMID: 11153045 [PubMed - indexed for MEDLINE] Free full text

What is interesting here Adam is that they were not looking for MS, they gave ELISA tests to 769 neurologically impaired patients over a

3 year period and the ones that tested positive for Lyme was only 26 patients but 1/3 of the time they were MS patients from that group of 769

That is a high correlation considering the 50 % failure rate of ELISA tests.

04/09/2012 02:09 AM
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Chronic cerebrospinal venous insufficiency, CCSVI, in Multiple Sclerosis, A Clinical Context Report

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This report is part of a 12-month Clinical Context series.

By John Gever, Senior Editor, MedPage Today

Published: April 07, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, Nurse Planner

Action Points

Chronic cerebrospinal venous insufficiency (CCSVI) refers to alterations of the main venous drainage pathways from the brain parenchyma to the periphery -- usually in the jugular veins, the azygos veins, and in the deepest of vertebral veins of the brain -- that are seen frequently in patients with multiple sclerosis.

Note that some healthy subjects, up to 25% in some studies, have evidence of CCSVI, and patients with other neurologic diseases have similar problems.


JOHN GEVER: I'm John Gever with MedPage Today, and we're doing part of a four-part video series on multiple sclerosis and clinical management.

I'm here with Dr. Robert Zivadinov of the University of Buffalo and the Buffalo Neuroimaging Analysis Center in the Department of Neurology at the university.

And we're going to talk about chronic cerebrospinal venous insufficiency in the context of MS, although I understand that it's not exclusively an MS issue, but certainly in the MS community this has been all the talk for 2 to 3 years.

And I'm wondering if you could just start out by explaining briefly, what's the origin of the so-called CCSVI hypothesis in MS.


So, chronic cerebrospinal venous insufficiency, or CCSVI as you mentioned, was put forward a couple of years ago by Professor Zamboni, a vascular surgeon from Ferrara, Italy.

According to his first findings, in patients with multiple sclerosis, but not in healthy subjects, there are alterations of the main venous drainage pathways from the brain parenchyma to the periphery, mostly related to the changes in jugular veins that are draining our brain when we are in the supine position and of the vertebral system represented mostly by the changes in the azygos veins that are draining our brain when we are in the upright position.

So he described, by using Doppler ultrasound as well as catheter venography, a number of different venous anomalies that he coined as chronic cerebrospinal venous insufficiency.

These anomalies originally have been found, as I mentioned, in the jugular veins, in the azygos veins, and he also evaluated the reflux of the blood in the brain, in the deep cerebral veins of the brain.

A combination of different criteria that he created gave 100% specificity and sensitivity for patients with multiple sclerosis versus zero sensitivity and specificity for healthy subjects.

In other terms, none of the healthy people showed this phenomenon, but there are 100% of MS patients who showed this phenomenon.

Given that your question is on historical connotations, we have been extremely interested in this phenomenon from when we first heard directly from Professor Zamboni, who came to this institute in early 2008 and presented his hypothesis.

Subsequently, we entered into collaboration with Professor Zamboni and did two studies, which led to a number of manuscripts now published.

And these were very pilot -- small studies that confirmed to us that it's worth it to proceed with much larger studies that will include not only healthy subjects and MS patients, but also patients with other neurological diseases that will include patients at first clinical onset, pediatric MS patients, as well as patients with more rare forms of multiple sclerosis.

And over the last two and a half years, we really recruited a huge number of subjects, over 1,100, that participated in a so-called CTEVD study, which stands for combined transcranial and ultrasound extracranial Doppler of venous anomalies in multiple sclerosis.

GEVER: And how is it actually diagnosed?

ZIVADINOV: So that's, I think, a very important point. Now, clearly, originally the hypothesis that was proposed by Professor Zamboni included use of the Doppler.

But it appeared almost immediately clear that training of the Doppler technicians as well as reproducibility of this method might really need some expert hands.

