Richard Cohen

Interview with Richard Cohen

Marc Stecker

Interview with Marc Stecker, the Wheelchair Kamikaze

David Baker

[intro music]   Host – Dan Keller Hello, and welcome to Episode Ninety-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview again features Dr. David Baker, Professor of Neuroimmunology at Queen Mary University of London in the U.K. We spoke at the ECTRIMS conference last fall. In part one of our interview he raised the issue of why there has been very poor translation from animal models to clinical trials. Today, Dr. Baker, also known as the ”Mouse Doctor” for his work with animal models, lays out why this situation exists and what to do about it.   Interviewee – David Baker I think there’s many reasons why, and I think we all have our failings. And one can point the finger at the animal models, which a lot of the clinicians do, saying it’s the animal model’s fault, which is possible. But I think also we have to look at humans and how humans use their animal models. And then how humans translate the data from the animal models into the clinic, because I think there’s many failings along the line, and I think that’s one of the reasons for the failing between the two.   I think one of the failings is, in terms of the animal models, that when we do our animal models for these, we’re looking for mechanisms not treatments. And so about 70% of studies give drug before disease is ever induced, which never happens in a human. You know, you go after you’ve had one or two or more attacks before you’re given drugs. We also use the drugs in a way that are never used in a human, so people will do what they call a prophylactic drug where they’ll give it before the disease manifests itself. Or a therapeutic dose, which is probably when the animals are showing their symptoms. But in reality, a human would be getting steroids at that time point. They would never get a DMT. So you’re not comparing, you know, apples with apples. You’re comparing apples with pears, and I think that’s one of the problems.   And I think, you know, if you try and block an immune response from being generated, that’s quite easy compared to stopping an immune response once it’s been generated, because immunity’s about giving life-long protection against infections. And so I think it’s a different type of beast to target. So I think this is where the animal models could do it, because EAE is one of the few where you have this relapsing-remitting disease course. But it’s very, very rare that people actually start to treat in between attacks to block further relapses. I think that’s one of the problems.   The other big problem is the dose; the dose relationship between animals and humans. There’s a tendency we just keep giving more and more and more and more, and eventually the drugs will work. But you’ve got this problem that animals are very liable to be stressed, and we call it the building site effect, so construction site effect. And if you have lots of loud noises, it scares animals. They get very stressed, and your EAE just disappears. And likewise, if you just give lots and lots of drug, that probably tastes nasty. They get stressed out as well. And I think many of the so-called wonder cures – cures of the week – are because we’re just giving too much, which doesn’t have a relationship to what the human dose is going to be.   And then, likewise, I think we’ve got too much of a publication bias for the need to generate positive data. And I think what we then have to do is we have to look at the quality of the data. And I think there has been a lot of failure to replicate data. I think some of that is because some studies lack quality control, and the way I look at that – and I could be wrong; obviously it’s an opinion – but if you look at the way that EAE is scored (it’s normally a scoring system 1 to 3 or 1 to 4) and then you have your drug, which may be, you know, takes your control down from 3 down to a 1. But then, every now again, you look at the studies where it goes either way, and your controls are at 1 and it goes up to 3, and I ask the question how do you get a score of 1? Because if you had four animals, they’re all scoring 1. Or is it three animals score 0 and one score 4, and that will give you a score of 1. And I think if people were made to actually put the data about how many animals got disease, we’d be able to interpret those line graphs. Because I feel that, in many cases, some of those graphs lack quality control.   If you have a robust quality control system, your control group should be giving you roughly the same type of scores every time. But in individual papers you can see, in some groups you have a score of 1 in the control group. The next experiment it’s a score of 3. To my mind I think if you look at that, then those are probably the experiments are much more likely not to replicate. So I think you have to be, obviously, skeptical, but I really would like people to actually probably give us the information about how many animals got disease – what is their mean score – in addition to those line graphs. Because without that, they’re impossible to interpret.   So that’s, you know, kind of one problem of the animals. And then for the humans, you have the same problems. So they over-interpret the animal data. The people doing the clinical trials are very, very rarely the people who came up with the idea. So if there’s a weird side effect that you may know about, you know, that’s not translated to the person who’s actually doing the study, because they don’t talk to the basic scientists. Then they probably underpower the studies. They don’t necessarily pick the right outcome measurements. So I think there’s many failings in both sides of the equation, and it’s not always the animal model. But I think unless we kind of up our game, I think it’s going to be very difficult for the people who are working on animal models, because you know, there are treatments that come along for, you know, the immune part of multiple sclerosis.   And if you’re thinking about the ethical use of animals, it’s much harder to make the ethical argument that you should be using disease models which are very severe for the animals to try and work out fundamental parts of biology. And, therefore, I think we’ll find that you know the funding agencies start to say, well, why are we funding this work? So I think we need to have good quality work, because if we don’t have good quality work, it allows that clinical view that animal work doesn’t really deliver the treatments. And I think they can deliver the treatments, but we just have to use our animal studies wisely to ask questions rather than, you know, blindly saying this will work in multiple sclerosis because it works in EAE. That doesn’t make sense to me.   Interviewer – Dan Keller Do you have any succinct tips for people who are either reviewing papers on animal studies or people who are reading those papers once they’re published or even the general public reading a news story?   Dr. Baker Well my first tip would be probably – and this is okay as an opinion – but, you know, EAE data is nonparametric. It goes 1, 2, 3, 4; it’s not a continuous scale, so first tip is don’t use, you know, the t-test of parametric data on nonparametric data. And that does make a difference. There is a Nature paper published this year that was analyzed with a t-test. If you analyze it with a Mann-Whitney test, which you should have done, the data becomes nonsignificant. So rather than the take home message is, you know, this is a new wonder drug for multiple sclerosis, their answer should have been you have to go back and reproduce your EAE experiment because it didn’t work. So I think that would be the first tip. And then the second tip, I would really like people to say, tell us how many animals get disease and on what level and when, so we can interpret the line graph.   MSDF This is something that you routinely see in oncology done right. They talk about percent of responders, and among responders, what was the shrinkage of the tumor? They don’t average it out among all the people who dilute it out by not responding.   Dr. Baker Well I think one of the problems as well is we’ve also got this publication bias. We’ve got you know this urge to see positive data, and I think that skews the whole system.   MSDF Has anything changed since you came out with a response to the animal checklist?   Dr. Baker I think, sadly, no, but we’re actually doing the checklist again, so we will be able to see if things have changed. I don’t think it has. I think the message hasn’t gotten through. But I think – this is, again, another one of those nails in the animal model coffin that, if we don’t up our game, we’ll be seen to be doing an inferior quality work and eventually we’ll get discarded. So I know that some of the grant councils are, as you know, saying this is a condition of your grant. But I think you know it’s been slow to change, and I think one of the reasons is actually people who are leaders of the field actually are some of the people who are some of the worst offenders. So we’re leading by bad example rather than good example.   MSDF We don’t want to leave the listener with the impression that you’re against animal models. I mean, you’re known as “Dr. Mouse,” so you know I guess you just want to see them done well.   Dr. Baker Yes, I’m passionate. I mean, I really you know believe animal models have a real positive impact to do. And I’ve been really lucky in the recent years is that, you know, some of those animal models – and work we’ve done from animal models – is going through into humans and you know is starting to make the difference. So you know our work with the Cannabis was great. You know, it shows that you know our animal work has validity. Without the animal model stuff we’ll never really understand the biology. You can’t do all the experiments in humans. You do need experimental systems to be able to ask questions. And you need to be able to invent.   And you know there is some fantastic work. You know I’ve picked up the papers, and I get really excited by it, but I think, at the same time, we have to also be a drum to say, you know, try and improve the quality. Because, at the end of the day, it’s more likely that if you’re doing good quality animal experiments, that other people will be able to replicate it. And it will move the field on further and faster. And I think if people believe what we produce as being good solid work, then it’s going to be a win-win situation.   MSDF It would be nice to see sort of a meta-analysis of animal studies that are considered to have been done well versus those not and see which ones translated into advances in the human situation, because so many times they say, well, sure it works in animals, but it doesn’t work in humans. Well if it works in animals because it was set up not so well, then that might be a reason not to work in humans.   Dr. Baker Yes. I think you know the problem of animal models has got nothing peculiar to the multiple sclerosis field. It’s just a common theme. And I think that tells me it’s not a problem of animal models, because if it’s so common in every other discipline, it tells us it’s something how we use the animals is the fundamental problem. Now, you know for MS, we don’t really know. I mean, I think this going to be the – we’re at ECTRIMS now, and I think the whole world can change a little bit today, or in the next few days, because we’ve always thought of MS as being a T cell-mediated disease. Now that may be still the true answer, but now we’re starting to see ocrelizumab, which is a big B cell depleting antibody probably – I’m predicting – to have as good an effect as anything that the T cell you know brigade has ever done. And, in fact, if you look at most of the MS drugs, you would say that most of them actually are inhibiting B cell function.   Now, does that tell us that B cells are driving the disease? It may well do. Or it may well not. Now some people could argue – and they will – you know they’re the reservoir for the virus that causes multiple sclerosis. And then other people will say, well, actually the antigen-presenting cells. And let’s see, but I think what we’ll find is you know EAE will have to have changed its focus. We’ve been focusing our studies on T cell biology, but in fact, the T cell-inhibitory molecules haven’t really delivered. So is that right? And it may well be you know we have to think of a different biology. But EAE can certainly do that if need be.   So we’ll have to you know try and work out how do these B cell-depleting agents work. Is it you know via antigen presentation or not? I don’t know.   MSDF We’ve always thought of T cells as regulating B cells. Now it looks like they both regulate each other.   Dr. Baker I mean, I have my history in skin diseases, and when I first started working, actually my boss was more interested in B-regulatory cells. T-regulatory cells kind of hadn’t really existed at that time point. So I think we’re trying to reinvent the wheel. If we look throughout the literature, it’s a cross-talk between T and B cells are probably the answer. And we’ll see. Again, from our animal studies, we’ve had animal studies where we’ve manipulated the immune system making sure that has a positive effect. We’ve been able to translate that, so we have an N of 1 where we’ve got rid of somebody’s neutralizing beta-interferon antibodies by antigen-specific mechanisms. Now if we could translate that into MS, then we may have a way of treating MS. But we’ll see.   MSDF Very good, thank you. I appreciate it.   Dr. Baker Okay.   [transition music]   MSDF Thank you for listening to Episode Ninety-eight of Multiple Sclerosis Discovery. This episode is the final one in our series of MS podcasts. We hope that the series has been enlightening and has spurred further discussion about the causes of MS and related conditions, their pathological mechanisms, potential ways to intervene, and new research directions. We’ve tried to communicate this information in a way that builds bridges among different disciplines, with a goal of opening new routes toward significant clinical advances. Although we won’t be adding any new podcasts, the series will remain available on the MS Discovery website for the foreseeable future.   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 nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.   [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.

[intro music] Host – Dan Keller Hello, and welcome to Episode Ninety-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Today's interview again features Dr. David Baker, Professor of Neuroimmunology at Queen Mary University of London in the U.K. We spoke at the ECTRIMS conference last fall. In part one of our interview he raised the issue of why there has been very poor translation from animal models to clinical trials. Today, Dr. Baker, also known as the ”Mouse Doctor” for his work with animal models, lays out why this situation exists and what to do about it. Interviewee – David Baker I think there’s many reasons why, and I think we all have our failings. And one can point the finger at the animal models, which a lot of the clinicians do, saying it’s the animal model’s fault, which is possible. But I think also we have to look at humans and how humans use their animal models. And then how humans translate the data from the animal models into the clinic, because I think there’s many failings along the line, and I think that’s one of the reasons for the failing between the two. I think one of the failings is, in terms of the animal models, that when we do our animal models for these, we’re looking for mechanisms not treatments. And so about 70% of studies give drug before disease is ever induced, which never happens in a human. You know, you go after you’ve had one or two or more attacks before you’re given drugs. We also use the drugs in a way that are never used in a human, so people will do what they call a prophylactic drug where they’ll give it before the disease manifests itself. Or a therapeutic dose, which is probably when the animals are showing their symptoms. But in reality, a human would be getting steroids at that time point. They would never get a DMT. So you’re not comparing, you know, apples with apples. You’re comparing apples with pears, and I think that’s one of the problems. And I think, you know, if you try and block an immune response from being generated, that’s quite easy compared to stopping an immune response once it’s been generated, because immunity’s about giving life-long protection against infections. And so I think it’s a different type of beast to target. So I think this is where the animal models could do it, because EAE is one of the few where you have this relapsing-remitting disease course. But it’s very, very rare that people actually start to treat in between attacks to block further relapses. I think that’s one of the problems. The other big problem is the dose; the dose relationship between animals and humans. There’s a tendency we just keep giving more and more and more and more, and eventually the drugs will work. But you’ve got this problem that animals are very liable to be stressed, and we call it the building site effect, so construction site effect. And if you have lots of loud noises, it scares animals. They get very stressed, and your EAE just disappears. And likewise, if you just give lots and lots of drug, that probably tastes nasty. They get stressed out as well. And I think many of the so-called wonder cures – cures of the week – are because we’re just giving too much, which doesn’t have a relationship to what the human dose is going to be. And then, likewise, I think we’ve got too much of a publication bias for the need to generate positive data. And I think what we then have to do is we have to look at the quality of the data. And I think there has been a lot of failure to replicate data. I think some of that is because some studies lack quality control, and the way I look at that – and I could be wrong; obviously it’s an opinion – but if you look at the way that EAE is scored (it’s normally a scoring system 1 to 3 or 1 to 4) and then you have your drug, which may be, you know, takes your control down from 3 down to a 1. But then, every now again, you look at the studies where it goes either way, and your controls are at 1 and it goes up to 3, and I ask the question how do you get a score of 1? Because if you had four animals, they’re all scoring 1. Or is it three animals score 0 and one score 4, and that will give you a score of 1. And I think if people were made to actually put the data about how many animals got disease, we’d be able to interpret those line graphs. Because I feel that, in many cases, some of those graphs lack quality control. If you have a robust quality control system, your control group should be giving you roughly the same type of scores every time. But in individual papers you can see, in some groups you have a score of 1 in the control group. The next experiment it’s a score of 3. To my mind I think if you look at that, then those are probably the experiments are much more likely not to replicate. So I think you have to be, obviously, skeptical, but I really would like people to actually probably give us the information about how many animals got disease – what is their mean score – in addition to those line graphs. Because without that, they’re impossible to interpret. So that’s, you know, kind of one problem of the animals. And then for the humans, you have the same problems. So they over-interpret the animal data. The people doing the clinical trials are very, very rarely the people who came up with the idea. So if there’s a weird side effect that you may know about, you know, that’s not translated to the person who’s actually doing the study, because they don’t talk to the basic scientists. Then they probably underpower the studies. They don’t necessarily pick the right outcome measurements. So I think there’s many failings in both sides of the equation, and it’s not always the animal model. But I think unless we kind of up our game, I think it’s going to be very difficult for the people who are working on animal models, because you know, there are treatments that come along for, you know, the immune part of multiple sclerosis. And if you’re thinking about the ethical use of animals, it’s much harder to make the ethical argument that you should be using disease models which are very severe for the animals to try and work out fundamental parts of biology. And, therefore, I think we’ll find that you know the funding agencies start to say, well, why are we funding this work? So I think we need to have good quality work, because if we don’t have good quality work, it allows that clinical view that animal work doesn’t really deliver the treatments. And I think they can deliver the treatments, but we just have to use our animal studies wisely to ask questions rather than, you know, blindly saying this will work in multiple sclerosis because it works in EAE. That doesn’t make sense to me. Interviewer – Dan Keller Do you have any succinct tips for people who are either reviewing papers on animal studies or people who are reading those papers once they’re published or even the general public reading a news story? Dr. Baker Well my first tip would be probably – and this is okay as an opinion – but, you know, EAE data is nonparametric. It goes 1, 2, 3, 4; it’s not a continuous scale, so first tip is don’t use, you know, the t-test of parametric data on nonparametric data. And that does make a difference. There is a Nature paper published this year that was analyzed with a t-test. If you analyze it with a Mann-Whitney test, which you should have done, the data becomes nonsignificant. So rather than the take home message is, you know, this is a new wonder drug for multiple sclerosis, their answer should have been you have to go back and reproduce your EAE experiment because it didn’t work. So I think that would be the first tip. And then the second tip, I would really like people to say, tell us how many animals get disease and on what level and when, so we can interpret the line graph. MSDF This is something that you routinely see in oncology done right. They talk about percent of responders, and among responders, what was the shrinkage of the tumor? They don’t average it out among all the people who dilute it out by not responding. Dr. Baker Well I think one of the problems as well is we’ve also got this publication bias. We’ve got you know this urge to see positive data, and I think that skews the whole system. MSDF Has anything changed since you came out with a response to the animal checklist? Dr. Baker I think, sadly, no, but we’re actually doing the checklist again, so we will be able to see if things have changed. I don’t think it has. I think the message hasn’t gotten through. But I think – this is, again, another one of those nails in the animal model coffin that, if we don’t up our game, we’ll be seen to be doing an inferior quality work and eventually we’ll get discarded. So I know that some of the grant councils are, as you know, saying this is a condition of your grant. But I think you know it’s been slow to change, and I think one of the reasons is actually people who are leaders of the field actually are some of the people who are some of the worst offenders. So we’re leading by bad example rather than good example. MSDF We don’t want to leave the listener with the impression that you’re against animal models. I mean, you’re known as “Dr. Mouse,” so you know I guess you just want to see them done well. Dr. Baker Yes, I’m passionate. I mean, I really you know believe animal models have a real positive impact to do. And I’ve been really lucky in the recent years is that, you know, some of those animal models – and work we’ve done from animal models – is going through into humans and you know is starting to make the difference. So you know our work with the Cannabis was great. You know, it shows that you know our animal work has validity. Without the animal model stuff we’ll never really understand the biology. You can’t do all the experiments in humans. You do need experimental systems to be able to ask questions. And you need to be able to invent. And you know there is some fantastic work. You know I’ve picked up the papers, and I get really excited by it, but I think, at the same time, we have to also be a drum to say, you know, try and improve the quality. Because, at the end of the day, it’s more likely that if you’re doing good quality animal experiments, that other people will be able to replicate it. And it will move the field on further and faster. And I think if people believe what we produce as being good solid work, then it’s going to be a win-win situation. MSDF It would be nice to see sort of a meta-analysis of animal studies that are considered to have been done well versus those not and see which ones translated into advances in the human situation, because so many times they say, well, sure it works in animals, but it doesn’t work in humans. Well if it works in animals because it was set up not so well, then that might be a reason not to work in humans. Dr. Baker Yes. I think you know the problem of animal models has got nothing peculiar to the multiple sclerosis field. It’s just a common theme. And I think that tells me it’s not a problem of animal models, because if it’s so common in every other discipline, it tells us it’s something how we use the animals is the fundamental problem. Now, you know for MS, we don’t really know. I mean, I think this going to be the – we’re at ECTRIMS now, and I think the whole world can change a little bit today, or in the next few days, because we’ve always thought of MS as being a T cell-mediated disease. Now that may be still the true answer, but now we’re starting to see ocrelizumab, which is a big B cell depleting antibody probably – I’m predicting – to have as good an effect as anything that the T cell you know brigade has ever done. And, in fact, if you look at most of the MS drugs, you would say that most of them actually are inhibiting B cell function. Now, does that tell us that B cells are driving the disease? It may well do. Or it may well not. Now some people could argue – and they will – you know they’re the reservoir for the virus that causes multiple sclerosis. And then other people will say, well, actually the antigen-presenting cells. And let’s see, but I think what we’ll find is you know EAE will have to have changed its focus. We’ve been focusing our studies on T cell biology, but in fact, the T cell-inhibitory molecules haven’t really delivered. So is that right? And it may well be you know we have to think of a different biology. But EAE can certainly do that if need be. So we’ll have to you know try and work out how do these B cell-depleting agents work. Is it you know via antigen presentation or not? I don’t know. MSDF We’ve always thought of T cells as regulating B cells. Now it looks like they both regulate each other. Dr. Baker I mean, I have my history in skin diseases, and when I first started working, actually my boss was more interested in B-regulatory cells. T-regulatory cells kind of hadn’t really existed at that time point. So I think we’re trying to reinvent the wheel. If we look throughout the literature, it’s a cross-talk between T and B cells are probably the answer. And we’ll see. Again, from our animal studies, we’ve had animal studies where we’ve manipulated the immune system making sure that has a positive effect. We’ve been able to translate that, so we have an N of 1 where we’ve got rid of somebody’s neutralizing beta-interferon antibodies by antigen-specific mechanisms. Now if we could translate that into MS, then we may have a way of treating MS. But we’ll see. MSDF Very good, thank you. I appreciate it. Dr. Baker Okay. [transition music] MSDF Thank you for listening to Episode Ninety-eight of Multiple Sclerosis Discovery. This episode is the final one in our series of MS podcasts. We hope that the series has been enlightening and has spurred further discussion about the causes of MS and related conditions, their pathological mechanisms, potential ways to intervene, and new research directions. We’ve tried to communicate this information in a way that builds bridges among different disciplines, with a goal of opening new routes toward significant clinical advances. Although we won’t be adding any new podcasts, the series will remain available on the MS Discovery website for the foreseeable future. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. [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.

