Full Transcript:
[intro music]
Host – Dan Keller
Hello, and welcome to Episode Seventy-three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.
Today's interview features Donna Osterhout, a cell biologist at Upstate Medical University in Syracuse, New York, USA. Dr. Osterhout talks about a new way of looking at myelin-making cells, which move and change shape in dramatic ways. Current MS drugs take aim at preventing new immune damage. In the future, researchers hope to figure out how to repair myelin and restore function.
But first, let’s look at new content on MS Discovery Forum. Spring brings rain, flowers, and a bouquet of scientific meetings related to multiple sclerosis. See the list at msdiscovery.org under the tab “professional resources.” MSDF sent the only journalist to cover the recent meeting of the American Society of Neurochemistry in Denver, but you can count on a blitz of news from the media pack at the next meeting on the calendar – the American Academy of Neurology in April, happening this year in Vancouver, BC, Canada. The number of research papers about multiple sclerosis has doubled in the last 10 years, and many findings are first reported at meetings before publication.
Moving on, let’s sample a few of the new papers we found in our weekly PubMed search of the world’s largest medical library, the National Library of Medicine. You can link to each week’s list of curated papers at msdiscovery.org.
Related to this week’s podcast, a new paper reviews the latest research about the molecular cues that allow precursor cells to mature and go through the stages of making myelin. These cues come from axons and from other surrounding tissue. Clinical drug development efforts focus on overcoming inhibitory cues, such as with the experimental agent anti-LINGO-1, now completing phase 2 clinical trials for MS and acute optic neuritis by Biogen. The review authors suggest future drugs to repair myelin could boost permissive and promotional cues, which may go wrong in disease. The paper is published by researchers at the Virginia Commonwealth School of Medicine in the journal Experimental Neurology.
Another report updates the Cochrane systematic review on teriflunomide, a daily oral medication for relapsing remitting MS marketed under the brand name Aubagio by Sanofi Genzyme. Cochrane’s systematic reviews are ranked among the highest level of medical evidence, because of the rigorous independent analysis of multiple studies, including randomized controlled trials. The authors write that, as a single drug, the high dose of teriflunomide was as effective as interferon beta 1-a, while the low dose was less effective. They recommended longer follow-up analyses and noted that the available evidence was low-quality, as well as subject to bias, in part because all studies were sponsored by pharmaceutical companies. In general, side effects were mild to moderate and do not usually lead to treatment being stopped, but the higher dose is more prone to cause these side effects. The study is available in the Cochrane Library.
The final editor’s pick this week takes a fresh look at how medical images transform a patient’s view of her own body. The paper describes an artistic collaboration between Devan Stahl, a bioethicist at Michigan State University with multiple sclerosis, and her sister Darian Goldin Stahl, a printmaker. The resulting art – some of it life sized – superimposes Devan’s narrative and MRI images with body photos. Devan wrote in the paper that the art collaboration has made it easier to talk about her MS. The paper is published in the journal Medical Humanities. If you're in town for the big Neurology meeting, you can catch Darian’s artist talk on April 17 at 2 pm at Malaspina Printmakers in Vancouver, Canada.
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And now to our interview. We caught up with Donna Osterhout in Denver, Colorado at the March meeting of the American Society for Neurochemistry. She organized a symposium that told a new story about myelin-making cells. In different labs, researchers started looking for clues in the radical shape changes that occur in the cells in their normal process of making myelin. These oligodendrocyte precursor cells sprout “arms” to reach out and touch neighboring axons. Then they push out slabs of fatty membrane and wrap them around and anchor them to the axons. In multiple sclerosis and other demyelinating diseases, the immune system attacks this myelin wrap, and the cells cannot keep up with repair. The unprotected axons may be damaged or destroyed, causing the worsening disability of MS. Learning how the cells make myelin may pave the way toward new therapeutic agents to repair demyelinated axons and restore function. Dr. Osterhout spoke with our executive editor, Carol Cruzan Morton.
Interviewer – Carol Cruzan Morton
So we are here, in Denver, at the annual meeting of the American Society for Neurochemistry, and you've put together a very interesting panel on a new way of looking at myelin. So can you sort of set the scene for us when you're talking about the myelin research that you're working on?
Interviewee – Donna Osterhout
Well, myelin is a specialized membrane that is wrapped around axons; it occurs in the last step of development. And oligodendrocyte progenitor cells are the cells that form myelin. They are going to migrate out through the developing brain and they're going to extend processes that come in contact with axons that need to be myelinated. And when they get the appropriate signals, they are going to start a process by which they synthesize and extend a large membrane, which wraps around this axon many times and compacts and forms myelin.
The way that this happens has been a mystery thus far, but recent research suggests that there has to be a lot of rearrangements of the internal cytoskeleton for this to happen. And so the symposium was organized to talk about how the cytoskeleton might be changing to allow for this membrane wrapping and myelin formation.
MSDF
Can you tell me more about the cytoskeleton?
Dr. Osterhout
The cytoskeleton is comprised of specialized proteins within cells, and every cell has a cytoskeleton; it gives it shape, but it also allows it to migrate, differentiate, and extend processes, so cells wouldn't be able to do much without a cytoskeleton. And in the case of oligodendrocytes, there are a lot of cytoskeletal rearrangements that occur to allow for myelination.
MSDF
Can you tell me more about the emerging view about how myelination may be working based on this new way of looking at it?
Dr. Osterhout
Initially, we know that there are early signals that trigger extensive process outgrowth from these cells. Once the axon sends a signal to the oligodendrocyte progenitor cell, they start to put out many, many processes, synthesize myelin proteins, and make this big membrane that will wrap around the axon. What winds up happening is that in the past everybody thinks that we've needed a driving force so that something pushes this forward, and it had been thought that perhaps the actin cytoskeleton was the driving force behind this.
The newer research indicates that initially you have to have signals that trigger the process outgrowth, but this is followed by an actual disassembly of the actin cytoskeleton. So it's somewhat opposite of what we had thought previously.
MSDF
Can you tell me more about the steps that are involved in the process of myelinating that you and your colleagues have been discovering?
Dr. Osterhout
Well, the initial step is the activation of a cellular kinase called Fyn tyrosine kinase; this is the earliest step in the differentiation of these progenitor cells. Fyn will be activated by any number of signals from the axon including, for example, glutamate that's released. And once Fyn is active, it initiates a rearrangement of cytoskeletal proteins called microtubules in order to facilitate process outgrowth so we can extend processes to form this membrane.