So that's something that, I think, leads to very different results in the prevalent studies between different centers and to subsequent publications in which some groups around the world found 0% of CCSVI in MS patients as well as zero in healthy controls.

We clearly performed very detailed training by Professor Zamboni, and over time improved [the method] in our own hands with two Doppler technicians that have been working with me over the last 3 years.

And we found the prevalence to be around 56% in MS patients and around 25% in healthy controls.

We also found that the prevalence was increased in patients with other neurological diseases, around 40% or more.

However, in these early days and the results that I mentioned to you are related to the first study that we published in Neurology last year, that was a prevalent study, the phase I of the CTEVD study.

Now we are almost done with the phase II, and, as I told you, instead of 499 subjects, we have more than 1,000 subjects in this study.

But it became very clear immediately from the beginning that if this venous anomalies is in jugular veins and azygos veins and other veins in the body, if they are really there, we should be able to see them, to diagnose them, to look at them with different multimodal imaging approaches.

That's why we, very early, began to do MRI studies of these veins, so-called magnetic resonance venography studies, and published a number of papers by looking at morphology of those veins.

In our original studies we did not find the differences between MS patients and healthy controls, and that was interpreted by many people, as a result, that there is no such problem.

But we looked at progressive versus nonprogressive patients, and we found that actually the progressive patients had much more of the stenosis.

That was also in these early days, you know -- when you don't understand something and there is information that is conflicting with the other imaging modality, you need to look at it to find out what's the cause, and that's what we began, by using so-called invasive and noninvasive imaging.

And nowadays we are completing studies that are evaluating these anomalies by using four different or actually five different techniques: three noninvasive and two invasive.

The invasive techniques that we rely on are catheter venography and so-called intraluminal ultrasound, which means you enter with a probe, with the Doppler probe, in the vein itself, and you image these anomalies directly in the vein, then outside of the vein.

For noninvasive imaging modalities we did MRV [magnetic resonance venography], Doppler, as well as computerized tomography venography.

Now, you can also read in these papers that have been extremely negative for the presence of CCSVI, referral to some gold standards like venography.

But I can argue that nobody really knows what's the gold standard for diagnosing of CCSVI.

As a matter of fact, we are establishing standards, and catheter venography is [not a] gold standard for a number of reasons that probably, with respect to the time, I cannot enter into.

But we published a very comprehensive review paper recently in -- last year -- in Expert Review of Neurotherapeutics, in which we provided pros and cons for use of every imaging modality.

Just to conclude on this question, which I think is the key; the key point is to understand what's the fastest screening approach for detection if there are not, or if there are, these anomalies.

The term coined, CCSVI, is a categorical term, black or white. CCSVI, yes or no. Now, nothing is black and white in life, and so it's not with the CCSVI.

Because people who do not meet the criteria, Doppler criteria, two criteria or more for having CCSVI, they might be found as negative, not having CCSVI.

Nevertheless, these people still can have significant venous anomalies in their veins and they are not completely normal.

That's why I think the categorical approach is going with time to be abandoned.

And a more quantitative approach is measuring the flow on Doppler, measuring the flow in velocity on MRV, trying to number -- trying to count the number of anomalies, trying to count the number of stenoses, trying to get the same information from MRV, and Doppler.

[This approach] will be the one to provide us a good screening practice for determining if somebody should go on to more invasive diagnostic approaches.

In a recent study that we published in Functional Neurology last year in December, we said that combination of the Doppler and the MRV is increasing sensitivity and specificity of those people who will go to the invasive diagnostic approach, and that's catheter venography and IVUS, to really have these problems, and I think that's the way to go, multimodal imaging.

GEVER: And so if this is a phenomenon that can be found in most patients who to some extent have some degree of venous insufficiency, and you're finding it in patients without MS and with other neurological conditions as well, what does this mean for the clinical application?