Multiple Sclerosis Discovery  --  Episode 98 with Dr. David Baker

[intro music]   Host – Dan Keller Hello, and welcome to Episode Ninety-seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview features Dr. David Baker, Professor of Neuroimmunology at Queen Mary University of London in the UK. We spoke at the ECTRIMS conference last fall, where I asked him about his work with cannabinoid compounds – work that has led to a better understanding of the cannabinoid system as well as to candidate drug compounds to treat spasticity.   Interviewer – Dan Keller In terms of what you're doing now with cannabinoids, can you tell me what you are looking for, and what you've found?   Interviewee – David Baker Many, many years ago, we actually were probably the first people to show that cannabis can actually alleviate muscle stiffness in animal models of multiple sclerosis, which then kind of underpinned the push to look for cannabis in MS. So people with MS were smoking cannabis and perceiving benefit. The question was, why? And what they didn't really understand that there was going to be an unfolding biology. And a few years later after our first discovery that actually cannabinoids can cause relaxation of the muscles, we understood that the function of the cannabinoid system is to regulate nerve signaling. And so because the cannabinoid system does regulate the strength of synaptic signaling, then it's obvious that it can inhibit signs and symptoms because of this excessive neurostimulation. So at the time of that, then we realized that the receptor is a CB1 receptor, and the compound within cannabis is THC, and they're the same molecules that cause all the side effects. So you could never really disassociate away the high from the medical benefit. So we started to think, well, how can we try and get the medical benefit from the cannabinoid system and at the same time try and limit the side effect potential.   So what we thought is, well, if we can stop the cannabinoid molecules getting in the brain, then they won't cause the side effects. But maybe we can target the aberrant signaling in the spinal cord and the peripheral system to try and get the benefits. And so that was our intention. So we tried to make a CNS-excluded drug. And that's, in fact, what we did. We made a drug that was very, very water soluble, so you know, you use the mechanism of the blood-brain barrier to actually exclude it from the brain. So we made the compound, and a few weeks later, we kind of started putting it into animal models, not really doing it the pharmaceutical way, which would be a methodical testing. So we showed that it didn't cause any of the unwanted side effects that are associated with cannabis in the animals. And then we put it in a system where we had a spasticity in a multiple sclerosis relevant system, and the drug worked.   Now what we did know is that the drug was blocked by the activity of the CB1 receptor antagonist, so it looked like we'd made what we set out to make. So we were really excited. And from that point, we started to try and see if we could develop it as a drug. Unfortunately what we realized very quickly actually is that it doesn't work by the known cannabinoid receptor system, and I think what we stumbled across is a whole new biology of the cannabinoid system.   And so we've been developing this drug bit by bit. We set up a university spinout company to try and develop it as a pharmaceutical drug. And over the years, bit by bit, we've been pushing it forward. So it's very safe in animals. It has a massive therapeutic window. And with grant funding agencies etc. we've managed to be able to take it into phase I study where it passed with flying colors. We tested it in 60 healthy humans. And a few weeks ago, we started our first testing in people with multiple sclerosis. So we'll have to see how it works. But we hope by early in 2016 we'll have the answer. So it could be a symptom modifying drug, but it doesn't have any of the side effects associated with drugs such as, you know, Sativex or baclofen as well. So it's not sedating as far as we know.   The way that the drug works is a new mechanism. And what we can probably say is it serves to block the excitation of nerves. So it dampens down excessive signaling, which are probably the consequences or the causes of spasms and spasticity and possibly the symptoms as well and maybe pain. We just have to do more work to see if it will work that way.   MSDF Is this a hyperexcitable system? Or is it a hypoinhibited system where you're getting this spasticity?   Dr. Baker Well, I think spasticity is largely caused by loss of the inhibitory circuitry. So there's probably less GABAergic signaling. And so one can, you know, drive the inhibitory system, like you do with GABA, but likewise you can actually kind of block the excitation. And this mechanism actually probably only exists in pathology. So this is probably why there isn't the side effect potential that the real target that we're actually after really only occurs when the nervous system is going a bit haywire. So that's why we think we've got good safety margin.   MSDF And you had told me that this does not induce hunger, which I guess is another sign that it's not getting into the CNS?   Dr. Baker Having said all that, it was made not to get in the central nervous system, but in reality, it doesn't matter if it does get in the central nervous system. So in fact, about 15% of the drug does get into the central nervous system, which would be as good as many drugs that are CNS penetrant. I guess when we were starting, we were hoping that, you know, it was going to be excluded because we thought it was a cannabinoid receptor agonist, but in reality, it doesn't matter. And in fact what we know is actually this targeting into the lesions. So there's actually more goes into the area. And what this kind of spins on to some other work that we've done with some of our sodium channel work.   We've been developing new sodium channel blockers as potential neuroprotectants. And what we've done is certain molecules actually get excluded by CNS drug pumps, and what we'd noticed in MS is that some of these drug pumps disappear. So we made a drug that was actually targeted specifically to one of those drug pumps, which would normally mean it would be excluded from the brain, but what we showed is that with these new sodium channel blockers, that actually they physically target into the lesion where the pump disappears. And so again, you increase this therapeutic window between effect versus side effect, because again with the sodium channels, you need them for health. You block them, and you have side effects. But what we've found with the sodium channel blockers is that in the animal models, sodium channel blockers were neuroprotective, and we then took that idea forward actually into the clinical trial.   So we first of all thought the trials with sodium channel blockers had failed. Why had they failed? Well, the reason they failed was the trial outcomes weren't right, and suddenly actually because of this unpleasant side effect, 50% of the people didn't take the drug. So the trial was doomed before it ever started. And then what we had was we had the bloods of the people in the trial. So we looked two years after the trial had finished and was seen to be a failure, and we found that 50% of people weren't taking the drugs. But if you look to the people who were taking the drugs, we could see that there was less neurofilament in their blood indicative that there is less nerve damage. And so actually in reality, the trial actually was positive, but it was seen to be negative because of this failure to take the drug.   So the question was, how could we then develop that forward? So the clinical guy said, well, let's think how we could best do a quick trial. And they came up with the idea of the optic nerve being the ideal target. And so what they said to us was, can you, you know, model this in the animal model? So we developed a new animal model. So we took Vijay Kuchroo's 2D2 mice, which are preprogrammed to get optic neuritis, and then we just made their eyes florescent so we could just look in their eyes and see nerves in real time and in life. And as a consequence of using the transgenic, which targeted myelin oligodendrocyte glycoprotein, the cells would go in, cause optic neuritis, that would cause nerve death, and then we could monitor the nerve death just by looking into the eye, because each nerve was labeled with a fluorescent protein. We'd see one single nerve die.   And so we started to use that as a way of testing different drugs for neuroprotection. And we put a whole stack of different compounds, minocycline, sodium channel blockers, glutamate receptor antagonist, we did a few. And we got some hits with the sodium channel blockers, and we tried a few of the different ones, some of them better than others. And unfortunately the one that they chose for the trial is probably the worst one in the animals, but they decided that you had to load drug quickly, so they selected phenytoin. So we showed that the sodium channel could work in the optic neuritis, and then the idea was then we translate that and then do a trial with optic neuritis in the human.   So this was a trial that Raj Kapoor did. And so the idea was that people go blind, and then you go to the doctors. And then they were randomized to either get steroids, which is the standard treatment, or they'd get steroids plus a sodium channel blocker, which was phenytoin at the time. And that was done because you can dose very quickly. So the idea was to get people on drug very quickly. So within seven days of their first symptom, people were on active drug. And people were treated for about six months. And then they looked at the retinal fiber thickness. So as a consequence of the ganglion in the retina dying, the retina thins, and then you can measure that with a machine called OCT, optical coherence tomography. And that was slowed. So they saved 30% of the nerves from dying, even though there were people getting a steroid. So it tells us that really certain channel blockers are neuroprotective.   And then the question is, is how then can we show that in reality? So what we've done from there is we've actually gone on with another sodium channel blocker, which was called oxcarbazepine, which was much more effective in the animal models. And we've been trying to initiate a new trial design whereby we're looking for people who are on current DMTs by showing evidence of neurofilament release, which is indicative that their nerves are being destroyed, because as the nerves are destroyed, they liberate their contents, and then we can pick that up in the biological fluids. So the idea is that if they've got neurofilaments in their cerebrospinal fluid, they get the option of having a sodium channel blocker in addition to their DMT. And then we'll monitor them by serial lumbar punctures to see if the neurofilament levels decrease as a way of a trench push on the trial design for phase II.   Because if you're thinking about the standard phase III, phase II trial for neuroprotection, you're talking about a two- or three-year trial, which will take you two years to recruit the 600 people and another year to do the analysis. So you're really talking about a seven-year trial with 600 people. This trial design will kind of push it down probably to 12 months to 18 months with 60 people. So we can do 10 times more people and a lot quicker this way. So that's started where we've been recruiting, and we're still recruiting, but fingers crossed that would be another way forward in terms of developing neuroprotection. I think it shows how we've been trying to use our animal models to translate things into the human. Because at the end of the day, there has been really, really poor translation between the animal models and humans. And I guess the question is, is why?   MSDF We’ll pick up on that question in part two of our interview with Dr. Baker next time, when he’ll describe some of the deficiencies he sees in the design and interpretation of animal experiments and how they could be improved to better relate to clinical trials and the clinical situation.   [transition music]   MSDF Thank you for listening to Episode Ninety-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. 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.

[intro music] Host – Dan Keller Hello, and welcome to Episode Ninety-seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Today's interview features Dr. David Baker, Professor of Neuroimmunology at Queen Mary University of London in the UK. We spoke at the ECTRIMS conference last fall, where I asked him about his work with cannabinoid compounds – work that has led to a better understanding of the cannabinoid system as well as to candidate drug compounds to treat spasticity. Interviewer – Dan Keller In terms of what you're doing now with cannabinoids, can you tell me what you are looking for, and what you've found? Interviewee – David Baker Many, many years ago, we actually were probably the first people to show that cannabis can actually alleviate muscle stiffness in animal models of multiple sclerosis, which then kind of underpinned the push to look for cannabis in MS. So people with MS were smoking cannabis and perceiving benefit. The question was, why? And what they didn't really understand that there was going to be an unfolding biology. And a few years later after our first discovery that actually cannabinoids can cause relaxation of the muscles, we understood that the function of the cannabinoid system is to regulate nerve signaling. And so because the cannabinoid system does regulate the strength of synaptic signaling, then it's obvious that it can inhibit signs and symptoms because of this excessive neurostimulation. So at the time of that, then we realized that the receptor is a CB1 receptor, and the compound within cannabis is THC, and they're the same molecules that cause all the side effects. So you could never really disassociate away the high from the medical benefit. So we started to think, well, how can we try and get the medical benefit from the cannabinoid system and at the same time try and limit the side effect potential. So what we thought is, well, if we can stop the cannabinoid molecules getting in the brain, then they won't cause the side effects. But maybe we can target the aberrant signaling in the spinal cord and the peripheral system to try and get the benefits. And so that was our intention. So we tried to make a CNS-excluded drug. And that's, in fact, what we did. We made a drug that was very, very water soluble, so you know, you use the mechanism of the blood-brain barrier to actually exclude it from the brain. So we made the compound, and a few weeks later, we kind of started putting it into animal models, not really doing it the pharmaceutical way, which would be a methodical testing. So we showed that it didn't cause any of the unwanted side effects that are associated with cannabis in the animals. And then we put it in a system where we had a spasticity in a multiple sclerosis relevant system, and the drug worked. Now what we did know is that the drug was blocked by the activity of the CB1 receptor antagonist, so it looked like we'd made what we set out to make. So we were really excited. And from that point, we started to try and see if we could develop it as a drug. Unfortunately what we realized very quickly actually is that it doesn't work by the known cannabinoid receptor system, and I think what we stumbled across is a whole new biology of the cannabinoid system. And so we've been developing this drug bit by bit. We set up a university spinout company to try and develop it as a pharmaceutical drug. And over the years, bit by bit, we've been pushing it forward. So it's very safe in animals. It has a massive therapeutic window. And with grant funding agencies etc. we've managed to be able to take it into phase I study where it passed with flying colors. We tested it in 60 healthy humans. And a few weeks ago, we started our first testing in people with multiple sclerosis. So we'll have to see how it works. But we hope by early in 2016 we'll have the answer. So it could be a symptom modifying drug, but it doesn't have any of the side effects associated with drugs such as, you know, Sativex or baclofen as well. So it's not sedating as far as we know. The way that the drug works is a new mechanism. And what we can probably say is it serves to block the excitation of nerves. So it dampens down excessive signaling, which are probably the consequences or the causes of spasms and spasticity and possibly the symptoms as well and maybe pain. We just have to do more work to see if it will work that way. MSDF Is this a hyperexcitable system? Or is it a hypoinhibited system where you're getting this spasticity? Dr. Baker Well, I think spasticity is largely caused by loss of the inhibitory circuitry. So there's probably less GABAergic signaling. And so one can, you know, drive the inhibitory system, like you do with GABA, but likewise you can actually kind of block the excitation. And this mechanism actually probably only exists in pathology. So this is probably why there isn't the side effect potential that the real target that we're actually after really only occurs when the nervous system is going a bit haywire. So that's why we think we've got good safety margin. MSDF And you had told me that this does not induce hunger, which I guess is another sign that it's not getting into the CNS? Dr. Baker Having said all that, it was made not to get in the central nervous system, but in reality, it doesn't matter if it does get in the central nervous system. So in fact, about 15% of the drug does get into the central nervous system, which would be as good as many drugs that are CNS penetrant. I guess when we were starting, we were hoping that, you know, it was going to be excluded because we thought it was a cannabinoid receptor agonist, but in reality, it doesn't matter. And in fact what we know is actually this targeting into the lesions. So there's actually more goes into the area. And what this kind of spins on to some other work that we've done with some of our sodium channel work. We've been developing new sodium channel blockers as potential neuroprotectants. And what we've done is certain molecules actually get excluded by CNS drug pumps, and what we'd noticed in MS is that some of these drug pumps disappear. So we made a drug that was actually targeted specifically to one of those drug pumps, which would normally mean it would be excluded from the brain, but what we showed is that with these new sodium channel blockers, that actually they physically target into the lesion where the pump disappears. And so again, you increase this therapeutic window between effect versus side effect, because again with the sodium channels, you need them for health. You block them, and you have side effects. But what we've found with the sodium channel blockers is that in the animal models, sodium channel blockers were neuroprotective, and we then took that idea forward actually into the clinical trial. So we first of all thought the trials with sodium channel blockers had failed. Why had they failed? Well, the reason they failed was the trial outcomes weren't right, and suddenly actually because of this unpleasant side effect, 50% of the people didn't take the drug. So the trial was doomed before it ever started. And then what we had was we had the bloods of the people in the trial. So we looked two years after the trial had finished and was seen to be a failure, and we found that 50% of people weren't taking the drugs. But if you look to the people who were taking the drugs, we could see that there was less neurofilament in their blood indicative that there is less nerve damage. And so actually in reality, the trial actually was positive, but it was seen to be negative because of this failure to take the drug. So the question was, how could we then develop that forward? So the clinical guy said, well, let's think how we could best do a quick trial. And they came up with the idea of the optic nerve being the ideal target. And so what they said to us was, can you, you know, model this in the animal model? So we developed a new animal model. So we took Vijay Kuchroo's 2D2 mice, which are preprogrammed to get optic neuritis, and then we just made their eyes florescent so we could just look in their eyes and see nerves in real time and in life. And as a consequence of using the transgenic, which targeted myelin oligodendrocyte glycoprotein, the cells would go in, cause optic neuritis, that would cause nerve death, and then we could monitor the nerve death just by looking into the eye, because each nerve was labeled with a fluorescent protein. We'd see one single nerve die. And so we started to use that as a way of testing different drugs for neuroprotection. And we put a whole stack of different compounds, minocycline, sodium channel blockers, glutamate receptor antagonist, we did a few. And we got some hits with the sodium channel blockers, and we tried a few of the different ones, some of them better than others. And unfortunately the one that they chose for the trial is probably the worst one in the animals, but they decided that you had to load drug quickly, so they selected phenytoin. So we showed that the sodium channel could work in the optic neuritis, and then the idea was then we translate that and then do a trial with optic neuritis in the human. So this was a trial that Raj Kapoor did. And so the idea was that people go blind, and then you go to the doctors. And then they were randomized to either get steroids, which is the standard treatment, or they'd get steroids plus a sodium channel blocker, which was phenytoin at the time. And that was done because you can dose very quickly. So the idea was to get people on drug very quickly. So within seven days of their first symptom, people were on active drug. And people were treated for about six months. And then they looked at the retinal fiber thickness. So as a consequence of the ganglion in the retina dying, the retina thins, and then you can measure that with a machine called OCT, optical coherence tomography. And that was slowed. So they saved 30% of the nerves from dying, even though there were people getting a steroid. So it tells us that really certain channel blockers are neuroprotective. And then the question is, is how then can we show that in reality? So what we've done from there is we've actually gone on with another sodium channel blocker, which was called oxcarbazepine, which was much more effective in the animal models. And we've been trying to initiate a new trial design whereby we're looking for people who are on current DMTs by showing evidence of neurofilament release, which is indicative that their nerves are being destroyed, because as the nerves are destroyed, they liberate their contents, and then we can pick that up in the biological fluids. So the idea is that if they've got neurofilaments in their cerebrospinal fluid, they get the option of having a sodium channel blocker in addition to their DMT. And then we'll monitor them by serial lumbar punctures to see if the neurofilament levels decrease as a way of a trench push on the trial design for phase II. Because if you're thinking about the standard phase III, phase II trial for neuroprotection, you're talking about a two- or three-year trial, which will take you two years to recruit the 600 people and another year to do the analysis. So you're really talking about a seven-year trial with 600 people. This trial design will kind of push it down probably to 12 months to 18 months with 60 people. So we can do 10 times more people and a lot quicker this way. So that's started where we've been recruiting, and we're still recruiting, but fingers crossed that would be another way forward in terms of developing neuroprotection. I think it shows how we've been trying to use our animal models to translate things into the human. Because at the end of the day, there has been really, really poor translation between the animal models and humans. And I guess the question is, is why? MSDF We’ll pick up on that question in part two of our interview with Dr. Baker next time, when he’ll describe some of the deficiencies he sees in the design and interpretation of animal experiments and how they could be improved to better relate to clinical trials and the clinical situation. [transition music] MSDF Thank you for listening to Episode Ninety-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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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.