In later stages, then we have Fyn helping to trigger the synthesis of myelin proteins, and then you start to get other proteins active that will disassemble the actin cytoskeleton. There is even some evidence that perhaps myelin basic protein can do this. So Fyn signaling will turn on early and promote the synthesis of myelin basic protein, and then myelin basic protein will proceed down these processes and help to disassemble the actin cytoskeleton so the membrane can wrap around the axon.
MSDF
Can you describe what the cells look like when they're going through this process?
Dr. Osterhout
Well, this is really interesting to study, especially in vitro. You can set up myelinating cultures of oligodendrocyte progenitor cells. They're very simple cells, they're like bipolar, two to three processes, and that's the earliest progenitor that we might look at. But once you trigger differentiation, they start to put out processes in a somewhat predictable manner. They will first extend five processes, and then these five processes start branching And they produce these intricate branches. At some point these mature cells will actually look like a lace doily; they are spectacular with the cell body in the center and all these highly branched processes surrounding it. And then you see a transformation of these processes into this huge membrane sheet, and in the absence of an axon it's just going to cover the tissue culture dish; it's amazing how large this can get. But if you had an axon in the culture, this membrane sheet would just form myelin. They would form a myelin segment wrapping around the axon.
MSDF
That’s so interesting. And then can you say, adding to that picture, the steps that are happening in those process that you and your colleagues have been discovering?
Dr. Osterhout
So when you have the initial process outgrowth, you have Fyn tyrosine kinase active, and that facilitates the initiation and that extensive process outgrowth. But the transition between the process outgrowth and the formation of membrane sheets is going to be the disassembly of the actin cytoskeleton.
MSDF
And that's the big news is that the actin cytoskeleton is breaking down instead of pushing the myelin forward as it's making its multiple wraps around?
Dr. Osterhout
Yes, this seems to be the way that this is happening mechanistically. The formation of that myelin membrane requires the actin disassembly, and two of the speakers that we had in our symposium gave evidence to this, using several different experimental systems. And then ultimately when you're going to anchor this myelin sheath, and you can get some specializations in the axonal membrane, and this is what one of the speakers talked about, anchoring the perinodal loops, kind of the ends of the myelin segment. And so we have a process by which we have extensive process outgrowth triggered by Fyn. Then once you get the process outgrowth, you have actin disassembly and you form these membrane sheets, and then they would wrap around the axon, forming myelin, and then you would stabilize it with special proteins in the axon that stabilize the ends at the perinodal loops.
MSDF
So what does this have to do with diseases like multiple sclerosis?
Dr. Osterhout
That's a very good question. If we understand what goes on in development, then we might be able to predict how we could facilitate this process in a demyelinating disease like multiple sclerosis. We do have oligodendrocyte progenitor cells in our brain and spinal cord. They persist as a population throughout adulthood. And any time you have a lesion or a trauma to the brain, and especially if you get demyelination, then you'll have these cells migrate to the area of demyelination. And if we can encourage them to remyelinate, they would undergo the same steps.
We have shown evidence that the inflammation and other conditions in a demyelinating disease upregulates chondroitin sulfate proteoglycans, and these can actually inhibit the process outgrowth and remyelination by oligodendrocytes, because they ultimately inhibit the activation of Fyn kinase.
So if you're considering a disease process, you want to stimulate these steps. And you want to look for agents that might trigger and make sure that these steps proceed, or neutralize things that would be present in the lesion that would inhibit this.
MSDF
One interesting aspect of your work, and perhaps of science more generally, is that some of these discoveries with relevance to multiple sclerosis come from your work on spinal cord injury. Can you talk about how that works in science?
Dr. Osterhout
Well, spinal cord injury is another type of lesion, it's a specialized lesion; you have damage to axons as well as demyelination due to trauma. But in diseases in general in the brain and the spinal cord, whenever you have an injury process or inflammation or some kind of destruction of tissue, you get an inflammation and immune influx, and you will get a process called reactive gliosis. And this is common to many diseases that you see in the brain. For example, you can see it easily in spinal cord injury, it's been well documented. You can see these proteoglycans' reactive gliosis in multiple sclerosis, you can see it in Alzheimer's disease, Parkinson's disease, and other conditions, because they all have a common element that you've got some kind of inflammation occurring and tissue destruction occurring at a specific place.
MSDF
Getting back to multiple sclerosis and the work on how cells myelinate axons, what are the next big questions that you and your colleagues are asking?
Dr. Osterhout
Well, there still are a lot of questions about exactly how this myelination process is accomplished even during development; we don't fully understand all of the triggers that would activate this process. And, likewise, we don't always understand things that might inhibit this process. So we need to more fully characterize what's going on in development so that we can take a look at it in the remyelinating situations, either in spinal cord injury, or multiple sclerosis, or any other demyelinating condition.
MSDF
Well, that's really interesting. Well, thank you for taking the time to explain the research.
Dr. Osterhout
And thank you for your interest; it's been my pleasure.
[transition music]
MSDF
Thank you for listening to Episode Seventy-three 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’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit 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.
[outro music]
Transcript:
[intro music]
Host — Dan Keller
Hello, and welcome to Episode Seventy-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.
Today's interview features Nathaniel Lizak, a young Australian investigator from the University of Melbourne who gave the first talk at the recent meeting in New Orleans of the Americas Committee for Treatment and Research in Multiple Sclerosis, or ACTRIMS. Mr. Lizak discusses new findings showing that moderately advanced and advanced multiple sclerosis are more unpredictable than anyone knew, but worsening disability may be slowed by highly effective therapies.
But first, let’s look at new content on Msdiscovery.org.
Our latest data visualization shows statistical snapshots of MS worldwide. Survey data from the MS International Federation show that, as of 2013, the estimated number of people in the world with MS increased to 2.3 million, or about 33 people with MS for every 100,000 people. But MS rates and access to care vary widely from country to country, as you can see from the data visualization.
In a new job posting, the Stanford-affiliated Santa Clara Valley Medical Center Department of Neurology seeks a general neurologist. Subspecialty training in MS, movement disorders, or vascular neurology is preferred. You can post your job at MSDF at no charge to reach researchers and clinicians specializing in MS and related demyelinating disorders.
[transition music]
And now to our interview. Australian medical student, Nathaniel Lizak, and his academic mentors took a second look at how disease progresses in people with moderate and advanced MS and what can be done about it. Researchers are looking for better measures of disability, but the most common one is the Expanded Disability Status Scale or EDSS for short. Lizak and colleagues looked at worsening disease from several starting points, using an international registry known as MSBase that tracks medical record data on nearly 38,000 people with MS. They divided people in three epochs ranging from EDSS 3.0 (where people are moderately disabled but are fully ambulatory) to EDSS 6.0 and higher (where people need assistance to walk short distances). An older study suggested a steady worsening of disease after EDSS 3.0, which Lizak and co-workers questioned. Executive editor, Carol Cruzan Morton, spoke with him about their findings.