Does this mean perhaps that the insufficiency is the result of the disease rather than a cause of the disease, and is it a target for intervention, or not?

ZIVADINOV: That's a very crucial question. Now, you know, the hypothesis has been created. It has been put forward.

It has been validated in first initial studies. Now it has been validated probably in more than 30, 40 studies, and you can see outcome studies.

I would say that just by trying to be neutral, although I did a lot of these studies by myself, I think that we have more and more studies showing that the prevalence of these venous anomalies is higher in MS patients with respect to the healthy population.

Now, if this is true, which I think -- you know, for a hypothesis to become a reality, you need a lot of data, a lot of confirmations, and I think this is where we stand at the moment with MS; that people are finding that -- and other researchers -- that more MS patients have this problem than healthy controls.

Now, the question is why some people, why some healthy subjects -- not none, as I said, 25, 30% -- have similar problems, and why patients with other neurologic diseases have similar problems.

And, clearly, only association studies are going to help us understand the value of the presence of CCSVI in these conditions.

For instance, do MS patients who have CCSVI have higher disability, more MRI damage, more iron in the brain, decreased CSF flow, lower visibility of the veins, et cetera, et cetera, et cetera?

And I would say and argue that we are one of the very few groups that are publishing on the importance of this.

We argue that if you have the CCSVI, you have a higher chance to have a secondary progressive disease.

Does that qualify for intervention? We do not know, but we are investigating in placebo-controlled studies that we are doing.

And also we don't know what is the cause of that. Is it related to inflammation?

Is it related to less mobility, to less exercise, to aging?

I don't know if you know, but we published a study of risk factors for CCSVI last fall in healthy subjects, and we found that three factors associated with MS predicted presence of CCSVI in healthy people:

infectious mononucleosis, which means Epstein-Barr virus;

presence of smoking in the past;

and history of irritable bowel syndrome.

These are all factors that are connected with MS.

But we also found that heart disease, which is again connected with MS, produced more risk for CCSVI.

GEVER: Which totally makes sense. I mean if you're talking about a vascular condition, then having other vascular conditions would clearly, at least, you know, you would think, would be a risk factor as well.

Of course, patients are going out to have angioplasties and stenting done. MS patients are, on the strength of the papers that have been published.

And, of course, Dr. Zamboni very early on, you know, performed angioplasties and stenting in some of the very first patients that he had studied.

Is that warranted at this point, and what do you tell the clinician whose patient asks about CCSVI?

ZIVADINOV: So that's an excellent question. I would say loud, as I said in all interviews and presentations that I did until now, that until it's established in well-controlled placebo, double-blind studies that this intervention can help patients with MS, they should not be done on a large clinical scale.

So my direct answer to your question is that we do not know and that's why we cannot recommend.

However, I think that we have enough information from diagnostic association studies and prevalent studies that should lead to more substantial research on whether correcting this type of problem may have impact on the disease.

As a matter of fact, Professor Zamboni did this open-label, uncontrolled study, and that's the best he could have done at that time when he -- he was very much criticized for that.

But we have to remember that [no condition has ever] been treated immediately with a 1,000-patient, placebo-controlled, double-blind study done according to the best criteria out there in the literature.

So we did, after that, a small pilot study with Professor Zamboni in which we had immediate vs. the late treatment group. And we showed that there have been some benefits for MS patients in terms of those measures that count in MS clinical trials, relapses, MRI.

Now we are doing a placebo-controlled trial on 30 patients in which we are looking at whether correction of this problem can decrease number of relapses, MRI outcomes, et cetera.

There will be other placebo-controlled trials.

I think only through this approach we will understand if is this helpful.

And not only helpful for so-called disease-modifying outcomes, which are relapses, disability, MRI, but also for quality-of-life outcomes -- sleep, headache, and other problems.

And I know we are out of time, but we are more and more of the opinion that CCSVI might be the disease per se and have its own clinical phenotype.