Multiple Sclerosis Discovery  --  Episode 97 with Dr. David Baker

Bibiana Bielekova

Mika Komori

[intro music]   Host – Dan Keller Hello, and welcome to Episode Ninety-six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview features Drs. Bibiana Bielekova, who is an investigator at the National Institutes of Health, and Mika Komori, a postdoctoral fellow in her lab. We caught up with the two physician-researchers at the ACTRIMS meeting in New Orleans earlier this year. At the meeting, Dr. Komori talked about a new and more sensitive way to evaluate what may be happening in the brains and spinal cords of people with progressive MS.   In a recent study, she examined samples of cerebral spinal fluid, or CSF, collected through a thin needle near the base of the spine. She was scouting for immunological biomarkers of progressive MS. In the analysis, a molecule called CD27, mostly from T cells, stood out, as did another marker specific to B cells. Even more revealing was the ratio of the CD27 molecule to the T cells. T cells are a big player in relapsing MS and not usually associated with the progressive, more neurodegenerative forms of MS. The unexpected results raise new questions about why immune-modulating drugs do not seem to be effective against progressive MS.   If validated, the new test may lead to better diagnosis and treatment of people with MS and other neurological disorders. And it may speed up clinical trials in progressive MS and reduce their cost. In fact, the same research team used their new biomarker test in a small phase 2 study of the anti-B cell drug, rituximab, delivered both intravenously in the blood and intrathecally in the spinal column. Unfortunately, the new biomarker test showed that the double delivery system did not work as expected to eliminate inflammatory B cells trapped in the brains of people with progressive MS. They stopped the study early for lack of efficacy.   In a change to our usual podcast format, Dr. Bielekova interviewed Dr. Komori about the specifics of the study and put the results in a larger context. Midway through the interview, Carol Morton, a past editor of MS Discovery Forum, asked both doctor-scientists about what the new test means for treating patients.   Interviewer – Dr. Bibiana Bielekova As a physician, when we see patients, we don’t really know what’s happening in their brains, right? We are using some tools that are supposed to help us to identify like, for example, MRI, but they are not perfect. So, how did you choose to address that problem?   Interviewee – Dr. Mika Komori So, when I saw patients, I can’t tell them that the drug, which are now available, is effective or not, especially for progressive MS patients, because currently so far all big clinical trials, they didn’t show any effects on them. Because of that result, we think progressive MS patients don’t have any intrathecal inflammation. So far we believe MS – multiple sclerosis – is inflammatory disease, but we don’t know if it’s true for progressive MS or not.   Dr. Bielekova Yes, and, in fact, it is because these tools are not that ideal, right? So, in fact, by using the tools that are available, such as MRI or these cerebrospinal fluid markers that have been developed more than 40 years ago, the conclusion is that there isn’t inflammation in progressive MS, right, because all of them are basically decreased, with exception of IgG index which, as you said, remains stable for many, many years. So somebody who had, for example, infection during childhood can have elevated IgG index for the rest of their life.   So that was really the reason why we wanted to develop something that is more sensitive. And also, I think, the question really was, does cerebrospinal fluid reflect what’s happening in the brain tissue? And can we somehow develop technology that can tell us what is happening in the brain tissue without taking, of course, the biopsy, which is extremely invasive, and we cannot really use it in people, right? So how did you address that problem?   Dr. Komori We developed a very good way to measure soluble biomarkers in the CSF with a new technique called Meso Scale Discovery.   Dr. Bielekova So I think we should probably step back a little bit and say that our goal was to really look at the biomarkers that can point towards a specific cell, right? Because there are proteins that can be released by all immune cells, such as for example, chemokines, and, in fact, the vast majority of cytokines. But we were especially interested in looking at the proteins than can specifically point to one particular cell type, and so you did something else to really measure that, right? In fact, we all helped you to do that because it was so difficult, right? So we employed the whole lab to do the separation of cells. And then you were looking at which cells are producing these biomarkers.   Dr. Komori Right.   Dr. Bielekova So tell us about those three that really panned out as the best.   Dr. Komori When we see the results of soluble CD27, soluble CD14, and soluble CD21, soluble CD27 correctly identified all inflammatory neurological disease and also only negative for noninflammatory neurological disease patients.   Dr. Bielekova Whereas all of the traditional markers together, if we put all of them together, they could identify only about two-thirds of the patients. We were really surprised, because – I mean, the field believed, as Mika had said, right, based on the fact you no longer have contrast-enhancing lesions; the treatments no longer work; you don’t have clear cytosis, meaning a large number of white blood cells in the cerebrospinal fluid – the field and us, we believed that what we are going to see, once Mika unblinds these two cohorts of close to 200 patients each that we will see that progressive patients have significantly lower amount of inflammation. But that’s not what she saw. She saw something completely different and surprising. So what did you see?   Dr. Komori Well we saw almost comparable level of intrathecal inflammation in both PPMS/SPMS to RRMS.   Dr. Bielekova Not almost, right? There wasn’t any statistically significant difference.   Dr. Komori No.   Dr. Bielekova So on the group level, we saw the same level.   Dr. Komori Absolutely. Yes, and it was so significant compared to a healthy donor and noninflammatory neurological diseases. So all healthy donor and neuro-inflammatory neurological diseases, they didn’t have high level of especially soluble CD27. But almost 90% of each MS subtypes had very high soluble CD27.   Dr. Bielekova But when you did the ratios…   Dr. Komori Then we did the ratio and calculated soluble CD27 per T cell in CSF. We found that even higher level of ratio results in progressive MS patients, both in primary progressive and secondary progressive. And for our MS patients the ratio is almost comparable to healthy donor and noninflammatory neurological diseases. That means, although we don’t see many immune cells in the CSF for progressive MS patients, those cells are in the CNS tissue. And it cannot move, but just shedding the soluble markers like soluble CD27 into the CSF. And we can detect that marker when we measure the CSF.   Dr. Bielekova And I think it really nicely ties with the beautiful pathology studies that have been published that demonstrate that patients with progressive MS no longer have this very dense inflammation around the vessel, which is the type inflammation that is capable of opening blood-brain barrier, right? Which means that that’s the type of inflammation that is associated with contrast-enhancing lesions. But instead, when pathologists looked at normal-appearing white matter, they could see, you know, one T cell here, one T cell there, right? It’s really difficult to quantify it on the pathology level, because they never assay the whole brain. But your assay is, in fact, looking at the entire brain. And what your assay is saying is that the number of cells is basically the same in all of these different stages of MS disease process. What is really different is where they are located, right?   So, in relapsing/remitting MS, they are located in the perivascular aggregates, not much in the normal appearing white matter. That’s where they open the blood-brain barrier. But in the progressive MS they are located in the brain. And I think our conclusion was that, in fact, this may be the major reason why current treatments are not working for progressive MS, because basically we would expect that only those drugs can work in progressive MS that have very good penetrance into the brain tissue.   Now, I think that we also have to realize that just the presence of the cells in the tissue doesn’t tell us that they are pathogenic, right? So it may be that they are there, but something else is driving disability. But on the other hand, the data we have, for example, from recently announced ocrelizumab trial is really suggesting that these cells are indeed pathogenic, right? So I think that we can say that progressive MS is neurodegenerative disease only if we can eliminate inflammation from the brain of progressive MS patients, and it does not translate into stopping disability or significantly inhibiting disability.   But the data that we have published, and we are still collecting, are really suggesting that current treatments, in fact, do not eliminate cells from the brain of progressive MS patients, right? So I think the question of compartmentalized inflammation versus neurodegeneration in progressive MS is really open. And I mean my view is that probably both of them are going to be important, right? I think that just because there are immune cells in the CNS tissue, it doesn’t necessarily mean that neurodegeneration is also not present. But I think the hypothesis that progressive MS is no longer inflammatory disease, and it’s pure neurodegenerative disease – I think that hypothesis is, at the moment, not confirmed, right, because we don’t have the experiment where we would eliminate the inflammation.   MSDF So both of you are physicians. Does this influence how you would treat people with progressive MS at all?   Dr. Komori Yes, absolutely. So from now, when I see high ratio results of progressive MS patients – soluble CD27 per T cell – if they have high ratio, then I will not treat them with current immunomodulatory drugs. But may be a good idea to try more effective drugs to penetrate in the brain. But if the progressive MS patients, although they have high soluble CD27 but low ratio results, then it will be worthwhile to use some immunomodulatory drugs for them.   Dr. Bielekova I would even kind of take a step back and say that in order to be able to use your tool for the treatment decision, I think we need to gain another type of knowledge which we don’t have yet and that is what are current treatments really doing on these type of assays and this type of pathology, right? So we really need to quantify each individual drug, how much it can affect intrathecal inflammation in patients with the open blood-brain barrier, where the drug actually can get into the tissue versus patients with closed blood-brain barrier, where potentially the penetrance is much, much, much more limited, right. I think that it brings back that case that I mentioned where, you know, we are using, for example, cyclophosphamide, and we are assuming that just because the drug is inhibiting immune response in the blood, it will inhibit immune response in the cerebrospinal fluid. And I think that those assumptions are just not tested, right? And, in fact, when we tested them, we realized that the effect on the intrathecal inflammation is extremely limited.   So I think that there is a knowledge that we need to gain, which is this knowledge of which MS drug is doing what. And, if we conclude that they are not doing a sufficient job, which I am afraid that’s going to be the conclusion, then we can use this technology to in fact develop new drugs, right? Because your technology is looking at the type of inflammation that cannot be measured by contrast-enhancing lesions. In fact cannot be measured by anything that we have available thus far, right? So how are we going to even try to develop new drugs for progressive MS?   Well, we can do it by doing large, Phase 3 trials like we have been doing thus far and looking at disability. But of course, that’s incredibly expensive, and it’s just very inefficient way to do it. So instead, doing small trials where you take patients because they have intrathecal inflammation, right. So you now measure; (A) how much inflammation; and (B) its compartmentalized inflammation. Then you can give them the drug, and then you say, ‘okay so now I’m going to measure’ – and you can do it in 3 months or 6 months, in much, much, much shorter time periods – and say, you know, ‘how much is this drug inhibiting intrathecal inflammation?’ And, in fact, that’s precisely what you have done in our RIVITALISE trial, right? Which, unfortunately, we stopped precisely because your assays determined that we are not achieving as much inhibition of inflammation as we were hoping to achieve. So I think that that makes drug development very efficient. And hopefully it will allow us as a society, to screen many, many more treatments on a yearly basis than what we can do currently.   Dr. Komori I think if we can measure the cell-specific or pathophysiology-specific biomarkers, we can combine treatments.   Dr. Bielekova Absolutely.   Dr. Komori If, like interferon, it doesn’t work, let’s try natalizumab. If not, let’s try this, but if we know that interferon works for this side of the pathophysiology, but natalizumab works for this side of the pathophysiology, then we can combine them to more effective treatment.   Dr. Bielekova Yes, and I think that I would say ‘more to come,’ right? So far Mika published data that relate to inflammation, but the lab is working very hard on biomarkers that reflect, for example, mitochondrial dysfunction, or neurodegenerative processes. And we absolutely believe that treatments will have to be combined, and that this, you know, basically assaying cerebrospinal fluid is going to be that tool that will, on one hand allow us to develop these new treatments, and on the other hand, allow us to treat patients smartly at the bedside.   [transition music]   MSDF Thank you for listening to Episode Ninety-six 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 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.

[intro music] Host – Dan Keller Hello, and welcome to Episode Ninety-six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Today's interview features Drs. Bibiana Bielekova, who is an investigator at the National Institutes of Health, and Mika Komori, a postdoctoral fellow in her lab. We caught up with the two physician-researchers at the ACTRIMS meeting in New Orleans earlier this year. At the meeting, Dr. Komori talked about a new and more sensitive way to evaluate what may be happening in the brains and spinal cords of people with progressive MS. In a recent study, she examined samples of cerebral spinal fluid, or CSF, collected through a thin needle near the base of the spine. She was scouting for immunological biomarkers of progressive MS. In the analysis, a molecule called CD27, mostly from T cells, stood out, as did another marker specific to B cells. Even more revealing was the ratio of the CD27 molecule to the T cells. T cells are a big player in relapsing MS and not usually associated with the progressive, more neurodegenerative forms of MS. The unexpected results raise new questions about why immune-modulating drugs do not seem to be effective against progressive MS. If validated, the new test may lead to better diagnosis and treatment of people with MS and other neurological disorders. And it may speed up clinical trials in progressive MS and reduce their cost. In fact, the same research team used their new biomarker test in a small phase 2 study of the anti-B cell drug, rituximab, delivered both intravenously in the blood and intrathecally in the spinal column. Unfortunately, the new biomarker test showed that the double delivery system did not work as expected to eliminate inflammatory B cells trapped in the brains of people with progressive MS. They stopped the study early for lack of efficacy. In a change to our usual podcast format, Dr. Bielekova interviewed Dr. Komori about the specifics of the study and put the results in a larger context. Midway through the interview, Carol Morton, a past editor of MS Discovery Forum, asked both doctor-scientists about what the new test means for treating patients. Interviewer – Dr. Bibiana Bielekova As a physician, when we see patients, we don’t really know what’s happening in their brains, right? We are using some tools that are supposed to help us to identify like, for example, MRI, but they are not perfect. So, how did you choose to address that problem? Interviewee – Dr. Mika Komori So, when I saw patients, I can’t tell them that the drug, which are now available, is effective or not, especially for progressive MS patients, because currently so far all big clinical trials, they didn’t show any effects on them. Because of that result, we think progressive MS patients don’t have any intrathecal inflammation. So far we believe MS – multiple sclerosis – is inflammatory disease, but we don’t know if it’s true for progressive MS or not. Dr. Bielekova Yes, and, in fact, it is because these tools are not that ideal, right? So, in fact, by using the tools that are available, such as MRI or these cerebrospinal fluid markers that have been developed more than 40 years ago, the conclusion is that there isn’t inflammation in progressive MS, right, because all of them are basically decreased, with exception of IgG index which, as you said, remains stable for many, many years. So somebody who had, for example, infection during childhood can have elevated IgG index for the rest of their life. So that was really the reason why we wanted to develop something that is more sensitive. And also, I think, the question really was, does cerebrospinal fluid reflect what’s happening in the brain tissue? And can we somehow develop technology that can tell us what is happening in the brain tissue without taking, of course, the biopsy, which is extremely invasive, and we cannot really use it in people, right? So how did you address that problem? Dr. Komori We developed a very good way to measure soluble biomarkers in the CSF with a new technique called Meso Scale Discovery. Dr. Bielekova So I think we should probably step back a little bit and say that our goal was to really look at the biomarkers that can point towards a specific cell, right? Because there are proteins that can be released by all immune cells, such as for example, chemokines, and, in fact, the vast majority of cytokines. But we were especially interested in looking at the proteins than can specifically point to one particular cell type, and so you did something else to really measure that, right? In fact, we all helped you to do that because it was so difficult, right? So we employed the whole lab to do the separation of cells. And then you were looking at which cells are producing these biomarkers. Dr. Komori Right. Dr. Bielekova So tell us about those three that really panned out as the best. Dr. Komori When we see the results of soluble CD27, soluble CD14, and soluble CD21, soluble CD27 correctly identified all inflammatory neurological disease and also only negative for noninflammatory neurological disease patients. Dr. Bielekova Whereas all of the traditional markers together, if we put all of them together, they could identify only about two-thirds of the patients. We were really surprised, because – I mean, the field believed, as Mika had said, right, based on the fact you no longer have contrast-enhancing lesions; the treatments no longer work; you don’t have clear cytosis, meaning a large number of white blood cells in the cerebrospinal fluid – the field and us, we believed that what we are going to see, once Mika unblinds these two cohorts of close to 200 patients each that we will see that progressive patients have significantly lower amount of inflammation. But that’s not what she saw. She saw something completely different and surprising. So what did you see? Dr. Komori Well we saw almost comparable level of intrathecal inflammation in both PPMS/SPMS to RRMS. Dr. Bielekova Not almost, right? There wasn’t any statistically significant difference. Dr. Komori No. Dr. Bielekova So on the group level, we saw the same level. Dr. Komori Absolutely. Yes, and it was so significant compared to a healthy donor and noninflammatory neurological diseases. So all healthy donor and neuro-inflammatory neurological diseases, they didn’t have high level of especially soluble CD27. But almost 90% of each MS subtypes had very high soluble CD27. Dr. Bielekova But when you did the ratios… Dr. Komori Then we did the ratio and calculated soluble CD27 per T cell in CSF. We found that even higher level of ratio results in progressive MS patients, both in primary progressive and secondary progressive. And for our MS patients the ratio is almost comparable to healthy donor and noninflammatory neurological diseases. That means, although we don’t see many immune cells in the CSF for progressive MS patients, those cells are in the CNS tissue. And it cannot move, but just shedding the soluble markers like soluble CD27 into the CSF. And we can detect that marker when we measure the CSF. Dr. Bielekova And I think it really nicely ties with the beautiful pathology studies that have been published that demonstrate that patients with progressive MS no longer have this very dense inflammation around the vessel, which is the type inflammation that is capable of opening blood-brain barrier, right? Which means that that’s the type of inflammation that is associated with contrast-enhancing lesions. But instead, when pathologists looked at normal-appearing white matter, they could see, you know, one T cell here, one T cell there, right? It’s really difficult to quantify it on the pathology level, because they never assay the whole brain. But your assay is, in fact, looking at the entire brain. And what your assay is saying is that the number of cells is basically the same in all of these different stages of MS disease process. What is really different is where they are located, right? So, in relapsing/remitting MS, they are located in the perivascular aggregates, not much in the normal appearing white matter. That’s where they open the blood-brain barrier. But in the progressive MS they are located in the brain. And I think our conclusion was that, in fact, this may be the major reason why current treatments are not working for progressive MS, because basically we would expect that only those drugs can work in progressive MS that have very good penetrance into the brain tissue. Now, I think that we also have to realize that just the presence of the cells in the tissue doesn’t tell us that they are pathogenic, right? So it may be that they are there, but something else is driving disability. But on the other hand, the data we have, for example, from recently announced ocrelizumab trial is really suggesting that these cells are indeed pathogenic, right? So I think that we can say that progressive MS is neurodegenerative disease only if we can eliminate inflammation from the brain of progressive MS patients, and it does not translate into stopping disability or significantly inhibiting disability. But the data that we have published, and we are still collecting, are really suggesting that current treatments, in fact, do not eliminate cells from the brain of progressive MS patients, right? So I think the question of compartmentalized inflammation versus neurodegeneration in progressive MS is really open. And I mean my view is that probably both of them are going to be important, right? I think that just because there are immune cells in the CNS tissue, it doesn’t necessarily mean that neurodegeneration is also not present. But I think the hypothesis that progressive MS is no longer inflammatory disease, and it’s pure neurodegenerative disease – I think that hypothesis is, at the moment, not confirmed, right, because we don’t have the experiment where we would eliminate the inflammation. MSDF So both of you are physicians. Does this influence how you would treat people with progressive MS at all? Dr. Komori Yes, absolutely. So from now, when I see high ratio results of progressive MS patients – soluble CD27 per T cell – if they have high ratio, then I will not treat them with current immunomodulatory drugs. But may be a good idea to try more effective drugs to penetrate in the brain. But if the progressive MS patients, although they have high soluble CD27 but low ratio results, then it will be worthwhile to use some immunomodulatory drugs for them. Dr. Bielekova I would even kind of take a step back and say that in order to be able to use your tool for the treatment decision, I think we need to gain another type of knowledge which we don’t have yet and that is what are current treatments really doing on these type of assays and this type of pathology, right? So we really need to quantify each individual drug, how much it can affect intrathecal inflammation in patients with the open blood-brain barrier, where the drug actually can get into the tissue versus patients with closed blood-brain barrier, where potentially the penetrance is much, much, much more limited, right. I think that it brings back that case that I mentioned where, you know, we are using, for example, cyclophosphamide, and we are assuming that just because the drug is inhibiting immune response in the blood, it will inhibit immune response in the cerebrospinal fluid. And I think that those assumptions are just not tested, right? And, in fact, when we tested them, we realized that the effect on the intrathecal inflammation is extremely limited. So I think that there is a knowledge that we need to gain, which is this knowledge of which MS drug is doing what. And, if we conclude that they are not doing a sufficient job, which I am afraid that’s going to be the conclusion, then we can use this technology to in fact develop new drugs, right? Because your technology is looking at the type of inflammation that cannot be measured by contrast-enhancing lesions. In fact cannot be measured by anything that we have available thus far, right? So how are we going to even try to develop new drugs for progressive MS? Well, we can do it by doing large, Phase 3 trials like we have been doing thus far and looking at disability. But of course, that’s incredibly expensive, and it’s just very inefficient way to do it. So instead, doing small trials where you take patients because they have intrathecal inflammation, right. So you now measure; (A) how much inflammation; and (B) its compartmentalized inflammation. Then you can give them the drug, and then you say, ‘okay so now I’m going to measure’ – and you can do it in 3 months or 6 months, in much, much, much shorter time periods – and say, you know, ‘how much is this drug inhibiting intrathecal inflammation?’ And, in fact, that’s precisely what you have done in our RIVITALISE trial, right? Which, unfortunately, we stopped precisely because your assays determined that we are not achieving as much inhibition of inflammation as we were hoping to achieve. So I think that that makes drug development very efficient. And hopefully it will allow us as a society, to screen many, many more treatments on a yearly basis than what we can do currently. Dr. Komori I think if we can measure the cell-specific or pathophysiology-specific biomarkers, we can combine treatments. Dr. Bielekova Absolutely. Dr. Komori If, like interferon, it doesn’t work, let’s try natalizumab. If not, let’s try this, but if we know that interferon works for this side of the pathophysiology, but natalizumab works for this side of the pathophysiology, then we can combine them to more effective treatment. Dr. Bielekova Yes, and I think that I would say ‘more to come,’ right? So far Mika published data that relate to inflammation, but the lab is working very hard on biomarkers that reflect, for example, mitochondrial dysfunction, or neurodegenerative processes. And we absolutely believe that treatments will have to be combined, and that this, you know, basically assaying cerebrospinal fluid is going to be that tool that will, on one hand allow us to develop these new treatments, and on the other hand, allow us to treat patients smartly at the bedside. [transition music] MSDF Thank you for listening to Episode Ninety-six 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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.