Interviewer – Carol Cruzan Morton
We are here at the ACTRIMS meeting in New Orleans, and you opened the conference with a really interesting paper. I wanted you to explain a little bit about what you were asking and why. What area of MS, what questions you are addressing?
Interviewee – Nathaniel Lizak
So we did this work under the MSBase group, which is an MS-based cohorts; it is an international really large study that has data from over 30,000 patients worldwide. We have access to all of their data, and we really thank our contributors throughout the world who have provided this.
We decided – because we have so much power with so many numbers and so much data from patients – to look at the latest stages of multiple sclerosis which, so far, haven't really been that well explored.
There have been three studies in the past which looked at disability and how it progresses in what they have called the moderately advanced stage of multiple sclerosis. So yeah, we looked at disability accumulation in the later stage of multiple sclerosis moderately advanced, which is defined before as between the EDSS steps of 3.0 or 4.0 and 6.0, and we wanted to look at what predicts how the disability accumulates, because a lot of the previous studies didn't really suggest anything really changes disability.
There is this notion amongst doctors that once it hits these thresholds the trajectory is set, and there is nothing you can do to help patients. We didn't believe that. We were hoping there was something you can still do for patients, even once they have already accumulated substantial amounts of disability.
We set this up to look at just how much variability there is in these later stages of disease and what we can do to take it from going really fast to going really slow, to preventing patients from getting even worse.
We used our cohorts, ran lots of statistics, and we found some very interesting results. The first is that this late stage of disease is quite independent from what happens before. How many relapses people have early in the disease, how fast they got to the early disability landmarks, how fast they accumulated disability, if they were on therapy in the past—all of those things don't really seem to impact what happens later on in the disease. That is what we call the amnesic disease phenomenon. That is something that has already been explored in the past. We kind of confirmed that and saw that, that happens at lots of stages in multiple sclerosis.
What is more interesting, though, is that we still found that patients have a lot of variability in what happens to them, even after they have accumulated substantial disability. So in technical terms, after EDSS 3.0, 4.0, and 6.0, there is still a lot of variability in what happens to patients after they have reached these steps, after they have already obtained disability. That suggestion that after the threshold the disease is set doesn't seem to be at all the case. That is all we observed in our patients.
We had over 3,400 patients— we had 3,415 patients exactly. So it is quite I think, generalizable, our results. There is a lot of variation in what will happen at these later stages of disease.
MSDF
You can't predict what happens next. And it is different.
Mr. Lizak
It is different for everyone. It is independent of what happened before, and almost nothing predicts what is going to happen next. The only things that we found which did predict such as how does disability progress in these later stages, the first one was how many relapses they are having now. Not before, not early in the disease, but how many relapses are they now having per year at these later stages?
We found that more relapses later in the disease still contribute to disability. That wasn't something that the other studies had actually shown, and I think that is to do with their methodology more than anything else. I think we are confirming that relapses are still important, inflammation is still important, we still need to treat it, no matter how far along the disability line the patients are. The relapse is still a problem.
A more exciting thing that we found was that the immunomodulatory medications that the disease modifying therapies, the higher efficacies ones, the new medications, the longer patients are on those in the later stages of disease—so again, after those landmarks, after EDSS 3.0, 4.0, and 6.0—he longer patients are on those after they have gone into that disability the lower their likelihood of progressing even further to EDSS 6.0 and 6.5, which is mobility issues needing unilateral assistance or a walking stick, EDSS 6.0 or bilateral walking assistance EDSS 6.5. So those are pretty, obviously, important to patients in being able to move around without needing any aid.
We found that we can prevent patients from getting to these later disability stages with longer time on disease therapies later on in the disease. So the conclusion we got from this is patients should continue being treated later in multiple sclerosis. Of course, it's always a risk/benefit calculation. You always need to take the side effects into consideration and look at the patient that you are seeing. It is not a blanket rule, but there are countries in the world where it's by policy you can't give therapies later on in disease after EDSS 4.0.
New Zealand is one example. In other places in the world, it is just practice to stop giving treatments later in multiple sclerosis, and we are suggesting no there still is a benefit and you should be weighing that up when considering whether or not to continue patients on therapy, whether to start them on stronger therapies. There is evidence that we can still slow down how the disability will accumulate. That was our main message. We were a bit surprised to find out it was not what we were expecting, but we are very happy that we found such results.
MSDF
In your study, what drugs were categories as the high efficacy?
Mr. Lizak
I don't remember exactly every single drug, but we just put into two groups. The low efficacy being primarily the initial very first-line drugs, so interferon, glatiramer acetate, and teriflunomide; everything else categorizes as high-efficacy therapy, so natalizumab, fingolimod, alemtuzumab, dimethyl fumarate, cladribine, mitoxantrone, I might be missing a few. By no means are we saying that one therapy is better than another. We're just looking at the class effect of the really strong medications. We don't yet have the power to say this is the best medication after EDSS 6.0, this is the best medication after EDSS 4.0, or don't go on that one. We're just trying to say that the stronger perhaps second-line therapies often used second-line do have a better effect in this later period of disease, and doctors should be considering that when deciding what treatments their patients should go on, and patients should obviously be made aware of that as well.
MSDF
The idea that things that happen before don't affect the later stages seems on the surface to be at odds with the idea that progressive disease starts early, like treat early.
Mr. Lizak
…to try to treat disease as early as possible. I don't think it is at odds. There's been a lot of work, so far, to say that the earlier you treat your patients the better. We agree with all of that. We are not saying treating later is any better. Probably believe that treating earlier is better, but what we are saying is: a) continue treating, and don't stop treating. I completely agree that all of the patients that we found that after EDSS 3.0, 4.0, and 6.0 improved with more therapy after those landmarks, still probably did better earlier on in their phase of disease with therapy then. But I guess what we saw is the therapy they had earlier in disease won't make an impact now. You need to continue treating these patients for them to have an improvement.
We still absolutely encourage the earlier treatment, the better. That evidence is beyond doubt in multiple sclerosis. We are definitely not challenging that. We completely agree with that. Our evidence just goes and takes it one step further of, the earlier the better, but it is not too late.