GEVER: Very good. Well, thank you so much, Dr. Zivadinov. That was extremely instructive, and I've certainly learned things that I did not know, and I hope our audience has as well.

ZIVADINOV: Thank you very much. Very nice, thank you.

GEVER: I'm John Gever, MedPage Today.

Robert Zivadinov, MD, has disclosed the following relevant financial relationships:

Received Salary/Honoraria and Consulting Fees from Biogen Idec, EMD Serono, and Novartis.

Consulting Fees: Biogen Idec, EMD Serono, Novartis Pharmaceuticals, sanofi-Genzyme, and Teva Pharmaceuticals.

Contracted Research: Biogen Idec, Bracco, EMD Serono, Questcor Pharmaceuticals, sanofi-Genzyme, and Teva Pharmaceuticals. MultipleSclerosis/31979?utm_content=&utm_medium=email& utm_campaign=DailyHeadlines&utm_source=

© 2012 Everyday Health, Inc. All rights reserved.

Post edited by: Bettyg, at: 04/09/2012 02:15 AM

Post edited by: Bettyg, at: 04/09/2012 02:20 AM

04/18/2012 01:55 AM
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By John Gever, Senior Editor, MedPage Today

Published: April 17, 2012

NEW ORLEANS -- An investigational oral drug for multiple sclerosis markedly reduced the number of brain lesions relative to placebo in a phase II study, researchers will report here next week.

Cumulative gadolinium-enhancing T1 lesion counts in patients treated with the drug, called ONO-4641, were lower by 77% to 92% compared with patients assigned to placebo in the dose-ranging study, according to data released in advance of the American Academy of Neurology's (AAN) annual meeting.

The study, led by Timothy Vollmer, MD, of the University of Colorado in Denver, assigned 407 patients with relapsing-remitting multiple sclerosis to placebo or one of three daily doses of ONO-4641.

The agent is a selective agonist at sphingosine-1-phosphate (S1P) receptors, especially the S1P1 and S1P5 subtypes, according to the study abstract released prior to the meeting.

The currently marketed oral drug fingolimod (Gilenya) has a similar mechanism of action.

To be eligible for the study, patients must have had at least one relapse during the previous year or two relapses in the past two years.

Patients without recent relapses but who had at least one gadolinium-enhancing lesion within the past three months also could be enrolled.

Treatment lasted 26 weeks, with MRI brain scans performed every four weeks starting at week 10.

The abstract included no quantitative results, but an AAN press release provided the numerical reduction in cumulative T1 lesions from weeks 10 to 26 seen with each of the three drug doses relative to placebo:

0.05 mg/day: 82%

0.10 mg/day: 92%

0.15 mg/day: 77%

Adverse events were similar to those seen with fingolimod, including bradycardia and lymphopenia in some patients.

These were dose-related, the press release said. For example, four patients on the highest ONO-4641 dose had grade 4 lymphopenia, as did one taking the middle dose.

One case of atrioventricular block was seen as well. Other adverse events included liver enzyme elevations, according to the press release.

Full details are to be presented on April 25 during the AAN meeting's late-breaking abstract session.

The study was sponsored by the drug's manufacturer, Ono Pharmaceutical. 32211?utm_content=&utm_medium=email& utm_campaign=DailyHeadlines&utm_source=

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04/25/2012 01:37 AM
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Fish Oil Flops in MS

By Kristina Fiore, Staff Writer, MedPage Today

Published: April 16, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

1 comment(s)

Action Points

In this multicenter, randomized clinical trial in patients with active relapsing-remitting multiple sclerosis, no beneficial effects on disease activity as measured by the number of gadolinium-enhancing lesions were seen from omega-3 fatty acid supplementation.

Note that the lack of clinical activity was seen despite and increase in serum fatty acids in the patients treated with omega-3 fatty acids compared with the placebo group.