Multiple Sclerosis Discovery  --  Episode 96 with Drs. Bibiana Bielekova and Mika Komori

Michael Levy

[intro music]   Host – Dan Keller Hello, and welcome to Episode Ninety-five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview features Dr. Michael Levy, associate professor of neurology at Johns Hopkins University. When we met in his office, he told me about his work on the role of T cells in neuromyelitis optica, or NMO. Finding antibodies to aquaporin-4 is indicative of NMO. But when Dr. Levy used aquaporin-4 reactive T cells, they could induce NMO in a mouse model, giving a clue to the role of T cells in the disease, and possibly opening up a new therapeutic avenue.   Interviewer – Dan Keller What's different about this approach than what has been thought of previously?   Interviewee – Michael Levy In neuromyelitis optica, there is the thought that the disease involves an antibody, the anti-aquaporin-4 antibody, that that antibody is involved in causing the disease. And what we demonstrated in this model is that we could recreate the disease simply by developing T cells against aquaporin-4. It's the exact same target as the antibody, but instead of using the antibody to exacerbate disease, we use T cells. And it works really well and causes optic neuritis and transverse myelitis, just like in the patient.   MSDF Can you briefly describe your method?   Dr. Levy We raised T cells in mice that don't have aquaporin-4. These mice see aquaporin-4 as a foreign antigen and mount an aggressive immune response against them, and we harvest those T cells from that animal. And what we do is we polarize them. We basically turn them into more aggressive types of immune cells in a dish. And then we transfer those T cells to a naïve mouse that does contain aquaporin-4. And those T cells attack the aquaporin-4, and it does so only in the optic nerves and the spinal cord and also a little bit in the brain.   MSDF But aquaporin-4 is distributed more widely than that in the body.   Dr. Levy That's correct. Actually, there's a higher level of aquaporin-4 in the lung, stomach, kidneys, muscle. Many tissues contain aquaporin-4, but the T cells decide which aquaporin-4 to attack. They are a thoughtful type of cell, and for whatever reason, and this is true in the human, too, the T cells only decide to go for those specific tissues.   MSDF How does a mouse with aquaporin-4 get to an age where you can actually get these T cells out of it? What's the use of aquaporin-4 if they really can survive without it?   Dr. Levy It's amazing that these knockout mice, they don't have any aquaporin-4, are completely viable. There are some abnormalities in function under certain stressful conditions, like stroke or brain trauma, but for the most part, they live normal lives. They must have a good compensatory mechanism that they don't need aquaporin-4, and that's fortunate for us because we can create these animal models.   MSDF When you transferred these T cells to wild-type mice, what did you see?   Dr. Levy Eight days after the transfer, the first thing we noticed is that the mice started blinking and the eyes became sunken into the head, and that's a sign of severe optic neuritis. And then two days later, they had a dragging tail. And a day after that, their hind limbs were paralyzed, and that indicated transverse myelitis.   MSDF What's the role of the antibody if you can induce the disease with the T cell? And does the antibody in itself without T cells have an effect?   Dr. Levy We looked at that, and what we found is that the antibody by itself has absolutely no effect. But in the context of a T cell attack, it can exacerbate the disease, and it does lend specificity to the pathology when you look at it under a microscope. If you add the antibody, there is more aquaporin-4 damage, and it recruits compliment, which causes that damage. So that's really the role of the antibody.   MSDF Can you induce the antibody without T cells? Essentially is aquaporin-4 a T-dependent antigen?   Dr. Levy We think it is, and that's based on the type of antibody it is. The antibody in a human is what's called an IgG1 subtype, which is a T cell-dependent subtype. And that bears out in the animal models as well.   MSDF So the antibody is really an enhancer in the disease as opposed to an initiator?   Dr. Levy That's our thinking. It's not just an enhancer, but also a biomarker of the disease. And maybe in some patients, the antibody is not as harmful, but more of just a biomarker.   MSDF What's the significance of these findings, especially as it relates to human conditions?   Dr. Levy We're always looking for a new target to treat NMO patients, and there were some who were thinking that we should be targeting the antibody to try to either remove it or soak it up somehow. And maybe our model suggests that we should be targeting the T cells. And if there were ways that we could retrain or reeducate those T cells not to attack aquaporin-4 and create a really specific therapy, then we could avoid these broader immunosuppressive therapies that are necessary now to treat these patients.   MSDF Since you have a defined antigen in this case, and I assume you can make some of it, do you have any hope of being able to induce high-zone tolerance using it?   Dr. Levy That is our goal, and we've partnered with a company now to try to create a vaccine therapy using that antigen target. Again, in the same way that a T cell is turned pathogenic with this antigen, we can then retrain that T cell to be tolerized to it. And so we're hoping to apply that sort of technology to humans.   MSDF Now you're coming in at a late stage of the disease. I mean, someone has to present with the disease for you to want to treat it. So really, you can't prevent it. This would be a therapeutic vaccine, not a preventative vaccine?   Dr. Levy Correct. A vaccine therapy more along the lines of retraining than preventing and preparing. Correct.   MSDF Now this applies to NMO, but what about applying it to MS? With NMO, you've got a defined antigen.   Dr. Levy That's exactly right. And with NMO, there isn't what we call antigen spreading, which is where the immune system decides instead of targeting that one antigen, it's going to spread. The epitope is going to spread to other areas of myelin and maybe other components of the central nervous system. With NMO, the antigen is really focused on aquaporin-4, and so that's our advantage. And in MS, there are a lot more targets, and it's probably more of a heterogeneous disease. It would be harder to develop a vaccine therapy for MS.   MSDF Where do you go from here? What's next?   Dr. Levy Next is demonstrating that the mouse model responds to a vaccine therapy approach. We'd like to show that the T cells can be stopped, even when they're pathogenically targeting the aquaporin-4. Transferred into a mouse, we need to demonstrate that a vaccine therapy can prevent their attacks.   MSDF Have you looked or demonstrated T cell receptors specifically for aquaporin-4 fragments?   Dr. Levy We're looking at that now. We're looking in human subjects. We isolate their T cells, and we're looking for a response to certain epitopes of aquaporin-4. That has been done by other groups, but we're looking for specifically pathogenic epitopes now.   MSDF Is there any thought towards some sort of suicide experiment where these T cells that have become activated could then be killed because they're proliferating?   Dr. Levy There is a company in Houston called Opexa Therapeutics. They're doing something similar to that. They're picking out patients' T cells that are reactive against aquaporin-4 and inducing apoptosis so that when these T cells are reintroduced to the body, there is a tolerization. So it is kind of the same thing that you're suggesting. And they are hoping to launch a trial like this by next year.   MSDF Is there anything we've missed or important to add?   Dr. Levy What I'd like to emphasize again is that by focusing on the T cells, we can really hone in on the very upstream early event and really specifically treat…I don't want to use the C word to say cure, but it's really focusing on the source of the problem, rather than treating all the downstream consequences, which is what we do now. So I think our approach has that specific advantage.   MSDF An advantage over a more global nonspecific immunosuppression?   Dr. Levy Exactly, which is what we're doing now.   MSDF Very good. Thanks.   Dr. Levy Thank you.   [transition music]   MSDF Thank you for listening to Episode Ninety-five 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 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.

[intro music] Host – Dan Keller Hello, and welcome to Episode Ninety-five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Today's interview features Dr. Michael Levy, associate professor of neurology at Johns Hopkins University. When we met in his office, he told me about his work on the role of T cells in neuromyelitis optica, or NMO. Finding antibodies to aquaporin-4 is indicative of NMO. But when Dr. Levy used aquaporin-4 reactive T cells, they could induce NMO in a mouse model, giving a clue to the role of T cells in the disease, and possibly opening up a new therapeutic avenue. Interviewer – Dan Keller What's different about this approach than what has been thought of previously? Interviewee – Michael Levy In neuromyelitis optica, there is the thought that the disease involves an antibody, the anti-aquaporin-4 antibody, that that antibody is involved in causing the disease. And what we demonstrated in this model is that we could recreate the disease simply by developing T cells against aquaporin-4. It's the exact same target as the antibody, but instead of using the antibody to exacerbate disease, we use T cells. And it works really well and causes optic neuritis and transverse myelitis, just like in the patient. MSDF Can you briefly describe your method? Dr. Levy We raised T cells in mice that don't have aquaporin-4. These mice see aquaporin-4 as a foreign antigen and mount an aggressive immune response against them, and we harvest those T cells from that animal. And what we do is we polarize them. We basically turn them into more aggressive types of immune cells in a dish. And then we transfer those T cells to a naïve mouse that does contain aquaporin-4. And those T cells attack the aquaporin-4, and it does so only in the optic nerves and the spinal cord and also a little bit in the brain. MSDF But aquaporin-4 is distributed more widely than that in the body. Dr. Levy That's correct. Actually, there's a higher level of aquaporin-4 in the lung, stomach, kidneys, muscle. Many tissues contain aquaporin-4, but the T cells decide which aquaporin-4 to attack. They are a thoughtful type of cell, and for whatever reason, and this is true in the human, too, the T cells only decide to go for those specific tissues. MSDF How does a mouse with aquaporin-4 get to an age where you can actually get these T cells out of it? What's the use of aquaporin-4 if they really can survive without it? Dr. Levy It's amazing that these knockout mice, they don't have any aquaporin-4, are completely viable. There are some abnormalities in function under certain stressful conditions, like stroke or brain trauma, but for the most part, they live normal lives. They must have a good compensatory mechanism that they don't need aquaporin-4, and that's fortunate for us because we can create these animal models. MSDF When you transferred these T cells to wild-type mice, what did you see? Dr. Levy Eight days after the transfer, the first thing we noticed is that the mice started blinking and the eyes became sunken into the head, and that's a sign of severe optic neuritis. And then two days later, they had a dragging tail. And a day after that, their hind limbs were paralyzed, and that indicated transverse myelitis. MSDF What's the role of the antibody if you can induce the disease with the T cell? And does the antibody in itself without T cells have an effect? Dr. Levy We looked at that, and what we found is that the antibody by itself has absolutely no effect. But in the context of a T cell attack, it can exacerbate the disease, and it does lend specificity to the pathology when you look at it under a microscope. If you add the antibody, there is more aquaporin-4 damage, and it recruits compliment, which causes that damage. So that's really the role of the antibody. MSDF Can you induce the antibody without T cells? Essentially is aquaporin-4 a T-dependent antigen? Dr. Levy We think it is, and that's based on the type of antibody it is. The antibody in a human is what's called an IgG1 subtype, which is a T cell-dependent subtype. And that bears out in the animal models as well. MSDF So the antibody is really an enhancer in the disease as opposed to an initiator? Dr. Levy That's our thinking. It's not just an enhancer, but also a biomarker of the disease. And maybe in some patients, the antibody is not as harmful, but more of just a biomarker. MSDF What's the significance of these findings, especially as it relates to human conditions? Dr. Levy We're always looking for a new target to treat NMO patients, and there were some who were thinking that we should be targeting the antibody to try to either remove it or soak it up somehow. And maybe our model suggests that we should be targeting the T cells. And if there were ways that we could retrain or reeducate those T cells not to attack aquaporin-4 and create a really specific therapy, then we could avoid these broader immunosuppressive therapies that are necessary now to treat these patients. MSDF Since you have a defined antigen in this case, and I assume you can make some of it, do you have any hope of being able to induce high-zone tolerance using it? Dr. Levy That is our goal, and we've partnered with a company now to try to create a vaccine therapy using that antigen target. Again, in the same way that a T cell is turned pathogenic with this antigen, we can then retrain that T cell to be tolerized to it. And so we're hoping to apply that sort of technology to humans. MSDF Now you're coming in at a late stage of the disease. I mean, someone has to present with the disease for you to want to treat it. So really, you can't prevent it. This would be a therapeutic vaccine, not a preventative vaccine? Dr. Levy Correct. A vaccine therapy more along the lines of retraining than preventing and preparing. Correct. MSDF Now this applies to NMO, but what about applying it to MS? With NMO, you've got a defined antigen. Dr. Levy That's exactly right. And with NMO, there isn't what we call antigen spreading, which is where the immune system decides instead of targeting that one antigen, it's going to spread. The epitope is going to spread to other areas of myelin and maybe other components of the central nervous system. With NMO, the antigen is really focused on aquaporin-4, and so that's our advantage. And in MS, there are a lot more targets, and it's probably more of a heterogeneous disease. It would be harder to develop a vaccine therapy for MS. MSDF Where do you go from here? What's next? Dr. Levy Next is demonstrating that the mouse model responds to a vaccine therapy approach. We'd like to show that the T cells can be stopped, even when they're pathogenically targeting the aquaporin-4. Transferred into a mouse, we need to demonstrate that a vaccine therapy can prevent their attacks. MSDF Have you looked or demonstrated T cell receptors specifically for aquaporin-4 fragments? Dr. Levy We're looking at that now. We're looking in human subjects. We isolate their T cells, and we're looking for a response to certain epitopes of aquaporin-4. That has been done by other groups, but we're looking for specifically pathogenic epitopes now. MSDF Is there any thought towards some sort of suicide experiment where these T cells that have become activated could then be killed because they're proliferating? Dr. Levy There is a company in Houston called Opexa Therapeutics. They're doing something similar to that. They're picking out patients' T cells that are reactive against aquaporin-4 and inducing apoptosis so that when these T cells are reintroduced to the body, there is a tolerization. So it is kind of the same thing that you're suggesting. And they are hoping to launch a trial like this by next year. MSDF Is there anything we've missed or important to add? Dr. Levy What I'd like to emphasize again is that by focusing on the T cells, we can really hone in on the very upstream early event and really specifically treat…I don't want to use the C word to say cure, but it's really focusing on the source of the problem, rather than treating all the downstream consequences, which is what we do now. So I think our approach has that specific advantage. MSDF An advantage over a more global nonspecific immunosuppression? Dr. Levy Exactly, which is what we're doing now. MSDF Very good. Thanks. Dr. Levy Thank you. [transition music] MSDF Thank you for listening to Episode Ninety-five 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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.

Multiple Sclerosis Discovery  --  Episode 95 with Dr. Michael Levy

Oscar Fernandez

[intro music]   Host – Dan Keller Hello, and welcome to Episode Ninety-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview features Dr. Oscar Fernandez, a senior investigator at the Málaga Regional University Hospital in Málaga, Spain. When we met at a neurology conference in Chile, he reviewed for me some of the elements of risk stratification for second-line therapies for MS. That implies there are first-line therapies and probably third-line ones, as well – terms that Dr. Fernandez is not particularly fond of.   Interviewee – Oscar Fernandez I am very much against that classification, but this is being used for clinicians, so I have to accept that. I believe that there is one drug for one patient, and I don't believe in lines. Because if you use lines, then you must be forced sometimes to do the passing through all these lines. And many times you must go indirectly from the very beginning to second or third line and the case is very severe. Anyhow, lines have been defined more or less just taking into account the benefit and the risk. And first line are those drug who are not terrible beneficial; they have more this efficacy, but they are very safe in the long term. This is the first line, and those are interferons, there are like four interferons so far, and glatiramer acetate, this is first line. And second line are those drug where are more efficacious but more risky also. So there you have natalizumab, fingolimod, alemtuzumab, and mitoxantrone.   And even you can go further for the third line, which is maybe bone marrow transplantation and some experimental therapies by now. There are many new drugs coming, and then we must try to classify these as first, second, or third lines. It's very difficult for clinicians today to image, for instance, ocrelizumab, which drug is that? Is it first, second, or third line? Is it very efficacious, is it very safe until now? So why it should be classified as second line? Probably the agencies will say this is for active relapsing or for active MS and just let the clinicians to use it properly.   Interviewer – Dan Keller So what goes into the risk stratification? What parameters do you consider?   Dr. Fernandez Yeah, the first thing is that most clinicians use a balance, for the balance of efficacy and safety. But then they put numbers. You must put numbers. I mean the numbers are there. I mean for low-risk drugs and for very mild diseases the number is 1 in 10,000. You can have severe adverse events 1 in 10,000. For moderate disease and moderate risk, a drug is 1 in 1,000; and for severe, this is risky drugs, is 1 in 100. Those are the numbers to put in the balance. And we know the numbers from the drugs, and we must tailor our decision based on that.   MSDF Are the risks you're looking at purely progressive multifocal leukoencephalopathy, PML, or are there other risks you're considering in those numbers?   Dr. Fernandez No, PML is just something that appear, but there are many other things to be taken into account. I mean all severe adverse events should be taken into account, and these are the numbers I have mentioned. MS is a very severe disease; it's a risky disease. So we can theorize independent of the severity of the disease and we must look for everything. I mean hematological alteration, hepatic alterations, opportunistic infections, and everything that can be produced by these drugs over these therapies.   MSDF Is it only the drug or do you also take into consideration patient characteristics besides their MS; age, comorbidities, gender, lots of things?   Dr. Fernandez Everything has to be put in the box; I mean all the things have to be consider. And it's not the same to use a drug in a patient which is also a hypothyroid, is diabetic or whatever. So comorbidity, age, sex, and everything has to be taken into account, particularly sex because many drugs can affect pregnancy issues. For instance, so we must take it all together and try to get the right decision.   MSDF Is it a collaborative effort taking into account what the patient preference is either for disease risk, therapeutic risk, or other factors?   Dr. Fernandez Yeah, I think there is to try to find out which is the best way. We know we has collaborate on that and there are a lot of people collaborating. For instance, in Spain, we have a network of MS, and we are doing tremendous advance publishing in this direction. And in Europe and in the world, I believe there is always networks trying to answer all of these questions. For instance, the latest one has been published more recently about the use of L-selectin to stratify the risk for PML in natalizumab users. And this has been very important collaborative study that has validated this measurement, L-selectin, as a factor to be taken into account to reduce the risk of natalizumab.   MSDF Is this something new looking at biomarkers for risk?   Dr. Fernandez Yeah, it's something new. It's still not implemented in most center. But we have been using that for the last two or three years. I have treated more than 250 and especially with natalizumab without a single PML case. Because we use everything at hand to try to reduce the risk of this severe complication.   MSDF How long have those patients been on therapy, natalizumab?   Dr. Fernandez Well, the longest one is 12 years already because this patient participated in clinical trials but they are still there. But all of them more than one year. And the majority of them more even than two years. But as soon as the risk gets over the figure that shouldn’t be got, these patients are withdrawn from the drug. And we have medical simulators now to use on different drugs. Although if you are able to keep the patients on this drug, the patients are perfectly well.   MSDF Do you think the field is going to move more towards that than just looking at JC virus, which is very prevalent anyway?   Dr. Fernandez No, I don't think we should necessarily look for JC virus in every patient. We must look for other things like, for instance, the cases of PML that appear with dimethyl fumarate. I mean there are two cases, as far as I know, but we must look for lymphocytes. I mean doctors always took care of toxicity degrees one, two, three, and four, and we know what to do with these toxicity degrees. And this has not been well done probably in the last years for some clinicians, so we are assisting to some complications because we don't follow the rules strictly. We must follow the rules. Lymphopenia shouldn't be maintained for long periods. Because lymphopenia can be associated with infections, can be associated with tumors. So we better control for these factors. So let's look everything.   MSDF Do databases like MSBase add to the knowledge or information?   Dr. Fernandez Yes, databases probably are fundamental. I mean there are many databases already around the world, and the possibility to share data and to have immediately data from many, many patients is helping us to tailor decisions.   MSDF Have we missed anything important, or is there anything interesting to add?   Dr. Fernandez Yes, I think still there is a tremendous variability between neurologists. And there must be some kind of educational effort in the next future to try to reduce variability. Because by now, there are many drugs; we have confusion. Neurologists treat patients very differently in different countries, even into the same country, into the same hospital. So we must still make a tremendous effort maybe through databases or through evidence-based medicine and try to reduce the variability of what we are doing for our patients.   MSDF Excellent. I appreciate it. Thank you.   Dr. Fernandez Okay, thanks to you.   [transition music]   MSDF Thank you for listening to Episode Ninety-four 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 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.

