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Published: April 29, 2015, 11:13 p.m.

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Host \u2013 Dan Keller

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Hello, and welcome to Episode Thirty-Nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I\u2019m your host, Dan Keller.

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This week\u2019s podcast features the second part of our interview with Joseph Berger of the University of Pennsylvania. But to begin, a couple of updates.

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Last week we told you about our Drug-Development Pipeline, which includes continually updated information on 44 investigational agents for MS. Since last week\u2019s podcast we added two new trials, we updated information on 10 other trials, and we added 10 other pieces of information. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, and phenytoin. To find information on all 44 compounds, visit msdicovery.org and click first on Research Resources and then on Drug-Development Pipeline

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Two weeks ago we described how we curate a weekly list of all newly published scientific papers on MS and related disorders. Last Friday\u2019s list included 53 papers. We selected two of them as Editor\u2019s Picks: One is a Cochrane meta-analysis of dimethyl fumarate \u2013 trade name Tecfidera \u2013 for treating MS. The other is a study from Paul Tesar\u2019s group at Case Western Reserve University. That study, which appeared in Nature, is entitled \u201cDrug-based modulation of endogenous stem cells promotes functional remyelination in vivo.\u201d To find the full weekly list and the Editor\u2019s Picks, click on the Papers tab at msdiscovery.org.

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Now to the interview. Dr. Joseph Berger is a professor of neurology at the Hospital of the University of Pennsylvania. In part one of his interview we talked about risk of progressive multifocal leukoencephalopathy. This week, Dr. Berger discusses diagnostic dilemmas in MS.

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Interviewer \u2013 Dan Keller

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Dr. Berger, how do these present, and what are some of them?

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Interviewee \u2013 Joseph Berger

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They\u2019re legion, actually. There are a lot of different diseases that can look very much like multiple sclerosis both in terms of the history and physical examination as well as in terms of the radiographic findings. And the question is, do you want to avoid treatment that is not very helpful and expensive? You know, once you\u2019ve made a diagnosis of multiple sclerosis you tend to put the patient on a disease-modifying therapy that they would remain on for the rest of their lives. And there\u2019s an expense and some risk depending on what you put them on, associated with that. Secondly, there are diseases that, if you miss the diagnosis, these are diseases that can be aggressive in and of their own right, and if you\u2019ve misdiagnosed it there\u2019s a concern that disease may go on and create its own problems for the patient. So there are a variety of reasons why you want to ensure that what you\u2019re dealing with is truly MS and not one of the MS mimics.

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Among the common MS mimics, one that we\u2019ve had increasing experience with in the recent past, is neuromyelitis optica. So, neuromyelitis optica was a disease that we lumped together with multiple sclerosis, but we\u2019ve realized recently that not only is the pathogenesis different than multiple sclerosis, it being a humoral immune disorder, but that the therapies that we employ for multiple sclerosis may actually aggravate neuromyelitis optica. So that\u2019s a common concern and one of the reasons why we frequently obtain neuromyelitis optica antibodies in patients, particularly when they present with optic neuritis or transverse myelitis, and certainly when they present with both of them.

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MSDF

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That would be aquaporin-4 antibodies?

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Dr. Berger

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That\u2019s correct. It\u2019s an aquaporin-4 antibody, but not everybody with neuromyelitis optica has the aquaporin-4 antibody that\u2019s demonstrable. A certain percentage of them have what appears to be an anti-MAG antibody, and others we simply don\u2019t know what the antigen is. And that\u2019s being worked out. So there\u2019s this whole spectrum of neuromyelitis optica that you certainly want to sort out from multiple sclerosis. But there are also a wide variety of other illnesses that can look like multiple sclerosis. In fact, if you take any broad classification of diseases \u2013 infection, vascular, neoplastic, toxic, metabolic, genetic, etc. \u2013 if you do that and say, are there diseases in these categories that can appear like multiple sclerosis and be mistaken for multiple sclerosis, there are. So every single one of these broad categories can have within it a disease that can be mistaken for multiple sclerosis.

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MSDF

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Would they be mistaken for multiple sclerosis on many measures or mainly signs and symptoms or is it radiologic on imaging? How do you sort out this kind of gamish of different diseases and how they present, and really nailing down an MS diagnosis, not even considering a diagnosis of what else it could be?

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Dr. Berger

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So it can be enormously difficult to do so. And I\u2019ll give you some examples from my own practice. I have, for instance, seen individuals with a disorder called hereditary spastic paraparesis where you were unaware of their hereditary nature of their disease. And the patient has come in with a progressive myelopathy. And you say, well, could this be primary progressive multiple sclerosis? And could be extraordinarily difficult to sort out, particularly if they don\u2019t have common mutations, and they don\u2019t have a family history. And you say, well, which is it? The spinal fluid can be very helpful in that regard.