MSDF
Now you are doing this study in the context of a clinical practice. How has that changed – or has it changed – how people with MS are treated in the decision making?
Mr. Lizak
The thing is, first of all, I am a medical student, so I don't make any of the decisions. Secondly, where we are based in Melbourne, Australia, there is already a tendency to treat patients later on in disease. Obviously we haven't published the results yet, so we haven't seen how much of an affect it will have worldwide. Perhaps now we will begin to start changing things. But in Australia where nothing was studied, no one was surprised to find that this was the case. All the doctors there already treat their patients later on in the disease. So it just confirmed that what they are doing is correct. No one has yet drastically changed how they are treating patients. We hope though that, say countries like New Zealand whereby policy after a certain EDSS score, after EDSS 4.0, after moderate disability has been accumulated, you can't put patients on disease-modifying therapy anymore—we hope that is where we will have the biggest impact.
MDSF
When you gave your talk, you talked about the earlier study. There wasn’t an appreciation for the variability. How did you come to ask that question in the first place?
Mr. Lizak
I have to give credit to my supervisor, as well as the whole MS based team that was behind this study, and obviously they conceptualized it a lot more than I: Dr. Thomas Kalincik and Helmut Butzkueven, in particular. But a lot of doctors, particularly our team, are not happy with that graph. Which it looks like everyone after EDSS 3.0 has the same trajectory. We looked at this, and we thought we wanted to do a study to prove this wrong. We didn't know exactly what we were going to find. We actually proved that what they first suggested of disease being independent to be quite correct. But they just missed the variance in the second half. It is independent, but it is still really variable.
We looked at the graphs carefully, and we looked at the study carefully, and we made the note of they only have a mean value on that top half, they don't show how much variability there may or may not be in disease. We got confused. We said it is unlikely that patients have no variability at all after EDSS 3.0, and we decided not only are we going to look at what predicts the later disease, but we need to know just how variable is this disease this late, and we found that it is extremely variable. After EDSS 6.0, patients might go straight through to worse disability, and many will improve, and many will stay stable for many years. We were just unhappy with the message that the graph gave. Then we tried to scrutinize exactly where can we change this message, where can we improve this.
MDSF
That’s great. What questions are your colleagues asking you here about the study?
Mr. Lizak
I have had a lot of questions about this study, some more helpful than others. A lot of people have asked how will this change management? And I think we have just spoken a little bit about that. I am asked, as well, how do you tell patients that we can no longer predict their disease? We used to think that we could and now we just outright can't predict their disease and that is something that is going to be difficult to tell the patients. I think you need to frame it differently. It is not we can't predict how your disease is going to go, it is, we have hope for making it better. You might have been doing not so well up until now, but we still have hope to continue fighting. We haven't given up yet. And I think that is what we need to be framing it as. That is one of the questions I have gotten the most.
A lot of people have asked about why we chose certain therapies, and there is very little evidence about which therapy is high and which therapy is low. We just used the available studies as well as the clinical experience and just compared how much they reduced relapse rates and so on. It was partly based on intuition and observation. It could be the case that some therapies should have been classified differently to what we did, but it is very hard to tell at this stage.
Even then, even looking at the list, you should be mindful that a therapy that we classified as high efficacy might have actually been bringing that group down. And maybe should have been a low efficacy therapy, and maybe a low efficacy therapy was the only one working in that group, and it should have been in the high efficacy group. So obviously, be very careful when you look at that.
At that strata, it is not meant to be telling anyone I should be on that drug or I shouldn't be on that drug. It is just meant to be saying that strong medications are better in this stage, but the decision of the medication should be a decision made entirely by the patient and their doctor, and it should only be used to influence and it shouldn't be taken any more than that.
MDSF
Is rituximab in your …. I was going to say before a B cell therapy.
Mr. Lizak
I don't think we have many patients on rituximab, but we would have had quite a few. Yes, because it was used quite extensively.
MDSF
Thanks. Is there anything else that I haven't asked or that you wanted to add?
Mr. Lizak
Rituximab wasn't the high efficacy group. I should mention that. Yes. Thank you for the fantastic opportunity to showcase the work we have been doing. I obviously have to give credit to everyone at MSBase who conceptualized and gave patients the study. We couldn't have done it without the help of our collaborators worldwide.
[transition music]
MSDF
Thank you for listening to Episode Seventy-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. MSDF’s executive editor is Carol Cruzan Morton. The data visualization was developed by Jean Mercier of Khawai Data Visualization at Khawai.com. Msdiscovery.org is part of the nonprofit 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.
[outro music]
We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.
For Multiple Sclerosis Discovery, I'm Dan Keller.
Transcript to come soon
[intro music]
Host – Dan Keller
Hello, and welcome to Episode Seventy of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.
In today's interview, we'll talk with Dr. Brian Weinshenker of the Mayo Clinic about new diagnostic criteria for neuromyelitis optica spectrum disorder and how it differs from MS. The new criteria build upon and broaden the definition of NMO that was based, in part, on the presence of antibodies to aquaporin-4.
But to begin, let’s sample a few of the new studies we found in our weekly PubMed search of the world’s largest medical library, the National Library of Medicine. You can link to each week’s list of curated papers at msdiscovery.org.
On topic with our interview, an international team led by researchers in Tianjin, China, found a unique group of people with neuromyelitis optica spectrum disorder, or NMOSD, who carried autoantibodies to both aquaporin-4 and myelin oligodendrocyte glycoprotein or MOG, a minor component of myelin. Among the 125 patients, 10 were double positive for both sets of antibodies, and 14 were positive only for MOG. The double-positive patients had a worse disease course, most having MS-like brain lesions and more disability. Those with only MOG antibodies had a milder disease and less disability. If verified in other studies, the findings may help predict the clinical course of NMOSD or even define a new phenotype somewhere between the two very different diseases of NMOSD and MS. The authors say their paper also raises a new challenge of how to diagnose and treat such patients. Three double-negative patients did not respond to rituximab, a highly effective anti-B cell therapy used off label for MS and NMO. The study is published in the journal Science China Life Sciences.
For people with MS and other demyelinating conditions, bladder issues can play an oversized role in the quality of life. A pair of review articles addresses the “neurogenic bladder.” One from Duke University researchers in North Carolina, USA, recommend an evaluation known as urodynamics, calling it the gold standard in helping to break down the complex problem into basic and treatable factors. In the other paper, researchers from Western University in Ontario, Canada, review the 16 different ways to measure patient reported outcomes for neurogenic bladder, and how to choose the best one to track patients’ quality of life. Both reviews are published in the journal Translational Andrology and Urology.