Fish oil doesn't appear to be of any help in treating multiple sclerosis, Norwegian researchers found.

In a randomized controlled trial, supplementation with omega-3 fatty acids had no effect on the number of brain lesions seen on MRI over two years compared with placebo, Oivind Torkildsen, MD, PhD, of Haukeland University Hospital in Norway, and colleagues reported online in the Archives of Neurology.

Though the Norwegian diet is usually associated with high levels of fish intake, Torkildsen told MedPage Today that serum omega-3 levels in the placebo group were low to normal, "which indicates that their fish intake was not higher than would be expected in other populations," and that those in the supplementation group did indeed see a rise in omega-3 levels while the placebo group did not.

Smaller trials have found a potential benefit for omega-3 fatty acids, which may be active in MS because of their anti-inflammatory and neuroprotective properties. But controlled trials haven't been able to draw any definitive conclusions, the researchers said.

Still, fish oils are the most common form of complementary medicine used by MS patients, they noted.

So Torkildsen and colleagues conducted a randomized, double-blind, placebo-controlled trial at 13 public neurology departments in Norway totaling 92 patients ages 18 to 55 with relapsing-remitting MS.

Patients were given either 1,350 mg of eicosapentaenoic acid (EPA) and 850 mg docosahexaenoic acid (DHA) every day, or placebo.

After the first 6 months of the trial, all patients were also given 44 mcg of interferon beta-1a three times a week for another 18 months.

The researchers found that at all time points -- 6, 9, and 24 months -- there were no differences in the number of gadolinium-enhancing MRI lesions between groups.

At 6 months, the median number of new lesions was three in the omega-3 group compared with two in the placebo group, which wasn't a significant difference.

Nor were there any significant between-group differences at 9 and 24 months, after patients started on interferon, they reported.

In fact, the lesion rate ratio was significantly lower after interferon treatment, they said (P<0.001).

"As expected, the MRI disease activity was significantly reduced when interferon beta-1a was introduced," they wrote.

There were no differences in relapse rates at any time point, and the proportion of patients who had no progression in disability was 70% in both groups, the researchers wrote.

Nor were there any differences in functionality, fatigue, or quality of life scores, they added.

Torkildsen and colleagues confirmed that patients were getting omega-3s via blood test and found that serum fatty acid levels were indeed higher in the supplementation group (P<0.001).

The study was limited because the sample size lacked the statistical power to detect small and medium treatment effect sizes.

The researchers also noted that the corn oil capsules used as placebo contained 52% linoleic acid, 33% oleic acid, and 13% saturated acids -- the first two of which are fatty acids with anti-inflammatory properties.

The dose was minor, however, compared with a usual diet and lower than intervention studies with omega-6 acids, they said.

Besides, they wrote, regular daily intake of linoleic and oleic acid in Norway is already high, so the amount in the placebo adds an insignificant amount to total intake.

Overall, they concluded that omega-3 fatty acids have no beneficial effects on disease activity in MS, either as monotherapy or in combination with interferon beta-1a.

The study was supported by the Western Norway Regional Health Authority, the Norwegian Multiple Sclerosis Society, Pronova Biocare, Amersham Health, and Merck-Serono.

Pronovo Biocare provided the omega-3 acids and placebo.

Torkildsen reported relationships with Merck-Serono, Novartis, and Biogen Idec.

Co-authors reported relationships with Merck-Serono, Novartis, Biogen Idec, AstraZeneca, Bayer Schering Pharma AG, GlaxoSmithKline, sanofi-aventis, and Smerud Medical Research International.

Primary source: Archives of Neurology

Source reference:

Torkildsen Ø, et al "Omega-3 fatty acid treatment in multiple sclerosis: A randomized, double-blind, placebo-controlled trial" Arch Neurol 2012; DOI: 10.1001/archneurol.2012.283. 32195?utm_content=&utm_medium=email& utm_campaign=DailyHeadlines&utm_source=

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