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Host \u2013 Dan Keller
Hello, and welcome to Episode Fifty-Two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I\u2019m your host, Dan Keller.

This week\u2019s podcast features Dr. David Tabby, who discusses the incidence of headache in MS. But first, here are some new items in the MS Discovery Forum.

According to our curated list of the latest scientific articles related to MS, 53 such articles were published between August 14 and 21. To see these publications and the articles we selected as Editors Picks, go to msdiscovery.org and click on Papers.

We\u2019ve made some recent updates to our Funding Opportunities and our Meetings and Events listings, both of which can be found under our Professional Resources tab. Be sure to take a look at a newly-posted funding announcement entitled, \u201cNational MS Society: Health Care Delivery and Policy Research Contracts.\u201d If you know of any meetings, events, or funding opportunities that are missing from our lists, please email us at editor@msdiscovery.org so that we can include them.

Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week, we\u2019ve added one new trial and 15 other pieces of information. The drugs with important additions are dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, and ofatumumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.
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And now to the interview. Dr. David Tabby is an adult general practice neurologist, with a subspecialty in multiple sclerosis, in Bala Cynwyd, Pennsylvania. He was formerly associated with Drexel University College of Medicine in Philadelphia where he carried out the study on headache and MS that we discussed.

Interviewer \u2013 Dan Keller
Could you just tell me what the aim was? I think you were looking the variables affecting headache occurrence in MS patients.

Interviewee \u2013 David Tabby
Well, to be perfectly frank about that, my business manager had noted that many of my MS patients also had migraine, and she asked what\u2019s going on with that. So we did a cursory review and found that close to 50% of my MS patients also had migraine. So that prompted the survey in a more formal fashion.

MSDF
Whom did you look at, and what were some of the variables you looked at?

Dr. Tabby
Well, we looked at everyone who was willing to answer a survey. And we wanted to include some typical migraine variables like frequency and intensity and triggers and age of onset and duration at that time and which came first, MS or migraine.

MSDF
And what were some of the major findings?

Dr. Tabby
I think our biggest contribution was that it seemed that we could correlate exacerbations with increase in headache, which I don\u2019t think was known before that. Sometimes headache a little bit before the exacerbation, and sometimes exacerbation first, then with headache. But that raised the question about the role of inflammation in both headache and MS exacerbations. You know, I don\u2019t think one is the cause of the other, but they\u2019re clearly related.

MSDF
What about migraine with aura or without? Are there differences in the MS presentations or symptoms or relations in time?

Dr. Tabby
We didn\u2019t have a lot of migraine with aura patients. That\u2019s only about 20% of the migraine population anyway. We didn\u2019t have a big enough number to make any kind of association that would be distinguishing migraine with or the migraine without aura.

MSDF
Do you have a proposed mechanism in mind how these two may be linked \u2013 mechanism of migraine, mechanism of MS?

Dr. Tabby
I don\u2019t think there\u2019s a lot of work about what the immune system\u2019s role is in migraine, but stress affects the immune system. My patients tell me that a particularly stressful event can seem to precipitate an exacerbation, and, no big secret, that stress can precipitate a migraine.

MSDF
Fatigue can be a trigger, and obviously, that\u2019s a large proportion of MS patients have it. So do you think there may be a link there, one triggering the other?

Dr. Tabby
90% of MS patients will complain of fatigue at some point, and I think that\u2019s clearly got something to do with it. So anyone with migraine will tell you that when they overdo it and get overtired, they get a migraine.

Interviewer \u2013 Dan Keller
I think I saw something in the paper was talking about metalloproteinases in the CNS and leakiness of vessels and allowing either antigens out or T cells in. Does that have any legs or where does that idea come from?

Dr. Tabby
That idea came from a paper that we found in our literature review of the basic pathophysiology of an MS exacerbation that matrix metalloproteinases have to be activated first, to increase vascular permeability of the CNS. Migraine was thought, at one time, to be a primarily vascular issue. It\u2019s not. It\u2019s primarily a neurochemical issue that affects the vasculature, but results in dramatic changes in blood vessel permeability. There\u2019s a kind of leakage of fluid around blood vessels, which helps make them more sensitive.

MSDF
There\u2019s also a component of calcium flux in migraine. Would that have any effect on the immune system? There\u2019s calcineurin inhibitors that are immunosuppressants, so I\u2019m wondering if calcium in itself \u2013 could be an imbalance be a stimulant?