In the news section, MS Discovery Forum correspondent Stephani Sutherland wrote about the recent negative results of fingolimod in a large Phase 3 clinical trial of people with primary progressive MS. Even in failure, studies can be informative and can help researchers design better investigations to test potential therapeutics for progressive disease.
Now, let’s move on to our drug development database. The drugs with important additions and changes are daclizumab, fingolimod, and ocrelizumab. One update reflects findings presented at last month’s ECTRIMS conference in New Orleans suggesting that in primary progressive MS, the experimental drug ocrelizumab reduces disease activity in subgroups of individuals with and without gadolinium-enhancing images at baseline.
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And now to our interview. It’s been 11 years since neuromyelitis optica, or NMO, was redefined as a separate disease from MS. Thanks to the discovery of the first biomarker for NMO, an antibody against aquaporin-4, diagnostic criteria for neuromyelitis optica, or NMO, were revised. In today's discussion, Dr. Brian Weinshenker of the Mayo Clinic in Rochester, Minnesota, USA, lays out further revisions to the criteria and the reasons for them. He uses a couple of terms that may warrant definition. One is IgG, which is immunoglobulin G, a particular class of antibody. Other terms are seropositive, meaning, in this case, the presence of antibodies to aquaporin-4, and conversely, seronegative, the absence of such antibodies. Finally, ADEM, A-D-E-M, is acute disseminated encephalomyelitis, a sudden, widespread attack of inflammation in the brain and spinal cord, usually seen in children. I spoke with Dr. Weinshenker at the ECTRIMS meeting last fall in Barcelona about the new consensus diagnostic criteria for NMO.
Interviewer – Dan Keller
Is there something that was lacking before?
Interviewee – Brian Weinshenker
Well, the first diagnostic criteria for neuromyelitis optica were proposed by our group at Mayo Clinic in 1999. And in 2006, with the advent of the first diagnostic biomarker for neuromyelitis optica, an antibody which we now know is directed against aquaporin-4 – I’ll call it aquaporin-4 IgG – the criteria were revised. But there was a need to revise them. We became increasingly confident in this diagnostic biomarker, and it was possible to make an earlier diagnosis, often after the very first symptom. So that was one key driving factor.
And furthermore, with the advent of this biomarker, we’ve appreciated that the spectrum of this disease is far broader than we had previously recognized. And there are a number of clinical syndromes that were previously not recognized as being part of the neuromyelitis optica spectrum that we now know are, and those needed to be integrated. Another key factor was the fact that a number patients that we recognize have this same condition now did not meet the old criteria. For example, you had to have both optic neuritis and myelitis to make this diagnosis, and we recognize some patients with this condition have just recurrent myelitis or just recurrent optic neuritis; they wouldn’t have satisfied the criteria. So those were the key reasons that drove developing new criteria.
MSDF
What are some of the new criteria?
Dr. Weinshenker
The first important point is that we’ve eliminated distinction between neuromyelitis optica – that is, having optic neuritis and myelitis – and having some of these more limited forms or unusual forms of the disease with brain lesions. And we’ve used the term neuromyelitis optica spectrum disorder to refer to all of them.
Second aspect of the diagnostic criteria is that we’ve stratified them based on whether or not you have this biomarker, the aquaporin-4 IgG. And we’ve separately defined patients with that biomarker and those without, the largest group being those with the biomarker. So in the patients with this biomarker, we really require only one clinical syndrome. The clinical criteria are very, very liberal, and we don’t even require, say, for myelitis, as we had before, we used to require having a long spinal cord lesion. We now recognize that about 10 to 20% of patients do not have those kind of long spinal cord lesions when they have a myelitis, so we no longer require it if you have that biomarker.
But we’ve left open a category that we call seronegative neuromyelitis optica spectrum disorder, because some patients who meet all of the various clinical criteria’s, even the strictest clinical criteria, seem to be seronegative for this biomarker. We recognize that’s a heterogeneous group of patients; some of them ultimately will become seropositive. In some of those patients, we’re recognizing other antibodies that seem to be associated with a similar clinical syndrome, so I think, ultimately, we may create new silos based on those biomarkers, but when these criteria were developed, it was felt to be premature to include other antibodies as diagnostic biomarkers. So we’ve grouped them into this group of seronegative NMO spectrum disorder.
But we’re much more strict in that category. We do require two clinical syndromes – two different clinical syndromes – and in some situations we do require additional MRI criteria in order to meet those criteria.
MSDF
Okay, because it was sounding like you were being so liberal about it people could lack this symptom and that symptom and antibody, but, in this case, if they’re lacking antibody, they need other criteria to qualify.
Dr. Weinshenker
That’s correct; both clinical and radiologic criteria. And we also have exclusionary – well, I shouldn’t say exclusionary. There are no exclusionary criteria. We refer to them as red flags. If you have certain characteristics that would make it more likely that you have MS, which is the major competing diagnosis, or if you have certain comorbidities like, say, cancer or sarcoidosis – we know sarcoidosis can sometimes mimic neuromyelitis optica – we add that as a note of caution, but strictly, no criteria is considered exclusionary for a diagnosis of neuromyelitis optica spectrum disorder.
MSDF
Would other systemic autoimmune states also fall into the category of red flags: we’re going to have to decide whether it really is NMO or not?
Dr. Weinshenker
Actually, that used to be excluded by some people that if patients had systemic lupus or Sjögren's disease they were excluded, but we recognize that patients with neuromyelitis optica spectrum disorder have an excess of those other autoimmune diseases. We very frequently detect comorbid disease, so we actually say that, say, a diagnosis of lupus or Sjögren's actually increases the chances that his patient has neuromyelitis optica spectrum disorder if they present, say, with optic neuritis or myelitis. The old literature was replete with patients who were described as having lupus myelitis. Actually the majority of those patients actually have comorbid neuromyelitis optica spectrum disorder. So it’s no longer an exclusionary criterion.
MSDF
There used to be a requirement for bilateral optic nerve involvement? Is that right? Has that gone by the wayside?
Dr. Weinshenker
Yes, this is before there were actually formal criteria, but yes, that was considered to be, say, a red flag that you might be dealing with neuromyelitis optica compared to standard MS. We recognize that that applies to a relatively small percentage of patients, so it doesn’t really appear in these current diagnostic criteria, but certainly it would not exclude it. And I would say that it does add to the suspicion that someone has neuromyelitis optica spectrum disorder compared to MS.
MSDF
What about pediatric neuromyelitis optica spectrum disorder?