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The MRIs can be very helpful in that regard, but not always. I\u2019ve seen individuals who\u2019ve had vascular disease where the MRI abnormalities have looked very much like multiple sclerosis. They\u2019ve had recurrent episodes of neurologic symptoms be it numbness or weakness or visual problems, and it be mistake for MS. I\u2019ve seen individuals with intravascular lymphoma, a rare disease, but one where they\u2019ve presented with both clinical picture and MRI that looks very much like multiple sclerosis.

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Although we have good diagnostic criteria, there is no single test that tells you that this is MS. But there are times when all of us, even the very best clinicians, scratch our heads when a patient\u2019s reappeared in the office; nothing new has happened to him. Ten years have elapsed, and you say to yourself, did they really have multiple sclerosis? So, again, it\u2019s a matter of comprehensive history and physical; the appropriate radiographic studies; looking at the spinal fluid when that\u2019s indicated; and doing the appropriate laboratory studies to rule out things that may mimic multiple sclerosis.

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MSDF

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Is that why there is a diagnosis of CIS? If it never returns, then it was CIS?

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Dr. Berger

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I guess one could say that, but I use the term CIS to mean the very first episode of multiple sclerosis. So when I label somebody with CIS, I already believe that they have multiple sclerosis. I think that if they have CIS in the absence of any radiographic findings, I\u2019d be unlikely to label them CIS. CIS to me is in the continuum of MS, so you have CIS, relapsing/remitting multiple sclerosis, secondary progressive multiple sclerosis. So that\u2019s how I use the term.

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MSDF

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Can you definitely rule in or rule out multiple sclerosis?

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Dr. Berger

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I think that there are probably rare instances where people fulfill all the criteria for multiple sclerosis. And at the time of autopsy you say, how about that? That wasn\u2019t multiple sclerosis. There\u2019s an old expression in medicine that you can never be a 100% certain. You can never have a 100% certainty. So I think that you do the best you can. And I think that probably the rate\u2019s 99% or better, but in these people fulfilling the criteria that have been established. However, you can never be entirely certain.

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And it is not that uncommon in my practice, and I\u2019ve been practicing medicine nearly 40 years, where an individual has presented the office after a long hiatus. And the chart is unavailable to me, and they come in with a diagnosis of multiple sclerosis, and I say, who made the diagnosis of multiple sclerosis in you? And they go, you did, Dr. Berger. So I think go down to the cave where they keep the charts that are over seven years old only to find out that they had all the criteria for multiple sclerosis; that they had oligoclonal bands, and they had hyperintense signal abnormalities on their MRI, and they had relapsing symptoms, but, you know, over the course of the last 10 years they\u2019ve had little. And you scratch your head and say, geeze I wonder if this is truly MS?

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There are probably people who carry this diagnosis, and there\u2019s literature on it, that carry it incorrectly.

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MSDF

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Those criteria, even though it never turned out to be MS, satisfied a diagnosis of MS. When you see something like radiologically isolated syndrome, do you work it up for MS, or only once it presents later does it become MS?

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Dr. Berger

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This is a very difficult question, and we see this with some regularity, that is, the individual that has hit his head in a car accident or developed a headache that somebody\u2019s decided to do an MRI on. And they come in with an MRI that looks all the world like a patient with multiple sclerosis, yet they have no symptoms and no signs on physical examination that is suggestive of multiple sclerosis. And the question then becomes, what do you do with them?

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There\u2019s currently a study in which that question is being addressed. However, I will tell you what I do, currently. I do look for multiple sclerosis. I look for lesions in their spinal cords because I think that if they have that, the prognosis can\u2019t be good, and I would likely start somebody with lesions in their spinal cord, who I\u2019m convinced has MS, on a disease-modifying drug.

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I look their spinal fluid. And I look at their spinal fluid for oligoclonal bands, and, if I see that, I\u2019m increasingly convinced that that\u2019s what we\u2019re dealing with. And I would be inclined to treat those people as well. Now whether I\u2019m doing the right thing or not, I don\u2019t know, but for others in whom there are no spinal cord lesions, there are no signs or symptoms, and the spinal fluid is pristine, I\u2019ve elected to wait. That is not necessarily the consensus among the MS community. That\u2019s simply how I practice, currently.

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MSDF

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People don\u2019t need oligoclonal bands to have MS, though, do they?