Dr. Tabby
The role of calcium in modulating neural function can\u2019t be overstated. I\u2019m not ready to give you an exact mechanism of how that might function.

MSDF
Patients with migraine supposedly have more symptomatic clinical course of MS. Do you have any numbers there? What did you find?

Dr. Tabby
We weren\u2019t a longitudinal study. We\u2019re really just a snapshot kind of picture to determine, you know, a relationship now. That was another one of our hypotheses that the worse headache you had the worse MS you were going to have. Our take-home message from the paper was MS doctors should be very aggressive about addressing migraine symptoms in their patients, because we think that it could have an effect in long-term prognosis in MS. And it\u2019s not just the patient complaining about, oh, I have a really bad headache. There is a relationship. It\u2019s been known for many years. I mean, you might have seen in our bibliography that some of the papers went back to the 1960s about the relationship with headache and MS. So, just to reiterate, migraine prophylactic therapy, migraine abortive therapy is important in the context of treating MS.

MSDF
Can pre-existing migraine before the MS diagnosis give you any clue as to being a risk factor in itself?

Dr. Tabby
That\u2019s an excellent point. We didn\u2019t have a big enough group to come to that conclusion, but 12% of Americans have migraine \u2013 18% of women, 6% of men. Less than 1% of the population has MS. Something else has to be happening.

MSDF
Also, I guess you found that people with stabbing pain had more acute MS exacerbations than if they had other more throbbing kinds of pain.

Dr. Tabby
Well, we were just using that as an indicator of severity of the headache. Stabbing\u2019s not a typical word used to describe migraine. We gave choices. We just didn\u2019t leave it open-ended. We gave some example words for their responses to the survey to tick off. Yes, stabbing was one of them, and there was a correlation between the ones who said stabbing and worse exacerbation.

MSDF
Some of the patients you surveyed did not have pre-existing migraine, only after their MS diagnosis. Do you think that migraine is something that one should investigate whether they actually may be in a prodrome of MS, if they present late - develop migraine late in life \u2013 later in life?

Dr. Tabby
In our world, pretty much everyone with a bad headache who sees a doctor about it, at some point is going to get some sort of imaging study of the brain. It might be a CAT scan, in which case there might not be enough information. But if it\u2019s an MRI, there\u2019s a good chance of seeing high-signal lesions scattered through the white matter. They may be real small and not particularly typical of MS. But not uncommonly, they\u2019ll see a pattern that looks really quite like MS. And you examine the patient, and you don\u2019t find anything that\u2019s consistent with MS. You do a history, and you don\u2019t find any symptoms that are consistent with MS. So this is the sort of thing you just file away and see what happens. I don\u2019t think anyone would suggest that treatment for MS should be started at that point.

There\u2019s an entity that\u2019s finally gotten a name, called radiologically isolated syndrome, which people get MRIs of their brain for some reason \u2013 head trauma, headache, anything really \u2013 and the pattern looks really quite like MS, but there\u2019s no clinical support of MS. So same thing; we don\u2019t forget about these people. You recheck their MRIs at some point in the future. You look for new lesions or enhancing lesions. I think the latest statistic is somewhere around 50% of them are eventually going to present as having multiple sclerosis.

MSDF
Would each entity be treated or each condition be treated as if it existed in isolation? Or do they complicate the management of the other?

Dr. Tabby
My approach has been to treat them independently. Just follow the basic principles of headache treatment for the headache and the basic principles for MS treatment and adjustments of therapy and symptomatic therapy for MS. I would not suggest some interlinked therapy system.

MSDF
But something like interferon and possibly other drugs may cause exacerbation of headache. Would that lead to noncompliance of the MS treatment or would you switch drugs or how do you handle that?

Dr. Tabby
That doesn\u2019t necessarily involve the headache issue. I think someone who has bad headaches on interferon who\u2019s not taking their medicine, you know, you might try to fix it \u2013 fix the headache that is. But you\u2019re probably fighting an uphill battle when that patient has negative associations with taking their medicine. I still tend to think of these two things as related but separate.

MSDF
So what\u2019s the big take-home message for a physician?

Dr. Tabby
Really just about treating migraine aggressively in their MS patients, and keeping in mind that we work very hard to preserve function to reduce the accumulation of disability, with drugs and other sorts of interventions. But intervening for migraine may be just one other way to reduce the burden of disability in the future, for your patients.

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MSDF
Thank you for listening to Episode Fifty-Two 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. 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.

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.

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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