Dr. Weinshenker
We did have several people, who were pediatrics experts, on our international panel and, in general, it was felt that the same criteria that we’ve applied to adults can be applied to children. We do recognize that certain brain syndromes are relatively more common in children, and there is one caveat, that is, in pediatric multiple sclerosis, sometimes patients will have long spinal cord lesions, and that’s one of the criteria that adds to the suspicion that somebody has NMO spectrum disorder as to MS. It may be somewhat less reliable in children.
MSDF
Is there any confounding or concern about ADEM in children?
Dr. Weinshenker
Well, neuromyelitis optica spectrum disorder can be associated with brain lesions that can be interpreted as ADEM. They can be large, tumefactive, extensive. Brain biopsy, which is not part of the criteria that we use for neuromyelitis optica spectrum disorder, can sometimes differentiate ADEM – standard ADEM – from the ADEM-like lesions that occur in neuromyelitis optica spectrum disorder, so yes, it can be a diagnostic problem. But generally speaking, if one relies on the other criteria – the presence of optic neuritis and myelitis, which can occur in both ADEM and neuromyelitis optica spectrum disorder – usually one can come to a clinical diagnosis. But there are some situations that can be confusing and occasionally additional tools, even brain biopsy, can be necessary to make a definitive diagnosis.
MSDF
If serologic testing is not available, do you still require the two other criteria to make the diagnosis?
Dr. Weinshenker
We propose that, for now, if serologic testing is not available – and there aren’t many places in the world where it’s strictly unavailable; it is offered worldwide – that you rely on the criteria for the seronegative and satisfy those criteria of seronegative NMO spectrum disorder.
MSDF
Are the criteria fairly straightforward that any neurologist up-to-speed can interpret them and use them clinically?
Dr. Weinshenker
Yes. We have designed these so that they can be used by neurologists in standard practice. Obviously, they don’t cover every single possibility, and there are complex patients where consultation will be necessary, but these are designed to be as good any diagnostic criteria can be. I think one has to realize that diagnostic criteria are for typical patients with conditions, and there are rare situations in difficult-to-interpret situations where one does need this kind of consultation.
MSDF
What about other historical terminology, and what kind of recommendations have you made vis-à-vis that?
Dr. Weinshenker
This has been a confusing element of the literature. For example, one term used in Asia, where it was recognized that you can have a relapsing condition that primarily targets the optic nerves and spinal cord was often referred to as Asian or Japanese opticospinal MS. And historically, this has been a very important contribution. I think our colleagues in Asia were the first to recognize that this relapsing condition was distinct from MS and may be something different, but the terminology was confusing. It was called opticospinal MS. Was this MS or something distinct from MS? And was it the same as neuromyelitis optica?
And the panel felt that this term is no longer useful in clinical practice, and it doesn’t distinguish from multiple sclerosis. So it was felt all of those patients could be probably put into either the NMO spectrum disorder category or multiple sclerosis category, proposed that, for clinical practice, that terminology be eliminated.
MSDF
This is a good way to make the diagnoses, but it leads into the question of then what do you do? And next week’s podcast will focus on new clinical approaches to looking at NMO.
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Thank you for listening to Episode Seventy 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’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit 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’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.
For Multiple Sclerosis Discovery, I’m Dan Keller.
[outro music]
Transcript will be available soon.
Transcript to come soon
Full Transcript
[intro music]
Host – Dan Keller
Hello, and welcome to Episode Sixty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.
We’ll hear from Neda Razaz, a doctoral candidate at the University of British Columbia in Vancouver, Canada, on her research looking at what it means for child development when a parent has MS. The findings may help parents and health care professionals define strategies and services for children when needed.
First, let’s check out a few of the 70 new research papers we found in the last week. You cn see each week’s list of curated papers at msdiscovery.org.
There’s a large and confusing cast of players in demyelinating diseases, such as MS and neuromyelitis optica spectrum disorders. But if the central nervous system was a stage set in a spaghetti Western movie, at least everyone knows the bad guys wearing black hats would be the T cells, right? Hold your horses, say the German and U.S. authors of a review paper in the journal Trends in Immunology. New findings in the last year reframe the story. Some T cells wear white hats. In fact, the central nervous system may need T cells to limit opportunistic infection, inflammation, and damage. Some MS drugs may work by redirecting T cell behavior. Side effects of other MS drugs may come from blanket suppression of all T cells.
Now is the time to cue the theme from the movie Jaws. In the history of life on Earth, the kind of myelin that researchers are trying to protect and restore in people with MS and related disorders first showed up in a family of shark-like fish and skates and rays. The first true myelin basic protein seems to have originated in this family of cartilaginous fish, called chondrichthyans, or their ancestors. This information comes from an article in a special issue on myelin evolution in the journal Brain Research.
A third paper that caught our attention looks at modern myelin. Almost every cell in the body has little energy packs called mitochondria. That’s true with brain cells, including the oligodendrocytes that make the myelin membrane that wraps around axons. Researchers from Norway say they have shown, for the first time, mitochondria moving into the myelin wrap. They also report that oligodendrocyte mitochondria are smaller, slower, and move less often than those in astrocytes and neurons.
Now, to our drug development database. The drugs with important updates this week are fingolimod, glatiramer acetate, interferon beta-1a, mitoxantrone, and natalizumab. One update summarizes a press release indicating that a generic version of fingolimod has been launched in Russia.
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And now to our interview. The University of British Columbia in Vancouver, Canada, has a strong program in MS. We spoke with several of their researchers at the ECTRIMS meeting in Barcelona last fall. Today Neda Razaz, a PhD candidate, fills us in on her work on the impact of living with a parent with MS on child development or wellbeing
Interviewee – Neda Razaz
I study a group of parents with MS and their children, and we actually use health administrative databases to capture our cohort of interest.
Interviewer – Dan Keller
And what were the outcomes of interest, and how did you assess them?
Razaz
So, for one particular study that was actually published recently, we were interested in child developmental outcome at kindergarten. So I used the Early Child development instrument, which is a routinely collected database by kindergarten teachers in their classroom. And the specific instrument measured children’s wellbeing from social, emotional, and physical wellbeing. And that was our outcome of interest for that particular study.
MSDF
What did you find?
Razaz
I actually found that children who have a parent with MS were doing as well as children without a parental MS, so having a parent with MS was not associated with adverse developmental outcome.
MDSF
Was any aspect of parental mental health associated with children’s outcomes?
Razaz
Actually, yes. In the study, when we did a sensitivity analysis, we found that, in parents who had mental health condition, children were at higher risk of developing some adverse developmental outcomes, specifically in their social and emotional domains of their development.