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Dr. Berger

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No, not at all. So, we certainly see a fair number of people \u2013 and it depends on the study \u2013 who have pristine spinal fluids. That means no oligoclonal bands, no cells, no increased protein, no elevated myelin basic protein or IgGs who still have multiple sclerosis.

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MSDF

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What about fatigue as an initial symptom of multiple sclerosis? A lot of people have fatigue \u2013 tiredness. Is there a way to differentiate the fatigue of multiple sclerosis from just being tired or a sleep apnea or an insomnia or they just don\u2019t feel good?

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Dr. Berger

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Well, I think your history is very helpful because the sleep deprivation and excessive daytime sleepiness is not the same as the fatigue that people with MS report. The fatigue that people with MS report is akin to the fatigue that one experiences when they have a viral illness. So when you have the flu you go, oh man, I just can\u2019t get out of bed. I feel terrible. And that\u2019s precisely what the people with multiple sclerosis have. And what\u2019s so interesting is how common it is. So it\u2019s been said to be the greatest cause of disability in the MS population. It\u2019s an acceptable cause of disability; not blindness, not incoordination, not weakness, but fatigue.

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And it\u2019s curious, when I practiced in Kentucky, I had a number of patients who were wheelchair-bound, had very poor vision or had double vision because of paralysis ocular palsies, who went to work every single day. And then I had patients that looked as healthy as you and I, and they were on disability. And I said, well, why is it that you can\u2019t work? They said, I\u2019m just too fatigued. I can\u2019t do anything. It\u2019s affected everything.

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So the fatigue is different, and getting back to the frequency of it, so in individuals who have been diagnosed with multiple sclerosis, and I was part of this study, if you look at large numbers of individuals diagnosed with MS or who are on disease-modifying drugs for MS and go back and look at their medical records prior to the time of the diagnosis, you will see that about a third of them had been labeled by their family physician or their internist as having one of two diagnoses: chronic fatigue syndrome or fatigue and malaise. They\u2019re the only two diagnoses with fatigue in them that you could put into the ICD-9 classification.

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So, this is striking that so many individuals have fatigue recognized, yet it\u2019s an advance of their having any neurologic symptoms that were believed to be the consequence of multiple sclerosis. It\u2019s not to say that they didn\u2019t have them. You know, it might have been some transient numbness or transient tingling or slight weakness that went away that nobody ever thought was due to multiple sclerosis. So that we don\u2019t know about. But what I can tell you is that prior to an established diagnosis of multiple sclerosis, roughly a third of individuals have been labeled by their family physicians with fatigue.

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MSDF

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It\u2019s interesting that you make the analogy between this sort of fatigue and that with a viral illness like the flu. Could this be a prodrome telling there\u2019s an inflammatory process going on? I mean, is there interferon release or are there other mediators that seem to be unique to this kind of fatigue?

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Dr. Berger

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I would like to think that that\u2019s the case. I would like to think that this is due to the very same cytokines that cause the fatigue that\u2019s associated with viral illness. That\u2019s not been convincingly demonstrated, although it\u2019s been proposed. I think it makes a lot of sense. Coming full circle, eventually, although most of my colleagues classify multiple sclerosis as an autoimmune disease, there must be a trigger for the autoimmune disease. And my own belief, coming to this from virological angles as opposed to coming at it from an immune angle, is that there\u2019s probably some infectious origin.

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One of the things that\u2019s so striking is the association between Epstein-Barr virus and multiple sclerosis where virtually every adult patient with multiple sclerosis has evidence serologically of having been exposed to Epstein-Barr virus. Now I\u2019m not saying that that\u2019s necessarily the cause, but in some way it must contribute to the development of the disease perhaps in a way that low vitamin D levels contribute to the genesis of the disease.

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MSDF

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Is there anything you\u2019d like to add about diagnostic dilemmas or any kind of a mental framework for approaching this sort of thing, in nutshell?

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Dr. Berger

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Yes. The one thing that I would say is never be too confident. Never be too confident. I found that my highest confidence levels were right before I took boards in neurology, which was a long time ago. And I thought I knew everything. And the more I practice neurology, the more humble I\u2019ve become in terms of establishing diagnoses and selecting right therapies for patients. So I always have a healthy skepticism. I have a healthy skepticism of things that I feel certain about. And when patients represent to office I always question myself, particularly if there\u2019s something that doesn\u2019t fit with the diagnosis. And I think that that\u2019s good advice to anybody practicing medicine.

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MSDF

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Very good! Thank you.

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Dr. Berger

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My pleasure.

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Thank you for listening to Episode Thirty-Nine of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF\u2019s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

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Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

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We\u2019re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

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