[intro music] Host – Dan Keller Hello, and welcome to Episode Ninety-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Today's interview features Dr. Oscar Fernandez, a senior investigator at the Málaga Regional University Hospital in Málaga, Spain. When we met at a neurology conference in Chile, he reviewed for me some of the elements of risk stratification for second-line therapies for MS. That implies there are first-line therapies and probably third-line ones, as well – terms that Dr. Fernandez is not particularly fond of. Interviewee – Oscar Fernandez I am very much against that classification, but this is being used for clinicians, so I have to accept that. I believe that there is one drug for one patient, and I don't believe in lines. Because if you use lines, then you must be forced sometimes to do the passing through all these lines. And many times you must go indirectly from the very beginning to second or third line and the case is very severe. Anyhow, lines have been defined more or less just taking into account the benefit and the risk. And first line are those drug who are not terrible beneficial; they have more this efficacy, but they are very safe in the long term. This is the first line, and those are interferons, there are like four interferons so far, and glatiramer acetate, this is first line. And second line are those drug where are more efficacious but more risky also. So there you have natalizumab, fingolimod, alemtuzumab, and mitoxantrone. And even you can go further for the third line, which is maybe bone marrow transplantation and some experimental therapies by now. There are many new drugs coming, and then we must try to classify these as first, second, or third lines. It's very difficult for clinicians today to image, for instance, ocrelizumab, which drug is that? Is it first, second, or third line? Is it very efficacious, is it very safe until now? So why it should be classified as second line? Probably the agencies will say this is for active relapsing or for active MS and just let the clinicians to use it properly. Interviewer – Dan Keller So what goes into the risk stratification? What parameters do you consider? Dr. Fernandez Yeah, the first thing is that most clinicians use a balance, for the balance of efficacy and safety. But then they put numbers. You must put numbers. I mean the numbers are there. I mean for low-risk drugs and for very mild diseases the number is 1 in 10,000. You can have severe adverse events 1 in 10,000. For moderate disease and moderate risk, a drug is 1 in 1,000; and for severe, this is risky drugs, is 1 in 100. Those are the numbers to put in the balance. And we know the numbers from the drugs, and we must tailor our decision based on that. MSDF Are the risks you're looking at purely progressive multifocal leukoencephalopathy, PML, or are there other risks you're considering in those numbers? Dr. Fernandez No, PML is just something that appear, but there are many other things to be taken into account. I mean all severe adverse events should be taken into account, and these are the numbers I have mentioned. MS is a very severe disease; it's a risky disease. So we can theorize independent of the severity of the disease and we must look for everything. I mean hematological alteration, hepatic alterations, opportunistic infections, and everything that can be produced by these drugs over these therapies. MSDF Is it only the drug or do you also take into consideration patient characteristics besides their MS; age, comorbidities, gender, lots of things? Dr. Fernandez Everything has to be put in the box; I mean all the things have to be consider. And it's not the same to use a drug in a patient which is also a hypothyroid, is diabetic or whatever. So comorbidity, age, sex, and everything has to be taken into account, particularly sex because many drugs can affect pregnancy issues. For instance, so we must take it all together and try to get the right decision. MSDF Is it a collaborative effort taking into account what the patient preference is either for disease risk, therapeutic risk, or other factors? Dr. Fernandez Yeah, I think there is to try to find out which is the best way. We know we has collaborate on that and there are a lot of people collaborating. For instance, in Spain, we have a network of MS, and we are doing tremendous advance publishing in this direction. And in Europe and in the world, I believe there is always networks trying to answer all of these questions. For instance, the latest one has been published more recently about the use of L-selectin to stratify the risk for PML in natalizumab users. And this has been very important collaborative study that has validated this measurement, L-selectin, as a factor to be taken into account to reduce the risk of natalizumab. MSDF Is this something new looking at biomarkers for risk? Dr. Fernandez Yeah, it's something new. It's still not implemented in most center. But we have been using that for the last two or three years. I have treated more than 250 and especially with natalizumab without a single PML case. Because we use everything at hand to try to reduce the risk of this severe complication. MSDF How long have those patients been on therapy, natalizumab? Dr. Fernandez Well, the longest one is 12 years already because this patient participated in clinical trials but they are still there. But all of them more than one year. And the majority of them more even than two years. But as soon as the risk gets over the figure that shouldn’t be got, these patients are withdrawn from the drug. And we have medical simulators now to use on different drugs. Although if you are able to keep the patients on this drug, the patients are perfectly well. MSDF Do you think the field is going to move more towards that than just looking at JC virus, which is very prevalent anyway? Dr. Fernandez No, I don't think we should necessarily look for JC virus in every patient. We must look for other things like, for instance, the cases of PML that appear with dimethyl fumarate. I mean there are two cases, as far as I know, but we must look for lymphocytes. I mean doctors always took care of toxicity degrees one, two, three, and four, and we know what to do with these toxicity degrees. And this has not been well done probably in the last years for some clinicians, so we are assisting to some complications because we don't follow the rules strictly. We must follow the rules. Lymphopenia shouldn't be maintained for long periods. Because lymphopenia can be associated with infections, can be associated with tumors. So we better control for these factors. So let's look everything. MSDF Do databases like MSBase add to the knowledge or information? Dr. Fernandez Yes, databases probably are fundamental. I mean there are many databases already around the world, and the possibility to share data and to have immediately data from many, many patients is helping us to tailor decisions. MSDF Have we missed anything important, or is there anything interesting to add? Dr. Fernandez Yes, I think still there is a tremendous variability between neurologists. And there must be some kind of educational effort in the next future to try to reduce variability. Because by now, there are many drugs; we have confusion. Neurologists treat patients very differently in different countries, even into the same country, into the same hospital. So we must still make a tremendous effort maybe through databases or through evidence-based medicine and try to reduce the variability of what we are doing for our patients. MSDF Excellent. I appreciate it. Thank you. Dr. Fernandez Okay, thanks to you. [transition music] MSDF Thank you for listening to Episode Ninety-four 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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 <a href="mailto:editor@msdiscovery.org">editor@msdiscovery.org</a>. For Multiple Sclerosis Discovery, I'm Dan Keller.

Multiple Sclerosis Discovery  --  Episode 94 with Dr. Oscar Fernandez

Lilyana Amezcua

[intro music]   Host — Dan Keller Hello, and welcome to Episode Ninety-three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview features Dr. Lilyana Amezcua, an assistant professor of neurology at the University of Southern California in Los Angeles. Part of her work focuses on defining racial disparities in MS, particularly among the Hispanic community. When we met, she said the prevalence of MS among Hispanics in Latin America has been increasing over the past 20 years, and their clinical characteristics are different from those of whites. As Hispanic Americans constitute one of the largest minorities in the U.S. population, she looked into their clinical picture, as well.   Interviewee – Lilyana Amezcua And so we initially did a first observation in 2011 noting when we examined close to 200 MS patients of Hispanic background self-identified that they were at twice the risk of presenting with optic neuritis and spinal cord problems compared to whites. There is some literature indicating throughout Latin America that these observations could be related to an Asian background. And so when we think about a Hispanic, we think about an umbrella that is related to an intermixing of European, African, and Asian derived background or Native American. So that diversity along with the cultural diversity could have some implications in the way that MS behaves and including risk. And that is one of the theories going around that that's why they don't get MS that much because of an Asian background. However, again, like I mentioned, in the last 20 years more cases have been reported.   Interviewer – Dan Keller Haven't Asians been reported to have this opticospinal sort of MS? So would that feed into this optic neuritis finding with the Hispanics?   Dr. Amezcua That is correct, and actually a second study of ours that we did several years ago was to actually specifically look for that definition of opticospinal MS. And so what we found within 200 or so patients was that indeed when we applied that definition, very few met that criteria. But irrespective of that, and we made sure that every case was negative for aquaporin 4, which is an antibody that you commonly find in more of the NMO spectrum disorders, that these individuals did not have this aquaporin 4, but yet close to 20% looked like they had spinal cord lesions that could be associated with opticospinal.   So that observation, of course, led us to think, well, okay, we should look further. If we do think that Asian ancestry could be important, would some of those clinical characteristics be associated with that type of global ancestry? And in fact today we have a poster related to taking the population that we just presented and looking at their genetic variants, which are mostly noting that the European genetic variants are also found in the Hispanic, but now going forward and looking at, well, what about global ancestry and their clinical characteristics? And in that poster, that abstract, we find that the higher proportion of Asian background you have, the higher risk of presenting with let's say, an optic neuritis. Now that doesn't necessarily say that this is just specific for optic neuritis, but it could going forward let us know about the mechanism behind optic neuritis, which is also found in MS, also found in NMO, and these optical spinal forms of MS.   MSDF How did you go about looking at the genetics of the population?   Dr. Amezcua Going about the genetics actually went back to the fact that when I would say, I'm studying Hispanics, people would ask, what is a Hispanic? And it is true…Hispanic…and so it is defined, you know, when you define it it's well, you can be from Cuba, you can be from Mexico, you can be from the US. But really what links us is…and I say linked us because I'm one of them…is the fact that there is a genetic background that is shared. And there's also cultural aspects that are shared. The cultural aspect is probably going to be important when we start examining the environmental aspects of MS.   MSDF What did you find?   Dr. Amezcua We just started basically with vitamin D. We looked at vitamin D levels in Hispanics with MS compared to whites with MS, and we found that significantly lower levels were among the Hispanics. This is not surprising. This is expected, actually, because of the skin coloration and sun exposure probably differences, but it's also widely known that Hispanics would have lower vitamin D levels. Of course, that doesn't answer, well, if they have lower vitamin D levels, if their risk of MS is less, it doesn't give us any explanation. But we know that their vitamin D levels are low.   Other aspects that we have looked at is just examining differences by migration. So we know in MS that migration, usually, depending on when you move from one place to the other and looking at the risk of MS in the underlying country, that will be modified depending on the age of migration. And so of course Hispanics in the US, again, along with their diversity, they're diverse in the fact that there are many that are US born and there are many that are immigrants. So we looked at differences by this, and we found tremendous amount of differences. One was that the US born appears to have an increased risk of developing MS at a younger age. And this again is just validating some of that information that we know about MS in the past, right, coming from a lower prevalent region and being born in a place of higher risk.   But the second was that, which we were surprised, was that the immigrant, despite being here, let's say 25 years, they developed MS after they had emigrated from their country, on average, 15 years later. So that's interesting. That's again calling for us to investigate, what environmental encounters might have they had when coming to this country? And the third was that respective of this, of, you know, disease duration, there was an independent risk factor for the immigrant to develop ambulatory disability at a shorter time. So that's telling us that, again, well, one is differential environmental exposures. But could the immigrant and the US-born also just be two different populations in terms of, again, what does Hispanic mean? That's where we are.   MSDF In that sense, could you correlate vitamin D levels or anything else with the amount of European background or indigenous Central and South American background they had?   Dr. Amezcua I think that's an excellent idea. You know, I think that could be done, to look at the US-born versus the immigrant. Now there is a large study conducted by Dr. Langer-Gould that's examining the risk of MS within Hispanics, whites, and African Americans in relationship to vitamin D and their HLA. So that will give us information on vitamin D. But absolutely we know that within Hispanics, we're going to have to separate groups because it's just such a big umbrella.   MSDF It's also a big umbrella in terms of cultural background. It's not uniform culture whether you're from the Caribbean or Mexico or born in the US.   Dr. Amezcua Absolutely. So culturally we're going to have to tease that out. And it's simply starts by learning about, well, what are those cultural differences? Which could be from simple perceptions and their access and utilization of care, which needs to be first addressed, or to go forward and then say, well, let's see if there's biological differences. First, I think, you know, between the US-born and the immigrant, the differences could be explained also by sociocultural factors. And those need to be teased out. And then from there look to see, well, is this really a health disparity? Or is it an inherent biological difference of the disease, which we also expect to find.   MSDF Do you think that the results you find in this population is going to be more generalizable or relatable and give you some clues into what's going on with anyone who is getting MS or not?   Dr. Amezcua Absolutely. That is the goal. While that diversity is complex, it's also a positive aspect because it will allow you to tease out a lot of those factors. And so within the admixture, of the genetic admixture, one can say, well, you have less European background. But what about that Asian component that is not found in your general European? It doesn't mean that it's not going to be found. Instead of looking for, I guess, a needle in a haystack, you will just be looking it in a block and maybe find something new or lead us to understanding of mechanisms, again, from the optic neuritis and the global ancestry. We are hoping that this is beyond just understanding one population, but understanding MS, which is the target population.   MSDF Have we missed anything important?   Dr. Amezcua There is definitely a lot to do, and I think it's an effort that cannot be done alone. And so combining it with different centers that have the same interests and population is what the goal is, is to create a network of centers that are interested in defining this population, to move faster.   MSDF Great. Thank you.   Dr. Amezcua Great. Thank you.   [transition music]   MSDF Thank you for listening to Episode Ninety-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. 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.

[intro music] Host — Dan Keller Hello, and welcome to Episode Ninety-three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Today's interview features Dr. Lilyana Amezcua, an assistant professor of neurology at the University of Southern California in Los Angeles. Part of her work focuses on defining racial disparities in MS, particularly among the Hispanic community. When we met, she said the prevalence of MS among Hispanics in Latin America has been increasing over the past 20 years, and their clinical characteristics are different from those of whites. As Hispanic Americans constitute one of the largest minorities in the U.S. population, she looked into their clinical picture, as well. Interviewee – Lilyana Amezcua And so we initially did a first observation in 2011 noting when we examined close to 200 MS patients of Hispanic background self-identified that they were at twice the risk of presenting with optic neuritis and spinal cord problems compared to whites. There is some literature indicating throughout Latin America that these observations could be related to an Asian background. And so when we think about a Hispanic, we think about an umbrella that is related to an intermixing of European, African, and Asian derived background or Native American. So that diversity along with the cultural diversity could have some implications in the way that MS behaves and including risk. And that is one of the theories going around that that's why they don't get MS that much because of an Asian background. However, again, like I mentioned, in the last 20 years more cases have been reported. Interviewer – Dan Keller Haven't Asians been reported to have this opticospinal sort of MS? So would that feed into this optic neuritis finding with the Hispanics? Dr. Amezcua That is correct, and actually a second study of ours that we did several years ago was to actually specifically look for that definition of opticospinal MS. And so what we found within 200 or so patients was that indeed when we applied that definition, very few met that criteria. But irrespective of that, and we made sure that every case was negative for aquaporin 4, which is an antibody that you commonly find in more of the NMO spectrum disorders, that these individuals did not have this aquaporin 4, but yet close to 20% looked like they had spinal cord lesions that could be associated with opticospinal. So that observation, of course, led us to think, well, okay, we should look further. If we do think that Asian ancestry could be important, would some of those clinical characteristics be associated with that type of global ancestry? And in fact today we have a poster related to taking the population that we just presented and looking at their genetic variants, which are mostly noting that the European genetic variants are also found in the Hispanic, but now going forward and looking at, well, what about global ancestry and their clinical characteristics? And in that poster, that abstract, we find that the higher proportion of Asian background you have, the higher risk of presenting with let's say, an optic neuritis. Now that doesn't necessarily say that this is just specific for optic neuritis, but it could going forward let us know about the mechanism behind optic neuritis, which is also found in MS, also found in NMO, and these optical spinal forms of MS. MSDF How did you go about looking at the genetics of the population? Dr. Amezcua Going about the genetics actually went back to the fact that when I would say, I'm studying Hispanics, people would ask, what is a Hispanic? And it is true…Hispanic…and so it is defined, you know, when you define it it's well, you can be from Cuba, you can be from Mexico, you can be from the US. But really what links us is…and I say linked us because I'm one of them…is the fact that there is a genetic background that is shared. And there's also cultural aspects that are shared. The cultural aspect is probably going to be important when we start examining the environmental aspects of MS. MSDF What did you find? Dr. Amezcua We just started basically with vitamin D. We looked at vitamin D levels in Hispanics with MS compared to whites with MS, and we found that significantly lower levels were among the Hispanics. This is not surprising. This is expected, actually, because of the skin coloration and sun exposure probably differences, but it's also widely known that Hispanics would have lower vitamin D levels. Of course, that doesn't answer, well, if they have lower vitamin D levels, if their risk of MS is less, it doesn't give us any explanation. But we know that their vitamin D levels are low. Other aspects that we have looked at is just examining differences by migration. So we know in MS that migration, usually, depending on when you move from one place to the other and looking at the risk of MS in the underlying country, that will be modified depending on the age of migration. And so of course Hispanics in the US, again, along with their diversity, they're diverse in the fact that there are many that are US born and there are many that are immigrants. So we looked at differences by this, and we found tremendous amount of differences. One was that the US born appears to have an increased risk of developing MS at a younger age. And this again is just validating some of that information that we know about MS in the past, right, coming from a lower prevalent region and being born in a place of higher risk. But the second was that, which we were surprised, was that the immigrant, despite being here, let's say 25 years, they developed MS after they had emigrated from their country, on average, 15 years later. So that's interesting. That's again calling for us to investigate, what environmental encounters might have they had when coming to this country? And the third was that respective of this, of, you know, disease duration, there was an independent risk factor for the immigrant to develop ambulatory disability at a shorter time. So that's telling us that, again, well, one is differential environmental exposures. But could the immigrant and the US-born also just be two different populations in terms of, again, what does Hispanic mean? That's where we are. MSDF In that sense, could you correlate vitamin D levels or anything else with the amount of European background or indigenous Central and South American background they had? Dr. Amezcua I think that's an excellent idea. You know, I think that could be done, to look at the US-born versus the immigrant. Now there is a large study conducted by Dr. Langer-Gould that's examining the risk of MS within Hispanics, whites, and African Americans in relationship to vitamin D and their HLA. So that will give us information on vitamin D. But absolutely we know that within Hispanics, we're going to have to separate groups because it's just such a big umbrella. MSDF It's also a big umbrella in terms of cultural background. It's not uniform culture whether you're from the Caribbean or Mexico or born in the US. Dr. Amezcua Absolutely. So culturally we're going to have to tease that out. And it's simply starts by learning about, well, what are those cultural differences? Which could be from simple perceptions and their access and utilization of care, which needs to be first addressed, or to go forward and then say, well, let's see if there's biological differences. First, I think, you know, between the US-born and the immigrant, the differences could be explained also by sociocultural factors. And those need to be teased out. And then from there look to see, well, is this really a health disparity? Or is it an inherent biological difference of the disease, which we also expect to find. MSDF Do you think that the results you find in this population is going to be more generalizable or relatable and give you some clues into what's going on with anyone who is getting MS or not? Dr. Amezcua Absolutely. That is the goal. While that diversity is complex, it's also a positive aspect because it will allow you to tease out a lot of those factors. And so within the admixture, of the genetic admixture, one can say, well, you have less European background. But what about that Asian component that is not found in your general European? It doesn't mean that it's not going to be found. Instead of looking for, I guess, a needle in a haystack, you will just be looking it in a block and maybe find something new or lead us to understanding of mechanisms, again, from the optic neuritis and the global ancestry. We are hoping that this is beyond just understanding one population, but understanding MS, which is the target population. MSDF Have we missed anything important? Dr. Amezcua There is definitely a lot to do, and I think it's an effort that cannot be done alone. And so combining it with different centers that have the same interests and population is what the goal is, is to create a network of centers that are interested in defining this population, to move faster. MSDF Great. Thank you. Dr. Amezcua Great. Thank you. [transition music] MSDF Thank you for listening to Episode Ninety-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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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 <a href="mailto:editor@msdiscovery.org">editor@msdiscovery.org</a>. For Multiple Sclerosis Discovery, I'm Dan Keller.