MSDF
Could you tell if these parental mental health aspects had anything to do with the MS
Razaz
We didn’t specifically look at that, but it is very well-known in the literature that mental health is highly associated with MS. So we kind of feel that it’s not the MS particular; it’s the comorbidities that come with MS that might have an impact on the child.
MSDF
Did it matter whether it was the father or the mother with the issues?
Razaz
We did look at gender specifics, and in one study we did find that having a father with MS who had a coexisting mental health morbidity was also having an impact on child developmental outcome. Specifically for the fathers, it was their emotional wellbeing. But, however, for most of our studies we probably didn’t have enough fathers to be able to see a meaningful difference.
MSDF
Could you get a handle on alcohol use?
Razaz
No, I – we didn’t specifically at that, no.
MSDF
In the case of maternal MS, did it matter whether the disease was present during pregnancy, or if it arose sometime later in childhood development?
Razaz
We didn’t specifically examine the timing of the maternal MS onset, so I can’t comment on that specifically, but our inclusion criteria was that MS had to occur some time before the child reached five years of age. And 60% of our MS cohort had their first onset of MS after their pregnancy
MSDF
Does that give you any clue into the child’s duration of exposure to these issues?
Razaz
We did look at that, and in one study we found that there was a significant association between the duration of the child’s exposure to parental MS and adverse developmental outcome. And I actually feel that’s a very important question, and I’m exploring this further in my future studies as well.
MSDF
Can you put this into context? How does it compare to parental issues in other diseases?
Razaz
Some of our findings are broadly consistent with other chronic illnesses and is actually a specific meta-analysis looking at children who have parents with medical illnesses found that, overall, these children higher rates of internalizing behavior such as anxiety, depression, compared to children who don’t have parents with MS. However, most of these studies, their study population were adolescents, and it’s kind of different from ours kindergarten-aged children. So that might explain some of the differences in the findings that we found. So maybe being that young, at age five, is too early to have any impacts. And also maybe the parents with MS, their disease is not as advanced
MSDF
Are you or someone else going to follow these children as they age?
Razaz
I am interested in actually – you know, my future studies I would like to do a longitudinal study of following these children until older ages; so at least until the time they are 18, and see whether they have a different rates of mental health disorder compared to children who don’t have a parent with MS. I’m interested in, like, specifically living with a parent with a chronic illness.
MSDF
What are the implications of your findings, and can you make any recommendations?
Razaz
While other studies are needed to confirm our findings, we believe that health professional need to be aware of the effect of mental health morbidity that is commonly associated with MS and its impact on their families. And we believe that mental illness such as anxiety and depression among MS patients should suggest the need for appropriate support for their children, because these children seem to be at higher risk of having some adverse developmental outcomes.
MSDF
What have we missed or is important to add?
Razaz
So I just want to say that these studies represent the first important steps in making a difference in MS. We are describing and exploring association, however; we and others in the field need to know if intervention at any way can make a real difference in the lives of parents and their kids.
MSDF
Whom would the intervention involve?
Razaz
The intervention should be family-centered intervention, having the MS patient and also the other parent and other children in the household. So it shouldn’t be individualistic, and it should be the whole family as well.
MSDF
Very good! I appreciate it. Thanks.
Razaz
Thank you very much.
MSDF
Two months after this interview, in late December, the findings were published in the journal Multiple Sclerosis. The paper is free and open to non-subscribers, and you can find a link to it on the podcast page on msdiscovery.org. There you can also find links to be papers and drug development database.
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MSDF
Thank you for listening to Episode Sixty-Seven 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’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit 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’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.
For Multiple Sclerosis Discovery, I'm Dan Keller.
[outro music]
Transcript will be available soon.
Transcript available soon.
[intro music]
Host – Dan Keller
Hello, and welcome to Episode Sixty-Three of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m Dan Keller.
We’ve just passed the winter solstice. What better time than the shortest daylight hours of the year to check in with research at the University of British Columbia on sunlight and MS? Today we talk with Dr. Helen Tremlett who is exploring sun exposure over a person’s life course and how that syncs with their MS risk and disease course.
In the weekly papers section on the MS Discovery Forum, this week’s list includes nearly 150 newly published research reports that could lead to better understanding and treatment of MS and related disorders.
We selected four papers as editor’s picks. In one paper, researchers think they may have the first experimental evidence that MS may start with damage or loss of myelin-making cells in the brain and spinal cord. In this new mouse model of progressive MS, experimentally damaged brain cells make it hard for the mice to walk. The mice recover when their brain cells repair on their own. Six months later, the MS-like disease returns. In the study, the team showed that nanoparticles targeting the autoimmune reaction prevent the second phase of the disease. The study shows support for an “inside-out” model of MS. That’s different from the “outside-in” model, in which some aspect about the immune system goes wrong and then initiates the attack on myelin-making cells. The paper is published in Nature Neuroscience by collaborating researchers from Northwestern University and the University of Chicago.
To grow and be healthy, all human cells need a signaling molecule named mTOR, named for the mammalian target of rapamycin. That’s true for myelin-making cells, or oligodendrocytes, as listeners may remember from an earlier podcast interview with Dr. Wendy Macklin. The ability to make myelin seems to depend on a key part known as mTOR complex 1, also called its raptor subunit. In a very basic advance, scientists have determined the atomic architecture of the raptor, or mTORC1, piece. The details are reported in the journal Science and provide a structural basis for studying mTORC1 function.
In another editor’s pick, a review of cases of pediatric neuromyelitis optica, or NMO, showed that new international diagnostic guidelines applied well to children. Unfortunately, they also found that children with NMO have delayed treatment and worse short-term outcomes compared to those with MS. The authors urged immediate adoption of the guidelines to select the best treatment and improve outcomes.
In the fourth editor’s pick, researchers found a potential new target to protect axons in a mouse model of neurodegeneration in multiple sclerosis. The target is a pore in the mitochondria, the cellular battery that provides energy. They designed a molecule to block the pore and showed it helped protect neurons and improved the mice’s mobility, all with minimal immunosuppression. The paper by mostly UK researchers is published in the Journal of Biological Chemistry.
Now, let’s take a look at the latest Drug Development Pipeline updates. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, and rituximab. One update reflects findings from post-hoc analysis of clinical trial data showing that the positive effects of fingolimod are apparent quite soon –within months – after initiation of treatment.
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And now to our interview. I spoke with Professor Helen Tremlett, Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia when we were at the ECTRIMS conference in Barcelona in October. She has been studying sun exposure over the course of the lifetime and its relation to MS risk. While MS may affect an individual's likelihood to go out in the sun, studies may also need to consider the influence of sun exposure before the disease develops.
Interviewer – Dan Keller
What are you doing in this area?
Interviewee – Helen Tremlett
So I was presenting at ECTRIMS yesterday on a really interesting study based out of the Nurses' Health Study, and this was a collaboration from my group in Vancouver and Harvard School of Public Health; and that's Alberto Ascherio's group and Sandy Munger. So we were looking at sun exposure over the life course and associations with multiple sclerosis. So here we were looking at both aspects of the spectrum, if you can imagine; we were looking at sun exposure and future risk of multiple sclerosis, but also once an individual has developed multiple sclerosis, we were looking at the impact that potentially has on an individual in terms of their propensity to go outdoors in the daylight hours, outdoors in the sun.
MSDF
Right. So it may be the cart is before the horse in that sense; not that sun exposure is causing it, but their disability is causing less sun exposure?
Dr. Tremlett
We were looking at both sides of the equation. And I think it is important, particularly in a disease such as MS where onset of MS is a little bit fuzzy, I think, to look at sun exposure of the life course is important, and certainly our findings are indicating that. Because you want to know sunlight exposure in MS risk, but you also want to know, once someone's developed multiple sclerosis, how that influences their behavior outdoors and what implications that has if you're then trying to design the study to look at what causes MS.
You need to be really careful who you recruit, because if that person has already changed their behavior, then that may influence your findings, and you're not then actually looking at what causes MS at all, you're just looking at a consequence of the disease. So I guess that's the first part of why we wanted to do that.
And the second part is if having MS, if having a chronic condition, does influence your propensity or ability or desire to go outside, what consequence could that have for your health in terms of maybe your serum vitamin D levels or your melatonin levels, and that may have a consequence in terms of long-term health.
MSDF
You segmented people by where they were and at what ages.
Dr. Tremlett
It was pretty interesting. So, first of all, over ages 5 to 15, we found there that there was a 48% lower risk of MS for women living in high, relative to low, ambient UVB areas during their sort of childhood and early adolescent years. So that was pretty interesting. But we found, kind of to our surprise because it goes against other studies that are out there, we found that time spent outdoors in summer or winter wasn't significantly associated with MS risk in that age group, 5 to 15 years. But what we didn't realize is that it wasn't until we combined that outdoor behavior with the UVB, then we could see that there was an association. So we found that less time spent outdoors in summer in low ambient UVB areas—that was associated with a two-fold increased risk of multiple sclerosis.
That was an important step for us; I mean, it might, you know, sound obvious to combine those two, but it was an important step because other studies in smaller geographical areas such as Tasmania, or there's a study out of Norway in a small region of Norway, they can find an association between time spent outdoors in summer/winter and MS risk. But I think we couldn't find it in the US, because the US is at such a diversity of latitudes – the study spanned over 14 US states – so it wasn't until we looked at that outdoor behavior in context of ambient UVB that we could find the association.
And then, I suppose, our next step was to look at outdoor behavior over the life course. And this was really interesting, that we found some avoidance behavior was apparent in later life in multiple sclerosis. And maybe that comes as no surprise to people, but I think our numbers are interesting to put a concrete figure on it. So, for instance, by age 50, our MS cases were 60% less likely to report high relative to low outdoor exposure compared to controls, and that was in winter and in summer.
So the bottom line is people with MS, once they have MS, are not going outside as much, so they're not getting that UVB exposure, so potentially they're not making that vitamin D and serum vitamin D. And then the winter exposure's important as well, because potentially they're not getting the same melatonin production and inhibition, and that may have a really important role in terms of immunology, the circadian rhythm and your sleep cycle, which, again, all knocks back into overall health and immunology of MS. And there have been some presentations actually at this conference looking into melatonin and its association with relapses in MS, and that's pretty interesting.
MSDF
There's even some emerging thought that sleep is essential for good brain function in terms of taking out the garbage – glymphatics and things like that. So melatonin disturbances may actually have some further consequences in an inflammatory brain disease.
Dr. Tremlett
And there's some interesting studies, not that we did but others have done, looking at shift work and risk of MS. And shift work may be associated with increased risk of MS. Maybe melatonin ties into that as well.
MSDF
Is there also potentially an effect, besides on vitamin D and melatonin, that sun exposure itself has an effect on the immune system, maybe suppressing it?
Dr. Tremlett
Yeah, modulating it in some way. No, absolutely. We don't really know the mechanism. I mean, the obvious one would be sun on human skin at the right time of year on the right skin color can result in really high levels of serum vitamin D being produced. Sunlight exposure the minute it actually hits the skin surface can have a direct immunomodulatory effect. And then, obvious, sun hitting the eye. Melatonin is one of the pathways in there that may then impact the immune system.
MSDF
Is it possible to make any conclusions or even recommendations at this point?
Dr. Tremlett
No. It's an observational study, and we do actually need to do more analysis on this group of individuals. The main recommendations we could make from this study is informing how to design future studies, and also two things you could take from this in terms of recommendations.
First of all, we saw sun avoidance behavior in individuals once they've developed multiple sclerosis. That's really important because it really means that if you want to look at what is causing MS, do not take serum vitamin D levels or look at skin cancer risk, for instance, in individuals who already have MS, because they've already changed in compare to controls, adding further somehow differences are related to what causes MS, because these individuals have already changed their behavior because they've got a chronic disease. So that's the first statement, which might be a no-brainer for some people, but it's amazing how many studies are still published like that in the MS literature at the moment.
And I suppose the second piece is trying to understand if we are going to do an interventional study, what time period in an individual's life or within a population do you need to target in order to change the course and prevent the disease from occurring? And we're trying to understand that more, looking beyond the window age 5 to 15, look more into adulthood to see if ambient UVB is associated with MS risk later in life and into adulthood. And others have shown that there does seem to be an association even into adulthood, which is exciting because if you do want to do an intervention study, then you haven't necessarily missed the boat because you've not intervened during childhood. But, I mean, the real question is how do you intervene and what with? And that's another topic in itself.
MSDF
We'll leave that for another day. Thank you.
Dr. Tremlett
Thank you very much.
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Next week, we'll continue our discussion with Professor Tremlett when she'll talk about her preliminary studies on pediatric MS patients and their gut microbiomes.
Until then, thank you for listening to Episode Sixty-Three 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’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit 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’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.
For Multiple Sclerosis Discovery, I'm Dan Keller.
[outro music]