Multiple Sclerosis Discovery  --  Episode 93 with Dr. Lilyana Amezcua

Shiv Saidha

[intro music]   Host – Dan Keller Hello, and welcome to Episode Ninety-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview features a conversation with Dr. Shiv Saidha, an associate professor of neurology in the Division of Neuroimmunology and Neuro-infectious Diseases at Johns Hopkins University in Baltimore, Maryland. His work has focused on the retina in MS, using the technique of optical coherence tomography, or OCT, to follow the disease, assess and monitor therapeutic strategies, and to better understand the pathobiology of MS. I asked him why the retina is of interest in MS and about the utility of OCT.   Interviewee – Shiv Saidha OCT is the optical analogue of ultrasound B mode imaging. And it's a noninvasive technique that has a lot of utility in quantifying the ultrastructure of various tissues, including the retina. We have a lot of interest in being able to quantify retinal structures specifically in multiple sclerosis because optic nerve pathology, which basically refers to affliction of the optic nerve as part of the MS disease process, is virtually ubiquitous. At the time of postmortem examination of MS patients, 94 to 99% of MS patients are found to have demyelinating plaques within their optic nerves.   So the premise is that demyelination within the optic nerve results in retrograde degeneration of the constituent fibers or axons within the optic nerve. And since those axons or fibers are derived from the retinal nerve fiber layer, which is the innermost layer of the retina, this layer is felt to thin out as part of the MS disease process. Additionally, the neurons – referred to as ganglion cell neurons located in the ganglion cell layer immediately below the retinal nerve fiber layer from which retinal nerve fiber layer axons are derived – are also thought to drop out as part of the MS disease process.   We traditionally conceptualize optic nerve pathology in MS as being an acute phenomenon, namely acute optic neuritis, which does occur in up to, you know, 20 to 70% of MS patients; and in 20 to 25% of cases of MS is the initial hallmark clinical manifestation of the disease process. But beyond acute optic neuritis, there is subclinical optic nerve pathology, which we refer to as subclinical optic neuropathy ongoing within the optic nerves of MS patients.   And so, if we had a technique or an ability to accurately quantify the effects of optic nerve pathology or optic neuropathy – in other words, if we had a way to quantify retinal nerve fiber layer thickness and thickness of ganglion cell…the layer within which ganglion cell neurons are located in the retina – that would provide a substrate or insight into the state or integrity of the optic nerve. And so, optical coherence tomography is a technique which allows us to do this. It allows us to measure thickness of the retinal nerve fiber layer not just around the optic disk which we refer to as the peripapillary retinal nerve fiber layer but also in the macular region.   And with the advent of novel segmentation techniques in OCT – many of which are now commercially available – we now are also afforded the capability of quantifying thickness of other discrete retinal layers such as the combined thickness of the ganglion cell layer and inner plexiform layer, which many of us refer to as GCIP or some also refer to it as GCIPL. Conventionally, peripapillary retinal nerve fiber layer thickness – at least in cross-sectional studies – was found to be associated with high and low contrast visual function, as might be expected since the retina subserves vision as a function.   But interestingly, early studies even found that thickness of the peripapillary retinal nerve fiber layer was associated with disability scores as determined by Expanded Disability Status Scale scores or EDSS scores in MS patients, as well as whole brain volume in MS patients, implying that these metrics derived from OCT somehow provide a window or insight into the global MS disease process. With time, we started to realize that the GCIP thickness might actually be an even more powerful measure of the state of integrity of the optic nerve.   GCIP thickness seems to be more reproducible than that of the retinal nerve fiber layer. It has a intraclass correlation coefficient of about 0.99 with a very tight confidence interval. It has superior structure function correlations with EDSS scores, brain volumes, as well as high and low contrast visual function, as compared to retinal nerve fiber layer thickness. This is really a very interesting and important point about, you know, the potential utility of OCT. Because with this thickness of the GCIP, what we were really getting is a very good estimate of neuronal integrity.   And, one of the factors that has been limited in terms of MRI – or magnetic resonance imaging – is the ability to really accurately and reproducibly quantify collections of axons and neurons. Now in terms of MRI, we often think that the white matter is a very good reflection of axonal integrity, and that gray matter is a good reflection of neuronal integrity. This is not necessarily the case, however. In terms of the white matter, quite a lot of inflammation obviously occurs within the white matter in MS brains. And when that inflammation occurs, white matter volume increases. And then, as that inflammation subsides, the white matter volume drops.   And then, as the next wave of inflammation comes in, again, there's swelling and the white matter volume goes up. And as it resolves, the white matter volume comes down. And so there's this waxing and waning in terms of white matter volume which limits the utility of white matter volume. And in fact, it's for that particular reason that many researchers have found that when you track MS patients over time that the bulk of change is actually seen within the gray matter.   In terms of the gray matter, there is a lot of axons present within the gray matter. And so, gray matter volume is not just a pure measure of neuronal integrity. And the other thing is that the axons within the gray matter are predominantly myelinated similar to within the white matter. And so these brain substructure volumetrics are confounded by myelin too. The retina is an unmyelinated central nervous system structure. And so the measurements that we derive with OCT are not confounded by myelin. And secondly, GCIP thickness does not seem to increase during inflammation of the optic nerve.   There's been a number of studies showing that during acute optic neuritis peripapillary retinal nerve fiber layer thickness increases. There's a number of reasons for that: there's inflammation within the optic nerve, and so there's edema. And so we think that some of that edema may track down to the retinal nerve fiber layer. And there may also be some impaired axonal transport resulting in congested axons within the retinal nerve fiber layer. In addition to that, the retinal nerve fiber layer also contains the bulk of glial cells. And by that, I was mainly referring to astroglia. Now microglia are thought to be present throughout the retina, but there's really no astroglial confound of GCIP thickness as well.   During acute inflammation in the optic nerve, GCIP thickness was not found to increase. And so if you take a patient, as an example, with an acute optic neuritis now, and then you repeat the OCT scan six months later, the GCIP thickness at six months subtracted from that at baseline is felt to be a fairly accurate reflection of net neurodegeneration in terms of net loss of ganglion cell neurons. That absence of edematous or inflammatory or swelling related confound of GCIP thickness yields yet another advantage for this particular measure.   Interviewer – Dan Keller How does the time course of changes in the GCIP correlate with brain MRI? Can it be predictive or are they in lockstep or how do they relate?   Dr. Saidha Yeah, so that's a great question. I think one of the things with OCT research has been that the bulk of research to date has been cross-sectional. And so it has really been one of those key things on our mind is does the way that the GCIP atrophies or thins really mirror what's happening in the brain? In other words, are they locked in together? Are the rates of GCIP atrophy and brain atrophy actually associated with one another, or are they a little disconnected?   So in a recent study, which we published in Annals in Neurology, we tracked a little over 100 MS patients for roughly a four-year period, and we did annual MRI scans with a 3-Tesla scanner, and we did six monthly OCT scans. And very importantly and interestingly, we found that the rate of GCIP atrophy was highly correlated with the rate of brain atrophy and a particular rate of gray matter atrophy. Of course, that's a little bit to be expected partly on the basis of what I said earlier that white matter atrophy in itself is not as well detected as gray matter atrophy.   And then when you look by subtypes of MS – meaning, you know, relapsing MS versus progressive MS – we found that the rate of atrophy was even better or more highly correlated in terms of its association with brain atrophy rate. In fact, it appeared that the rate of retinal atrophy could predict 80% of variance in rate of brain atrophy, which is fascinating because it really does imply that what we're seeing within the retina of MS patients is a reflection of global central nervous system pathology.   And the pathobiological changes that we can detect and monitor with OCT appear to very nicely reflect what's happening within the brain. And that this cheap, noninvasive, easily tolerated, easily repeatable technique that's painless can provide so much insight into this disease process is really quite fascinating and really phenomenal when you consider the increasing and growing need for an ability to measure and monitor neurodegeneration in this disease process. We traditionally conceptualize MS as being an inflammatory demyelinating disorder of the central nervous system, and absolutely there's inflammation that occurs as part of the disease process. And when acute inflammation occurs, there's some immediate damage to axons on the form of axonal transection. And then when axons do not have enough myelin around them or are devoid of myelin over sustained periods of time, that normal protective environment for axons is not present, and so we feel that those axons slowly neurodegenerate.   The advent of putatively neuroprotective and putatively remyelinating therapies now more than ever increases our need for an ability to be able to track neurodegeneration. And in fact, it is neurodegeneration that is the principal substrate of disability in MS. And while the inflammation may be at the root cause of this neurodegeneration, the disability that patients have is better associated with the amount of neurodegeneration that's present. So, it's possible – and we postulate – that OCT could be a very useful outcome measure in terms of assessing therapies which are putatively neuroprotective and/or even neurorestorative or remyelinating.   MSDF Do you think that there is a common process going on more centrally and in the retina causing the changes in both? Or is it possible that there is more central degeneration, which then is transmitted peripherally causing problems in the retina?   Dr. Saidha So that's a great question. We think that the bulk of the retinal changes that we're observing are related to pathology within the optic nerve. And because optic nerve pathology is basically ubiquitous as part of the disease process, we think that the changes that we're seeing within the retina are really just a reflection of what's happening throughout the central nervous system.   Now, you do raise a very important point though. Although we think that the bulk of the change that we're seeing within the retina is related to pathology within the optic nerves, that does not exclude the possibility that some of the changes that we're seeing – in terms of thinning of the retinal nerve fiber layer and GCIP, in particular – are actually related to transsynaptic degeneration. Meaning that if you have a distant lesion or distant pathology that as an axon dies that the next neuron and axon, as part of a sequential chain, is not affected. And that's something that we're actively studying at the moment to try to better understand the effects of transsynaptic degeneration on retinal measures. There is some data to suggest that there is transsynaptic effects on retinal measures, but my own view is that longitudinal studies to definitively establish this are currently lacking.   MSDF Do you have to watch out for a history of optic neuritis when you look at the OCTs? Does that affect what you're finding?   Dr. Saidha I think it does. So, if we are kind of going to say that what we're seeing in the retina is a general reflection of what's happening in the brain, we have to at least consider the possibility that a severe inflammatory event with disproportionate local retinal tissue injury might have an affect on the global relationships between OCT derived measures and brain measures. So, when we look at the relationships between rates of GCIP atrophy and rates of brain atrophy, we find that in eyes with a history of optic neuritis that that relationship is not as strong. And we think that that may be the case because immediately following optic neuritis there's an excessive amount of local tissue injury. And that local tissue injury that results in excessive loss of retinal nerve fiber layer and GCIP tissue somehow masks the global information that we're deriving from OCT.   But then what's interesting is that although a history of optic neuritis seems to be relevant at least in the relapsing-remitting subtype it seems to be less relevant in secondary progressive MS. Part of our hypothesis for this – although it needs to be better elucidated and studied – is that brain atrophy continues on following the optic neuritis, and let's just say it carries on, as an example, at the same rate that it did beforehand. Well eventually, the rate of retinal atrophy, although there was initial disproportionate surge in neurodegeneration within the retina, there will be some ongoing neurodegeneration occurring too. And eventually the two rates will become realigned again in the future.   Kind of to get at that point we also looked at rather than just history of optic neuritis we looked at whether baseline GCIP thickness might have an impact on rate of GCIP atrophy to kind of expand a little bit upon that hypothesis. And indeed, what we found was that rate of GCIP thickness at baseline is highly associated with rate of GCIP atrophy. In kind of simplistic terms the way I conceptualize this is that the more retinal tissue that's available the faster the potential rate of retinal atrophy is. And if there's less retinal tissue available, then there's maybe less potential for that rate to be as fast. If the rate was to remain steady the entire time from the day that the disease first begins – and I think this also applies to the brain too – it wouldn't be very long before there's no tissue left.   MSDF You had alluded to looking at new potential therapies using OCT as an outcome. Does that also mean that it may have utility in looking at current disease-modifying therapies and being able to compare them?   Dr. Saidha So that's an excellent question. In fact, that's actually currently no data available that I'm aware of that has assessed the effect of currently available disease-modifying therapies on rates of GCIP or retinal nerve fiber layer thickness atrophy. And I think that's something that a lot of academics and people who do research utilizing the visual system and a particular OCT would be interested in seeing. We have such data – and such data is routinely collected in terms of effects of disease-modifying therapies – on brain volume, and this is something that's now fairly standard to be collected as part of clinical trials. It may be useful to know whether currently available disease-modifying therapies have differential effects on rates of retinal atrophy. Which would imply that maybe in addition to having a role as an outcome measure in trials of putative neuroprotectants, as well as neurorestorative agents, that maybe OCT might actually also have a role in studies of potentially anti-inflammatory treatments or treatments which modulate or suppress the immune system, as do most currently available licensed disease-modifying therapies.   MSDF Very good. I appreciate it.   Dr. Saidha Thank you very much.   [transition music]   MSDF Thank you for listening to Episode Ninety-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 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.

[intro music] Host – Dan Keller Hello, and welcome to Episode Ninety-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Today's interview features a conversation with Dr. Shiv Saidha, an associate professor of neurology in the Division of Neuroimmunology and Neuro-infectious Diseases at Johns Hopkins University in Baltimore, Maryland. His work has focused on the retina in MS, using the technique of optical coherence tomography, or OCT, to follow the disease, assess and monitor therapeutic strategies, and to better understand the pathobiology of MS. I asked him why the retina is of interest in MS and about the utility of OCT. Interviewee – Shiv Saidha OCT is the optical analogue of ultrasound B mode imaging. And it's a noninvasive technique that has a lot of utility in quantifying the ultrastructure of various tissues, including the retina. We have a lot of interest in being able to quantify retinal structures specifically in multiple sclerosis because optic nerve pathology, which basically refers to affliction of the optic nerve as part of the MS disease process, is virtually ubiquitous. At the time of postmortem examination of MS patients, 94 to 99% of MS patients are found to have demyelinating plaques within their optic nerves. So the premise is that demyelination within the optic nerve results in retrograde degeneration of the constituent fibers or axons within the optic nerve. And since those axons or fibers are derived from the retinal nerve fiber layer, which is the innermost layer of the retina, this layer is felt to thin out as part of the MS disease process. Additionally, the neurons – referred to as ganglion cell neurons located in the ganglion cell layer immediately below the retinal nerve fiber layer from which retinal nerve fiber layer axons are derived – are also thought to drop out as part of the MS disease process. We traditionally conceptualize optic nerve pathology in MS as being an acute phenomenon, namely acute optic neuritis, which does occur in up to, you know, 20 to 70% of MS patients; and in 20 to 25% of cases of MS is the initial hallmark clinical manifestation of the disease process. But beyond acute optic neuritis, there is subclinical optic nerve pathology, which we refer to as subclinical optic neuropathy ongoing within the optic nerves of MS patients. And so, if we had a technique or an ability to accurately quantify the effects of optic nerve pathology or optic neuropathy – in other words, if we had a way to quantify retinal nerve fiber layer thickness and thickness of ganglion cell…the layer within which ganglion cell neurons are located in the retina – that would provide a substrate or insight into the state or integrity of the optic nerve. And so, optical coherence tomography is a technique which allows us to do this. It allows us to measure thickness of the retinal nerve fiber layer not just around the optic disk which we refer to as the peripapillary retinal nerve fiber layer but also in the macular region. And with the advent of novel segmentation techniques in OCT – many of which are now commercially available – we now are also afforded the capability of quantifying thickness of other discrete retinal layers such as the combined thickness of the ganglion cell layer and inner plexiform layer, which many of us refer to as GCIP or some also refer to it as GCIPL. Conventionally, peripapillary retinal nerve fiber layer thickness – at least in cross-sectional studies – was found to be associated with high and low contrast visual function, as might be expected since the retina subserves vision as a function. But interestingly, early studies even found that thickness of the peripapillary retinal nerve fiber layer was associated with disability scores as determined by Expanded Disability Status Scale scores or EDSS scores in MS patients, as well as whole brain volume in MS patients, implying that these metrics derived from OCT somehow provide a window or insight into the global MS disease process. With time, we started to realize that the GCIP thickness might actually be an even more powerful measure of the state of integrity of the optic nerve. GCIP thickness seems to be more reproducible than that of the retinal nerve fiber layer. It has a intraclass correlation coefficient of about 0.99 with a very tight confidence interval. It has superior structure function correlations with EDSS scores, brain volumes, as well as high and low contrast visual function, as compared to retinal nerve fiber layer thickness. This is really a very interesting and important point about, you know, the potential utility of OCT. Because with this thickness of the GCIP, what we were really getting is a very good estimate of neuronal integrity. And, one of the factors that has been limited in terms of MRI – or magnetic resonance imaging – is the ability to really accurately and reproducibly quantify collections of axons and neurons. Now in terms of MRI, we often think that the white matter is a very good reflection of axonal integrity, and that gray matter is a good reflection of neuronal integrity. This is not necessarily the case, however. In terms of the white matter, quite a lot of inflammation obviously occurs within the white matter in MS brains. And when that inflammation occurs, white matter volume increases. And then, as that inflammation subsides, the white matter volume drops. And then, as the next wave of inflammation comes in, again, there's swelling and the white matter volume goes up. And as it resolves, the white matter volume comes down. And so there's this waxing and waning in terms of white matter volume which limits the utility of white matter volume. And in fact, it's for that particular reason that many researchers have found that when you track MS patients over time that the bulk of change is actually seen within the gray matter. In terms of the gray matter, there is a lot of axons present within the gray matter. And so, gray matter volume is not just a pure measure of neuronal integrity. And the other thing is that the axons within the gray matter are predominantly myelinated similar to within the white matter. And so these brain substructure volumetrics are confounded by myelin too. The retina is an unmyelinated central nervous system structure. And so the measurements that we derive with OCT are not confounded by myelin. And secondly, GCIP thickness does not seem to increase during inflammation of the optic nerve. There's been a number of studies showing that during acute optic neuritis peripapillary retinal nerve fiber layer thickness increases. There's a number of reasons for that: there's inflammation within the optic nerve, and so there's edema. And so we think that some of that edema may track down to the retinal nerve fiber layer. And there may also be some impaired axonal transport resulting in congested axons within the retinal nerve fiber layer. In addition to that, the retinal nerve fiber layer also contains the bulk of glial cells. And by that, I was mainly referring to astroglia. Now microglia are thought to be present throughout the retina, but there's really no astroglial confound of GCIP thickness as well. During acute inflammation in the optic nerve, GCIP thickness was not found to increase. And so if you take a patient, as an example, with an acute optic neuritis now, and then you repeat the OCT scan six months later, the GCIP thickness at six months subtracted from that at baseline is felt to be a fairly accurate reflection of net neurodegeneration in terms of net loss of ganglion cell neurons. That absence of edematous or inflammatory or swelling related confound of GCIP thickness yields yet another advantage for this particular measure. Interviewer – Dan Keller How does the time course of changes in the GCIP correlate with brain MRI? Can it be predictive or are they in lockstep or how do they relate? Dr. Saidha Yeah, so that's a great question. I think one of the things with OCT research has been that the bulk of research to date has been cross-sectional. And so it has really been one of those key things on our mind is does the way that the GCIP atrophies or thins really mirror what's happening in the brain? In other words, are they locked in together? Are the rates of GCIP atrophy and brain atrophy actually associated with one another, or are they a little disconnected? So in a recent study, which we published in Annals in Neurology, we tracked a little over 100 MS patients for roughly a four-year period, and we did annual MRI scans with a 3-Tesla scanner, and we did six monthly OCT scans. And very importantly and interestingly, we found that the rate of GCIP atrophy was highly correlated with the rate of brain atrophy and a particular rate of gray matter atrophy. Of course, that's a little bit to be expected partly on the basis of what I said earlier that white matter atrophy in itself is not as well detected as gray matter atrophy. And then when you look by subtypes of MS – meaning, you know, relapsing MS versus progressive MS – we found that the rate of atrophy was even better or more highly correlated in terms of its association with brain atrophy rate. In fact, it appeared that the rate of retinal atrophy could predict 80% of variance in rate of brain atrophy, which is fascinating because it really does imply that what we're seeing within the retina of MS patients is a reflection of global central nervous system pathology. And the pathobiological changes that we can detect and monitor with OCT appear to very nicely reflect what's happening within the brain. And that this cheap, noninvasive, easily tolerated, easily repeatable technique that's painless can provide so much insight into this disease process is really quite fascinating and really phenomenal when you consider the increasing and growing need for an ability to measure and monitor neurodegeneration in this disease process. We traditionally conceptualize MS as being an inflammatory demyelinating disorder of the central nervous system, and absolutely there's inflammation that occurs as part of the disease process. And when acute inflammation occurs, there's some immediate damage to axons on the form of axonal transection. And then when axons do not have enough myelin around them or are devoid of myelin over sustained periods of time, that normal protective environment for axons is not present, and so we feel that those axons slowly neurodegenerate. The advent of putatively neuroprotective and putatively remyelinating therapies now more than ever increases our need for an ability to be able to track neurodegeneration. And in fact, it is neurodegeneration that is the principal substrate of disability in MS. And while the inflammation may be at the root cause of this neurodegeneration, the disability that patients have is better associated with the amount of neurodegeneration that's present. So, it's possible – and we postulate – that OCT could be a very useful outcome measure in terms of assessing therapies which are putatively neuroprotective and/or even neurorestorative or remyelinating. MSDF Do you think that there is a common process going on more centrally and in the retina causing the changes in both? Or is it possible that there is more central degeneration, which then is transmitted peripherally causing problems in the retina? Dr. Saidha So that's a great question. We think that the bulk of the retinal changes that we're observing are related to pathology within the optic nerve. And because optic nerve pathology is basically ubiquitous as part of the disease process, we think that the changes that we're seeing within the retina are really just a reflection of what's happening throughout the central nervous system. Now, you do raise a very important point though. Although we think that the bulk of the change that we're seeing within the retina is related to pathology within the optic nerves, that does not exclude the possibility that some of the changes that we're seeing – in terms of thinning of the retinal nerve fiber layer and GCIP, in particular – are actually related to transsynaptic degeneration. Meaning that if you have a distant lesion or distant pathology that as an axon dies that the next neuron and axon, as part of a sequential chain, is not affected. And that's something that we're actively studying at the moment to try to better understand the effects of transsynaptic degeneration on retinal measures. There is some data to suggest that there is transsynaptic effects on retinal measures, but my own view is that longitudinal studies to definitively establish this are currently lacking. MSDF Do you have to watch out for a history of optic neuritis when you look at the OCTs? Does that affect what you're finding? Dr. Saidha I think it does. So, if we are kind of going to say that what we're seeing in the retina is a general reflection of what's happening in the brain, we have to at least consider the possibility that a severe inflammatory event with disproportionate local retinal tissue injury might have an affect on the global relationships between OCT derived measures and brain measures. So, when we look at the relationships between rates of GCIP atrophy and rates of brain atrophy, we find that in eyes with a history of optic neuritis that that relationship is not as strong. And we think that that may be the case because immediately following optic neuritis there's an excessive amount of local tissue injury. And that local tissue injury that results in excessive loss of retinal nerve fiber layer and GCIP tissue somehow masks the global information that we're deriving from OCT. But then what's interesting is that although a history of optic neuritis seems to be relevant at least in the relapsing-remitting subtype it seems to be less relevant in secondary progressive MS. Part of our hypothesis for this – although it needs to be better elucidated and studied – is that brain atrophy continues on following the optic neuritis, and let's just say it carries on, as an example, at the same rate that it did beforehand. Well eventually, the rate of retinal atrophy, although there was initial disproportionate surge in neurodegeneration within the retina, there will be some ongoing neurodegeneration occurring too. And eventually the two rates will become realigned again in the future. Kind of to get at that point we also looked at rather than just history of optic neuritis we looked at whether baseline GCIP thickness might have an impact on rate of GCIP atrophy to kind of expand a little bit upon that hypothesis. And indeed, what we found was that rate of GCIP thickness at baseline is highly associated with rate of GCIP atrophy. In kind of simplistic terms the way I conceptualize this is that the more retinal tissue that's available the faster the potential rate of retinal atrophy is. And if there's less retinal tissue available, then there's maybe less potential for that rate to be as fast. If the rate was to remain steady the entire time from the day that the disease first begins – and I think this also applies to the brain too – it wouldn't be very long before there's no tissue left. MSDF You had alluded to looking at new potential therapies using OCT as an outcome. Does that also mean that it may have utility in looking at current disease-modifying therapies and being able to compare them? Dr. Saidha So that's an excellent question. In fact, that's actually currently no data available that I'm aware of that has assessed the effect of currently available disease-modifying therapies on rates of GCIP or retinal nerve fiber layer thickness atrophy. And I think that's something that a lot of academics and people who do research utilizing the visual system and a particular OCT would be interested in seeing. We have such data – and such data is routinely collected in terms of effects of disease-modifying therapies – on brain volume, and this is something that's now fairly standard to be collected as part of clinical trials. It may be useful to know whether currently available disease-modifying therapies have differential effects on rates of retinal atrophy. Which would imply that maybe in addition to having a role as an outcome measure in trials of putative neuroprotectants, as well as neurorestorative agents, that maybe OCT might actually also have a role in studies of potentially anti-inflammatory treatments or treatments which modulate or suppress the immune system, as do most currently available licensed disease-modifying therapies. MSDF Very good. I appreciate it. Dr. Saidha Thank you very much. [transition music] MSDF Thank you for listening to Episode Ninety-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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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 <a href="mailto:editor@msdiscovery.org">editor@msdiscovery.org</a>. For Multiple Sclerosis Discovery, I'm Dan Keller.

Multiple Sclerosis Discovery  --  Episode 92 with Dr. Shiv Saidha      

Jorge Nogales-Gaete

[intro music]   Host – Dan Keller Hello, and welcome to Episode Ninety-one of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview features Dr. Jorge Nogales-Gaete, who is Chief of the Department of Neurology and Neurosurgery in the Faculty of Medicine at the University of Chile in Santiago. We spoke at a neurology conference in Santiago about MS patients' perceptions of their clinical care and the importance of the healthcare team's understanding those perceptions.   Interviewer – Dan Keller Let me ask you about the ethical and clinical imperatives for the healthcare team when they encounter an MS patient to learn their perceptions, to learn their desires, their approach to therapy.   Interviewee – Jorge Nogales-Gaete I think the patient has at least two different condition on other disease, chronical disease. The first is the age. They're too young to have a chronical disease. There's nobody is prepared to have one. You have think about your lives, your project of life, and then you have a strong situation that is the diagnosis. Then, this is unexpected. It's a disruption. It's not natural. When you are old and you have blood hypertension, well you have time to right it. But when you are so young and you have this kind of disease, it's very strong.   And the other situation is that this disease is not usually the same all the time. You have period that you are normal, you have no manifestation, even the diseases on you. And other you have problem. And in each situations, you are thinking very different. Then you must consider in relation with the patient that nothing is stable. In the consideration of the disease, then you must go again to talk about doubt, about risk again and again. And this is different to other chronical disease.   MSDF There's so many variables: there's the patient, the nature of the illness, the nature of the clinician. But also, within the patient is education, knowledge, understanding, age, gender, family, economics. How do you make sense of it all?   Dr. Nogales-Gaete Well I think that the first situation is fear. All patients have fear; it's something new. They have doubts, and this is common. You have more prepare in your cognitive system to aware about this. But the fear is just for all equal. If you are warned, if you listen, what they want to know is more easy. Right situation for each patient, each patient is different. Then you must make the effort to be different for your each patient that you have in this moment.   MSDF Each patient is different from the other patient, but each patient is different over time from what he was before.   Dr. Nogales-Gaete Yes, this is the situation. Then, you must be prepared to take the situation again and again and again and be prepared. I never said we're talking about this. When we talk, we add in another situation, I have another fear, I have another sensation, I have not this problem that now is my problem I want to talk that again.   MSDF When you first see these patients, when they're first diagnosed, do you lay out an entire treatment plan? How do you prepare them for the varying course of the disease?   Dr. Nogales-Gaete I try to never give all the information in one meeting. I prepare the patient. I said well we are searching something, we find something, but we need to see again. Even when you have a second opinion demanded, I just take my time to say well this is the first situation. You are in this, but not to say all the things. Not to say well this is the disease, you need this treatment, this is the situation. No. You’re having a chronical problem, it seems to be autoimmunity, it seems to be of the central nervous system. Probably it's MS, and we need to work it. Then I prepare first the patient, the family, and then arrive to the diagnosis. And what's meaning in term of care, treatment.   MSDF Do you try not to make predictions because if you're wrong the patient may lose trust, may have even more doubt?   Dr. Nogales-Gaete Yes. It's not possible to make prediction; that's the first thing. Then, if you make prediction, probably you are wrong. When you are able to make prediction, it has some value because to make a good prediction you need at least 10 years. And it has in sense a prediction 10 years later. I think well, the general population goes in that way, but it hasn’t sense for you specifically.   MSDF So it sounds like all you can predict is the unpredictability of the disease.   Dr. Nogales-Gaete Yes. And this is important. This is important because you have the possibility to think in a bad scenario but also in a good one.   MSDF Do patients want frequent contact and updates or does it vary by who you're talking to?   Dr. Nogales-Gaete General, at the beginning, the patient need more contact or when the disease goes worse. But in general, no. When they are in good condition, they need to live the good time without a physician or a medical care team.   MSDF What about patients talking to patients or support groups?   Dr. Nogales-Gaete Well, this is a difficult situation. Because you have a vast selection of the person who are very good; they don't want to go to see the person who had in bad condition. Then the selection is person in bad condition. And this not reinforce the spirit. It's a political good situation to represent needs. But to work the spirit it's not a good solution.   MSDF What about learning coping techniques when they have an exacerbation or even emotional coping techniques because of the doubt and unpredictability?   Dr. Nogales-Gaete In this situation, probably it's important the background of the patient: the culture, the individual level. It's more easily the person who have a better condition – educational and economical condition – to adopt methodologies of coping.   MSDF How is it, as a physician, being in a specialty that has such wide-ranging disease type and unpredictability of disease course in the patients? I mean some medical specialties the orthopedist says that's a bad hip; I'm going to replace it. You're in sort of the area that we might say is like nailing Jell-O to the wall; it's very hard to nail it down.   Dr. Nogales-Gaete I think that MS give you the opportunity to think about the real reality. All are vulnerable, all of us. Then people with MS has this more clear. But just more clear, we are talking now, but nobody know about tomorrow. Then life is uncertainty. Then you must to admit that you don't have the control. You have the possibility to moderate something, but then you don't have the control.   MSDF What about approaching general health concerns? Do people look to the neurologist as their general practitioner, or do you have to reinforce with them, yes you have to watch out for your cholesterol and everything else, you need to see someone else also?   Dr. Nogales-Gaete We have a public organization based on family physicians general practice. And then you have to be sended to a specialist. And the specialists in general are more aware about the proper field. Then it's a little bit separate, each problem. It's not a good situation. But, cardiologists give the cardiology solution; neurologists make theirs. We have probably internal medicine is the more complete possibility to see all the patient in a comprehensive way.   MSDF I guess the real question is, do you have to encourage them to also remember they have general health needs too, and those should be addressed by the generalist.   Dr. Nogales-Gaete Yes. You have a problem, but you have the possibility to won two lotteries. Then, you need to attend it. If you are in a good health situation, it's better for all. Then try to be in a good situation about your cholesterol and other things: blood pressure, don't smoke.   MSDF Have we missed anything that's important to address?   Dr. Nogales-Gaete I think that we are in the hope era. Twenty years ago we have no the same tool that we have now. We have another drugs, we have another meaning of the disease; we understand more the patient necessities. Then it's mean more than a single drug that modify the disease. Patient have fatigue, has fear, has doubt, have pain, have depression. And you need to understand all of these things. Because if you make the correct diagnosis and give the drug that modify the illness, nothing happen with the everyday life of the patient. The everyday life need another answer. That mean it's not just a neurologist, it's not just the physician. You need all the health team that work in this patient.   MSDF I appreciate it. Thank you.   Dr. Nogales-Gaete Thank you.   [transition music]   MSDF Thank you for listening to Episode Ninety-one 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 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.

[intro music] Host – Dan Keller Hello, and welcome to Episode Ninety-one of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Today's interview features Dr. Jorge Nogales-Gaete, who is Chief of the Department of Neurology and Neurosurgery in the Faculty of Medicine at the University of Chile in Santiago. We spoke at a neurology conference in Santiago about MS patients' perceptions of their clinical care and the importance of the healthcare team's understanding those perceptions. Interviewer – Dan Keller Let me ask you about the ethical and clinical imperatives for the healthcare team when they encounter an MS patient to learn their perceptions, to learn their desires, their approach to therapy. Interviewee – Jorge Nogales-Gaete I think the patient has at least two different condition on other disease, chronical disease. The first is the age. They're too young to have a chronical disease. There's nobody is prepared to have one. You have think about your lives, your project of life, and then you have a strong situation that is the diagnosis. Then, this is unexpected. It's a disruption. It's not natural. When you are old and you have blood hypertension, well you have time to right it. But when you are so young and you have this kind of disease, it's very strong. And the other situation is that this disease is not usually the same all the time. You have period that you are normal, you have no manifestation, even the diseases on you. And other you have problem. And in each situations, you are thinking very different. Then you must consider in relation with the patient that nothing is stable. In the consideration of the disease, then you must go again to talk about doubt, about risk again and again. And this is different to other chronical disease. MSDF There's so many variables: there's the patient, the nature of the illness, the nature of the clinician. But also, within the patient is education, knowledge, understanding, age, gender, family, economics. How do you make sense of it all? Dr. Nogales-Gaete Well I think that the first situation is fear. All patients have fear; it's something new. They have doubts, and this is common. You have more prepare in your cognitive system to aware about this. But the fear is just for all equal. If you are warned, if you listen, what they want to know is more easy. Right situation for each patient, each patient is different. Then you must make the effort to be different for your each patient that you have in this moment. MSDF Each patient is different from the other patient, but each patient is different over time from what he was before. Dr. Nogales-Gaete Yes, this is the situation. Then, you must be prepared to take the situation again and again and again and be prepared. I never said we're talking about this. When we talk, we add in another situation, I have another fear, I have another sensation, I have not this problem that now is my problem I want to talk that again. MSDF When you first see these patients, when they're first diagnosed, do you lay out an entire treatment plan? How do you prepare them for the varying course of the disease? Dr. Nogales-Gaete I try to never give all the information in one meeting. I prepare the patient. I said well we are searching something, we find something, but we need to see again. Even when you have a second opinion demanded, I just take my time to say well this is the first situation. You are in this, but not to say all the things. Not to say well this is the disease, you need this treatment, this is the situation. No. You’re having a chronical problem, it seems to be autoimmunity, it seems to be of the central nervous system. Probably it's MS, and we need to work it. Then I prepare first the patient, the family, and then arrive to the diagnosis. And what's meaning in term of care, treatment. MSDF Do you try not to make predictions because if you're wrong the patient may lose trust, may have even more doubt? Dr. Nogales-Gaete Yes. It's not possible to make prediction; that's the first thing. Then, if you make prediction, probably you are wrong. When you are able to make prediction, it has some value because to make a good prediction you need at least 10 years. And it has in sense a prediction 10 years later. I think well, the general population goes in that way, but it hasn’t sense for you specifically. MSDF So it sounds like all you can predict is the unpredictability of the disease. Dr. Nogales-Gaete Yes. And this is important. This is important because you have the possibility to think in a bad scenario but also in a good one. MSDF Do patients want frequent contact and updates or does it vary by who you're talking to? Dr. Nogales-Gaete General, at the beginning, the patient need more contact or when the disease goes worse. But in general, no. When they are in good condition, they need to live the good time without a physician or a medical care team. MSDF What about patients talking to patients or support groups? Dr. Nogales-Gaete Well, this is a difficult situation. Because you have a vast selection of the person who are very good; they don't want to go to see the person who had in bad condition. Then the selection is person in bad condition. And this not reinforce the spirit. It's a political good situation to represent needs. But to work the spirit it's not a good solution. MSDF What about learning coping techniques when they have an exacerbation or even emotional coping techniques because of the doubt and unpredictability? Dr. Nogales-Gaete In this situation, probably it's important the background of the patient: the culture, the individual level. It's more easily the person who have a better condition – educational and economical condition – to adopt methodologies of coping. MSDF How is it, as a physician, being in a specialty that has such wide-ranging disease type and unpredictability of disease course in the patients? I mean some medical specialties the orthopedist says that's a bad hip; I'm going to replace it. You're in sort of the area that we might say is like nailing Jell-O to the wall; it's very hard to nail it down. Dr. Nogales-Gaete I think that MS give you the opportunity to think about the real reality. All are vulnerable, all of us. Then people with MS has this more clear. But just more clear, we are talking now, but nobody know about tomorrow. Then life is uncertainty. Then you must to admit that you don't have the control. You have the possibility to moderate something, but then you don't have the control. MSDF What about approaching general health concerns? Do people look to the neurologist as their general practitioner, or do you have to reinforce with them, yes you have to watch out for your cholesterol and everything else, you need to see someone else also? Dr. Nogales-Gaete We have a public organization based on family physicians general practice. And then you have to be sended to a specialist. And the specialists in general are more aware about the proper field. Then it's a little bit separate, each problem. It's not a good situation. But, cardiologists give the cardiology solution; neurologists make theirs. We have probably internal medicine is the more complete possibility to see all the patient in a comprehensive way. MSDF I guess the real question is, do you have to encourage them to also remember they have general health needs too, and those should be addressed by the generalist. Dr. Nogales-Gaete Yes. You have a problem, but you have the possibility to won two lotteries. Then, you need to attend it. If you are in a good health situation, it's better for all. Then try to be in a good situation about your cholesterol and other things: blood pressure, don't smoke. MSDF Have we missed anything that's important to address? Dr. Nogales-Gaete I think that we are in the hope era. Twenty years ago we have no the same tool that we have now. We have another drugs, we have another meaning of the disease; we understand more the patient necessities. Then it's mean more than a single drug that modify the disease. Patient have fatigue, has fear, has doubt, have pain, have depression. And you need to understand all of these things. Because if you make the correct diagnosis and give the drug that modify the illness, nothing happen with the everyday life of the patient. The everyday life need another answer. That mean it's not just a neurologist, it's not just the physician. You need all the health team that work in this patient. MSDF I appreciate it. Thank you. Dr. Nogales-Gaete Thank you. [transition music] MSDF Thank you for listening to Episode Ninety-one 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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 <a href="mailto:editor@msdiscovery.org">editor@msdiscovery.org</a>. For Multiple Sclerosis Discovery, I'm Dan Keller.

Multiple Sclerosis Discovery  --  Episode 91 with Dr. Jorge Nogales-Gaete  

The Multiple Sclerosis Discovery Forum (MSDF) is an online resource that aims to accelerate progress toward cures for multiple sclerosis and related disorders by sparking new ideas and catalyzing unforeseen connections. The site focuses attention on what is known and not yet known about the causes of these conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we will open new routes toward significant clinical advances. The podcast will include the latest in MS research news as well as one-on-one interviews with prominent MS researchers and clinicians. While the podcast is intended mainly for other researchers and clinicians, we welcome people with MS, their caregivers, and anyone else with an interest in multiple sclerosis and related disorders.

I am a new graduate student and will be conducting MS research. This podcast has allowed me to quickly get an overview of active research areas. Each interview helps to flesh out the research stories and personalities of research labs across the country, which improves both my enjoyment of reading their papers and my retention of the information. 

The website is a rich resource for me as I get my feet wet in MS research. I am extremely grateful for all of the hardwork that goes into both the website and podcast.

Excellent resource for novice MS researchers

Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

Brian Weinshenker

Multiple Sclerosis Discovery Forum -- Episode 71 with Brian Weinshenker

Brenda Banwell

[intro music]   Hello, and welcome to Episode Twenty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. Brenda Banwell about a new journal on multiple sclerosis and related disorders, of which she is a co-editor-in-chief. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   This week we published two stories related to articles published in the December 2014 issue of JAMA Neurology. The first article is about the interim results of the Halt MS trial. In this phase 2 clinical trial, physicians performed autologous hematopoietic stem cell transplants on 24 patients with relapsing-remitting MS. In other words, the team obliterated the patients’ existing immune systems and attempted to hit the reset button by infusing the patients’ own stem cells. Three years after the treatment, 78% of patients showed no signs of disease activity, significantly higher than similar studies using conventional MS treatments. However, not everyone is popping the champagne yet. Some are concerned that the treatment may not have been aggressive enough to eradicate the patients’ entire immune systems, and it will be only a matter of time before some patients start showing signs of disease activity once more. Others are concerned that the treatment was unnecessarily intense and risky, suggesting safer methods of stem cell transplant would be effective in resetting the immune system.   Halt MS is one of the trials using a new primary outcome measure called “no evidence of disease activity” or NEDA for short. NEDA is basically a fancy way of saying “remission”; that is, no relapses, no disability progression, and no new lesions on MRI. NEDA sets a new treatment standard for patients and their doctors, reflecting the hope of a new generation of disease-modifying therapies.   But is NEDA really a feasible clinical care target? Our second story this week takes a look at this issue with the first real-world cohort study. Researchers asked how many people with relapsing-remitting MS maintained NEDA status seven years after diagnosis. While that goal remained elusive for all but 8% of patients, NEDA status at two years was highly predictive of no disease progression at seven years. Many questions remain about NEDA. But in an editorial accompanying the study, researchers suggest that NEDA is still a worthy, albeit very ambitious, goal.   What do you think? Let us know on the discussion forums at msdiscovery.org/forums/discussion.   [transition music]   Now to the interview. Dr. Brenda Banwell is Professor of Neurology and Pediatrics at the Perelman School of Medicine of the University of Pennsylvania and is chief of the Division of Neurology at The Children’s Hospital of Philadelphia. We met to talk about a fairly new journal called Multiple Sclerosis and Related Disorders, of which she is one of the co-editors-in-chief.   [Interview]   Interviewer – Dan Keller I’m here at The Children’s Hospital of Philadelphia with Dr. Banwell, and someone from the public affairs office is here with us. I’m just wondering why did you see a need for a new journal?   Interviewee – Brenda Banwell At the time that we launched Multiple Sclerosis and Related Disorders, there were journals focused solely on multiple sclerosis and journals on neurology broadly, but not one that focused specifically on multiple sclerosis and the various and increasing number of demyelinating disorders of the central nervous system that are being recognized. So Multiple Sclerosis and Related Disorders was meant to be a home for sometimes comparisons, sometimes new insights, and certainly thoughtful reflection on the scope and breadth of demyelinating disorders in the central nervous system in adults and in children.   MSDF Is there a certain amount of waiting, or it’s just the volume of papers that you get in that determines the mix between multiple sclerosis and other demyelinating disorders?   Dr. Banwell Really it’s actually the quality of the papers we receive that drive the selection into the journal. To date, we have been blessed to receive some very interesting manuscripts, some of which relate to multiple sclerosis but many others relate to neuromyelitis optica, which is one of the disorders we were interested in; in antibody-associated encephalopathies; in patient perceptions of demyelinating disease, which is from the area that I think is very interesting and relevant; and then even some basic science, manuscripts that have looked at mechanisms of the immune system targeting the central nervous system.   MSDF Is there a particular editorial philosophy?   Dr. Banwell I guess the one my co-editors and I would say that we’re looking for manuscripts that push the envelope a little bit in terms of hypothesis generation. We like to see a thoughtful reflection on where the next step needs to be in the papers that we accept. And we’re not at all uncomfortable with being a little bit provocative in terms of perhaps people broaching new hypotheses as long as those hypotheses are well defended and can generate the next step of research.   MSDF So it sounds like you’re also delving into basic science, or at least early clinical studies here, too?   Dr. Banwell We’ll delve into it. We are not a basic science journal, so we would not pretend to be Cell or Nature or any of those sorts of journals. But certainly many of the manuscripts that we’ve accepted have discussed potential hypotheses based on basic science research and how that might tie to the clinical picture.   MSDF One question that always arises with a new journal is why should people want to publish in this journal as opposed to some of the more established ones?   Dr. Banwell Well, I think like any new journal, we have a lot of opportunity to accept manuscripts. We have very quickly gotten to the point where we have a very high caliber of manuscripts, which I think speaks to the interest in the field, so the journals that are arguably in competition with us are also now increasingly receiving high quality manuscripts as well. And I think overall it reminds us that there is actually quite a bit of research going on in multiple sclerosis and related disorders, and therefore there’s room for several journals in the field at this time.   MSDF Is it now being indexed in PubMed?   Dr. Banwell We have applied for indexing and we’ll hope to hear very shortly.   MSDF Is there any problem or have you faced any barriers?   Dr. Banwell No barriers. It’s just that you have to have a certain number of manuscripts published, you have to show that the manuscripts are of high quality, and you have to have been in the field long enough to actually have enough publications for them to judge the quality of what we’re doing.   MSDF I see that you have co-editors-in-chief. Who are your colleagues in this?   Dr. Banwell So there’s Dr. Chris Hawkes and Dr. Gavin Giovannoni from England, and Dr. Fred Lublin from the United States.   MSDF Anything else important to add about the new journal or the things that it’s come out with lately?   Dr. Banwell Well, we have a lay review author as well, and we do hope to increase some scholarly input from the lay public over time. Certainly we’re interested in maintaining the sort of price we put on novelty and in encouraging people to submit work that is perhaps looking at a new angle in the field. I think the related disorders aspect of our journal is an important component, both of the title and also of the concept. We are particularly interested in some of the emerging disorders that we now realize are potentially, if not multiple sclerosis, certainly in the field of immune-directed responses in the central nervous system. So I think that aspect of our journal speaks to an area of the field that might not have been previously quite so well captured in the existing journals.   MSDF Does this journal lend itself to a more global approach to demyelinating diseases, since it’s multiple sclerosis and related disorders as opposed to just looking at MS as an isolated condition?   Dr. Banwell Certainly in concept, yes. I think in fairness to the other journals that I think are all excellent and also in the field, we are not the only ones that are broadening the scope. And I think that speaks to the discoveries. So with the identification in 2004 of the aquaporin-4 antibody, and then subsequent to that really compelling evidence that the aquaporin-4 neuromyelitis optica story broadened and recognized a very specific subgroup of patients, that is also happening with other antibodies potentially, and there’s some emerging information about, for example, NMDA receptor encephalitis and other disorders that weren’t really recognized as such a few years ago. Our journal is prioritizing this type of sort of patient base and diagnostic categories, but so too are other journals that are also excellent in the field. So I think in fairness, everyone is recognizing that there’s more to the story.   MSDF Is the NMDA antibody story with the catatonia?   Dr. Banwell So NMDA receptor encephalitis is a disorder actually discovered by Josep Dalmau at Penn, so very near and dear to our heart here. The patients present sometimes with psychotic features, they can become quite catatonic. There’s been some lay publications on that. “Brain on Fire” was a book written by a survivor of NMDA receptor encephalitis. In children we certainly see – and in adults, but certainly in children – we see a number of patients present with severe seizures and then with abnormalities of movement. When these patients present they can be catastrophically ill, often in intensive care unit. Over time as the patients recover, miraculously it seems because it really does appear to be quite miraculous, the patients can have a full recovery. So it is a disorder that’s extremely important to recognize and can be misdiagnosed quite easily as an infectious encephalitis, as initially other psychiatric disorders, and in some patients as a really severe form of epilepsy, all of which it is, but it has a better overarching diagnosis. And making the diagnosis certainly gives hope in terms of long-term prognosis, and we do use specific therapies for the patients with the diagnosis.   MSDF Very good, I appreciate it. Thanks.   Dr. Banwell My pleasure.   [transition music]   Thank you for listening to Episode Twenty-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 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.   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.    [outro music]

[intro music] Hello, and welcome to Episode Twenty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features an interview with Dr. Brenda Banwell about a new journal on multiple sclerosis and related disorders, of which she is a co-editor-in-chief. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a>. This week we published two stories related to articles published in the December 2014 issue of JAMA Neurology. The first article is about the interim results of the Halt MS trial. In this phase 2 clinical trial, physicians performed autologous hematopoietic stem cell transplants on 24 patients with relapsing-remitting MS. In other words, the team obliterated the patients’ existing immune systems and attempted to hit the reset button by infusing the patients’ own stem cells. Three years after the treatment, 78% of patients showed no signs of disease activity, significantly higher than similar studies using conventional MS treatments. However, not everyone is popping the champagne yet. Some are concerned that the treatment may not have been aggressive enough to eradicate the patients’ entire immune systems, and it will be only a matter of time before some patients start showing signs of disease activity once more. Others are concerned that the treatment was unnecessarily intense and risky, suggesting safer methods of stem cell transplant would be effective in resetting the immune system. Halt MS is one of the trials using a new primary outcome measure called “no evidence of disease activity” or NEDA for short. NEDA is basically a fancy way of saying “remission”; that is, no relapses, no disability progression, and no new lesions on MRI. NEDA sets a new treatment standard for patients and their doctors, reflecting the hope of a new generation of disease-modifying therapies. But is NEDA really a feasible clinical care target? Our second story this week takes a look at this issue with the first real-world cohort study. Researchers asked how many people with relapsing-remitting MS maintained NEDA status seven years after diagnosis. While that goal remained elusive for all but 8% of patients, NEDA status at two years was highly predictive of no disease progression at seven years. Many questions remain about NEDA. But in an editorial accompanying the study, researchers suggest that NEDA is still a worthy, albeit very ambitious, goal. What do you think? Let us know on the discussion forums at <a href="http://msdiscovery.org/forums/discussion" rel="nofollow" target="_blank">msdiscovery.org/forums/discussion</a>. [transition music] Now to the interview. Dr. Brenda Banwell is Professor of Neurology and Pediatrics at the Perelman School of Medicine of the University of Pennsylvania and is chief of the Division of Neurology at The Children’s Hospital of Philadelphia. We met to talk about a fairly new journal called Multiple Sclerosis and Related Disorders, of which she is one of the co-editors-in-chief. [Interview] Interviewer – Dan Keller I’m here at The Children’s Hospital of Philadelphia with Dr. Banwell, and someone from the public affairs office is here with us. I’m just wondering why did you see a need for a new journal? Interviewee – Brenda Banwell At the time that we launched Multiple Sclerosis and Related Disorders, there were journals focused solely on multiple sclerosis and journals on neurology broadly, but not one that focused specifically on multiple sclerosis and the various and increasing number of demyelinating disorders of the central nervous system that are being recognized. So Multiple Sclerosis and Related Disorders was meant to be a home for sometimes comparisons, sometimes new insights, and certainly thoughtful reflection on the scope and breadth of demyelinating disorders in the central nervous system in adults and in children. MSDF Is there a certain amount of waiting, or it’s just the volume of papers that you get in that determines the mix between multiple sclerosis and other demyelinating disorders? Dr. Banwell Really it’s actually the quality of the papers we receive that drive the selection into the journal. To date, we have been blessed to receive some very interesting manuscripts, some of which relate to multiple sclerosis but many others relate to neuromyelitis optica, which is one of the disorders we were interested in; in antibody-associated encephalopathies; in patient perceptions of demyelinating disease, which is from the area that I think is very interesting and relevant; and then even some basic science, manuscripts that have looked at mechanisms of the immune system targeting the central nervous system. MSDF Is there a particular editorial philosophy? Dr. Banwell I guess the one my co-editors and I would say that we’re looking for manuscripts that push the envelope a little bit in terms of hypothesis generation. We like to see a thoughtful reflection on where the next step needs to be in the papers that we accept. And we’re not at all uncomfortable with being a little bit provocative in terms of perhaps people broaching new hypotheses as long as those hypotheses are well defended and can generate the next step of research. MSDF So it sounds like you’re also delving into basic science, or at least early clinical studies here, too? Dr. Banwell We’ll delve into it. We are not a basic science journal, so we would not pretend to be Cell or Nature or any of those sorts of journals. But certainly many of the manuscripts that we’ve accepted have discussed potential hypotheses based on basic science research and how that might tie to the clinical picture. MSDF One question that always arises with a new journal is why should people want to publish in this journal as opposed to some of the more established ones? Dr. Banwell Well, I think like any new journal, we have a lot of opportunity to accept manuscripts. We have very quickly gotten to the point where we have a very high caliber of manuscripts, which I think speaks to the interest in the field, so the journals that are arguably in competition with us are also now increasingly receiving high quality manuscripts as well. And I think overall it reminds us that there is actually quite a bit of research going on in multiple sclerosis and related disorders, and therefore there’s room for several journals in the field at this time. MSDF Is it now being indexed in PubMed? Dr. Banwell We have applied for indexing and we’ll hope to hear very shortly. MSDF Is there any problem or have you faced any barriers? Dr. Banwell No barriers. It’s just that you have to have a certain number of manuscripts published, you have to show that the manuscripts are of high quality, and you have to have been in the field long enough to actually have enough publications for them to judge the quality of what we’re doing. MSDF I see that you have co-editors-in-chief. Who are your colleagues in this? Dr. Banwell So there’s Dr. Chris Hawkes and Dr. Gavin Giovannoni from England, and Dr. Fred Lublin from the United States. MSDF Anything else important to add about the new journal or the things that it’s come out with lately? Dr. Banwell Well, we have a lay review author as well, and we do hope to increase some scholarly input from the lay public over time. Certainly we’re interested in maintaining the sort of price we put on novelty and in encouraging people to submit work that is perhaps looking at a new angle in the field. I think the related disorders aspect of our journal is an important component, both of the title and also of the concept. We are particularly interested in some of the emerging disorders that we now realize are potentially, if not multiple sclerosis, certainly in the field of immune-directed responses in the central nervous system. So I think that aspect of our journal speaks to an area of the field that might not have been previously quite so well captured in the existing journals. MSDF Does this journal lend itself to a more global approach to demyelinating diseases, since it’s multiple sclerosis and related disorders as opposed to just looking at MS as an isolated condition? Dr. Banwell Certainly in concept, yes. I think in fairness to the other journals that I think are all excellent and also in the field, we are not the only ones that are broadening the scope. And I think that speaks to the discoveries. So with the identification in 2004 of the aquaporin-4 antibody, and then subsequent to that really compelling evidence that the aquaporin-4 neuromyelitis optica story broadened and recognized a very specific subgroup of patients, that is also happening with other antibodies potentially, and there’s some emerging information about, for example, NMDA receptor encephalitis and other disorders that weren’t really recognized as such a few years ago. Our journal is prioritizing this type of sort of patient base and diagnostic categories, but so too are other journals that are also excellent in the field. So I think in fairness, everyone is recognizing that there’s more to the story. MSDF Is the NMDA antibody story with the catatonia? Dr. Banwell So NMDA receptor encephalitis is a disorder actually discovered by Josep Dalmau at Penn, so very near and dear to our heart here. The patients present sometimes with psychotic features, they can become quite catatonic. There’s been some lay publications on that. “Brain on Fire” was a book written by a survivor of NMDA receptor encephalitis. In children we certainly see – and in adults, but certainly in children – we see a number of patients present with severe seizures and then with abnormalities of movement. When these patients present they can be catastrophically ill, often in intensive care unit. Over time as the patients recover, miraculously it seems because it really does appear to be quite miraculous, the patients can have a full recovery. So it is a disorder that’s extremely important to recognize and can be misdiagnosed quite easily as an infectious encephalitis, as initially other psychiatric disorders, and in some patients as a really severe form of epilepsy, all of which it is, but it has a better overarching diagnosis. And making the diagnosis certainly gives hope in terms of long-term prognosis, and we do use specific therapies for the patients with the diagnosis. MSDF Very good, I appreciate it. Thanks. Dr. Banwell My pleasure. [transition music] Thank you for listening to Episode Twenty-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 Robert Finn. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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.  [outro music]

Multiple Sclerosis Discovery -- Episode 27 with Dr. Brenda Banwell 

Neda Razaz

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. [transition music] 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. [transition music] 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]

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 <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a>. 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. [transition music] 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 <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a>. There you can also find links to be papers and drug development database. [transition music] 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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]

Multiple Sclerosis Discovery -- Episode 67 with Neda Razaz

Tim Kennedy

[intro music]   Host – Dan Keller Hello, happy new year, and welcome to Episode Twenty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Tim Kennedy about remyelination and neural development. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   According to a new clinical trial, azathioprine, or AZA, may be as effective as interferon beta. The generic immunosuppressant was effective in both reducing relapses and reducing new brain lesions in the multicenter trial. This may not be surprising since the drug has been used off-label to treat MS for several decades. If trials continue to go well, AZA may become the go-to alternative for patients who can’t afford brand name interferons.   A pair of Canadian studies recently showed that both neurodegeneration and inflammation may start in the early stages of pediatric multiple sclerosis. One team found epitope spreading in the blood of children shortly after the onset of MS, suggesting a potential new diagnostic tool. Though children comprise only 2 to 10 percent of the MS population, data gleaned from them may provide insights into the disease as a whole.   If you enjoyed our end-of-the-year interview with Alan Alda and find MSDF to be helpful, please consider supporting us with a donation. We share Mr. Alda’s philosophy that closing the gaps between scientific disciplines is key to improving scientific progress. To make a donation, visit msdiscovery.org and click on the green “Support MSDF” button next to “Research Resources”.   [transition music]   Now to the interview. Tim Kennedy is a researcher at the Montreal Neurological Institute. He met with MSDF to talk about the role of certain molecules and receptors necessary for oligodendrocyte development, maintenance, and function and their implications for remyelination.    Interviewer – Dan Keller Welcome, Dr. Kennedy. Let's talk about the life of oligodendrocytes. These are important for myelination and probably play a role in remyelination. What is the life of an oligodendrocyte? How does it start out? And what does it react to?   Interviewee – Tim Kennedy  Many labs around the world have been studying the life history of an oligodendrocyte and also the lineage of the cells and how they differentiate during normal development. One of the reasons for doing this is that oligodendrocyte precursor cells are present in the mature nervous system and almost certainly contribute to remyelination in demyelinating diseases like MS. Oligodendrocyte precursors are born in the early embryonic CNS, and from the very restricted regions where they're born they then migrate away to populate all of the regions of the mature CNS where myelin occurs. In the lab here, we've been very interested in the molecular cues that direct and influence oligodendrocyte precursor migration. These include a family of proteins called netrins that we work on. And receptors for netrin like a protein called DCC. DCC stands for deleted in colorectal cancer. It was originally identified in cancer, and we now know that it has a critical role in the central nervous system in the migration, maturation, and maintenance of myelin by mature oligodendrocytes.   MSDF Some of these molecules take on different functions as the oligodendrocytes mature. How do they react, or what do these molecules do over time?   Dr. Kennedy When an oligodendrocyte precursor is born, it makes the netrin receptor DCC, but it doesn't make netrin. What the cell does is it responds to netrin in the environment, and through DCC reacts to it, and the netrin directs the cells to migrate. It tells them to initially migrate away from the position where they're born and sends them in the direction of axon tracks that require myelination. In mature myelinating oligodendrocytes, one of the huge surprises we had is that both of these proteins are made. Now, both netrin and DCC are required for normal neural development. If we examine a conventional knockout mouse that lacks either netrin-1 or DCC, those mice die within a few hours of being born, and there's a massive disorganization of the nervous system. So these are essential for normal neural development. When we look at the mature nervous system, we see that every single oligodendrocyte, every single mature myelination oligodendrocyte, makes readily detectable levels of netrin-1 and also the receptor for netrin-1, DCC. And a very simple statement of the question that we wanted to answer is what's the point of that? Why do these cells make these proteins that are essential for normal neural development but make them in the adult nervous system? In every adult human that we encounter, every single person, we're making netrin-1 and DCC in our brains right now. So what's the point? One of the functions that we've recently identified is that DCC produced by oligodendrocytes is required for the maintenance of myelin. Now what that means is that initially when we looked at the distribution of netrin-1 and DCC in relation to myelin we see that they're enriched at paranodal junctions. Paranodes are at the ends of internodes that are the regions of compact myelin that wrap and insulate an axon. The paranodes are a specialization that's made by the oligo that then connects it and ties it down to the surface of the axon. The paranodes flank the node of Ranvier, which is the key point, the specialized region along an axon that regenerates the action potential. So if we think of the internode of compact myelin as the region where the oligodendrocyte insulates the axon and allows the action potential to jump from node to node, the paranodes are the specializations at the end that tie it down. Now, the paranode is where we see the netrin and DCC enriched. If we take away either netrin-1 or DCC from oligodendrocytes, what we see is that the paranodes begin to come apart. Now in a very recent publication, what we did was use a genetic trick called cre-lox recombination to selectively take DCC out of mature myelinating oligodendrocytes. In these mice, the mice develop perfectly normally, the nervous system develops normally, the myelin develops normally. But then, at two months of age, we induce the deletion of DCC only from oligodendrocytes. Now having taken DCC out of oligodendrocytes, what we see is that first the paranodal junctions start to come apart, and then as we let the mice age the compact myelin itself starts to become disorganized. Now, that's interesting because what we're able to document in these mice is a progressive disorganization of the myelin produced by the oligodendrocyte. The progression is interesting, obviously, because we believe that this has identified a new mechanism that maintains myelin, and we would then relate that to the progression of demyelinating disorders like multiple sclerosis. A consequence of having lost DCC is that the action potential conduction velocity in the nervous system is delayed, and when we look at the mice themselves – and look at their behavior, put them through behavioral tests – what we see is that they become uncoordinated and slower in their movements. So again, this would all be consistent with this disruption of the myelin along the axons in the central nervous system due to the loss of DCC. And it's an indication that DCC being made by oligodendrocytes is absolutely essential to maintain the appropriate organization of myelin.   MSDF That explains why myelin may become disorganized. Now, if there is a state in which it's already disorganized, which we look at someone with MS, is there any indication here how to remyelinate knowing what you now know about what's required for maintenance of myelin?   Dr. Kennedy Certainly. What's really exciting having found that DCC is essential to maintain myelin is that this is a new biochemical mechanism that is required to organize and maintain the structural paranodal junctions, and that that's critical for the integrity and the maintenance of compact myelin. Now, DCC is a transmembrane receptor, and every single component of the signal transduction pathway downstream of DCC is potentially a drug target that could be manipulated to enhance the maintenance of myelin. So this is a new biochemical mechanism that exists in oligodendrocytes that promotes myelin maintenance. And that has enormous potential for trying to encourage the persistence of myelin in demyelinating disease.   MSDF What about remyelination? I think you've said oligodendrocytes are born to myelinate. What's stopping them?   Dr. Kennedy If we go back to the oligodendrocyte precursor in early development, what our studies of the developing nervous demonstrated was that oligodendrocyte precursors are repelled by netrin-1. The normal function of netrin-1 in the early embryo is to drive oligodendrocyte precursors away from where they're born so that they can go out into the rest of the central nervous system, find axons that need to be myelinated and myelinate them. That indicates that in the early embryo netrin-1 is a repellent for these cells. Again, we recently reported that in human MS plaques netrin-1 is present in those plaques. Where that's likely coming from is from the wreckage of cells that have died in those plaques. So I had said that mature myelinating oligodendrocytes express netrin-1. When those cells die and when the myelin is lost, the debris from those cells remains behind and potentially even builds up in plaques. There are a number of inhibitors of oligodendrocyte precursor migration that we now know are present in human MS plaques. These include proteins like chondroitin sulfate proteoglycans, semaphorins, and now netrin. What that strongly suggests is that when oligodendrocyte precursors are migrating in the adult brain to sites of demyelination with the intention of remyelinating an axon that has been demyelinated these inhibitors will very likely prevent those cells from entering the plaque and doing what they were born to do, which is to remyelinate. A very exciting thing about MS research today is that we know that the brain contains stem cells that produce oligodendrocyte precursor cells that readily give birth to these cells. So all of us have oligodendrocyte precursor cells in our head. Those cells are born to myelinate. They will migrate towards plaques where demyelination has happened, and if they're allowed to enter the plaque find the axon that needs to be remyelinated. And if they can be encouraged to overcome whatever it is that is blocking them from remyelinating, potentially that aspect of MS remyelination could be encouraged to happen.   MSDF Do you have some ideas on how to overcome this blockage either clearing away the debris or making the oligodendrocytes insensitive to the inhibitors and the debris?   Dr. Kennedy Both of those approaches would be very appropriate. So encouraging the nervous system to clear away the debris we would predict that that would encourage remyelination to happen. In addition, although I said there were multiple inhibitors present in MS plaques – and those inhibitors have different receptors – downstream of those receptors it's very likely that common signal transduction mechanisms are engaged. So targeting those common signal transduction mechanisms inside the migrating oligodendrocyte precursor cell could very potentially nullify all of the inhibitors at once. If it was possible to turn off the sensitivity to those inhibitors, then we would predict that the cells would enter the plaque more readily, and more of the cells would then be able to encounter the axons that require remyelination, and we would obviously predict that that would promote remyelination happening.   MSDF What are some of the big questions now to look at, solve?   Dr. Kennedy The oligodendrocyte is an absolutely fascinating cell type. It's a highly specialized cell type, critically clinically important. We still understand very little about these cells. The mechanisms that I've been talking about that regulate the maintenance of myelin, those have only very recently been discovered. And I think it's extremely exciting that this type of thing is being found in oligodendrocytes. But these are still very mysterious cell types. I think the more we understand about the cell biology of the oligo the more we'll be able to target pathways in the biochemistry of oligodendrocytes to try and promote things like myelin maintenance and the ability to remyelinate. Being able to do those things and essentially manipulate these cells in specific ways, we can then overcome specific clinical issues.   MSDF Does this go beyond MS? Are there other conditions that it applies to?   Dr. Kennedy I think there are two things built into that question. One is that there are many diseases for which the cause either isn't clear – and MS would be in that category – or there are also diseases that have many different causes, but they may manifest in similar ways. So by understanding oligodendrocytes and being able to encourage oligodendrocytes to remyelinate, that could have broad applicability for treating the symptoms of many different forms of demyelinating disease irrespective of the cause of those diseases. Beyond that, as we come to better understand how cells move in the nervous system, how they migrate, how they form attachments, how they connect to each other, and how they maintain those connections, those kinds of insights are going to have broad applicability for all sorts of neurodegenerative diseases where the basic problem in the neurodegenerative disease is that the networks that are the nervous system are coming apart. And if we can encourage those networks to just stay together or rebuild themselves, then I think that again has broad applicability to many types of neurodegenerative diseases in the myelinating field and outside of myelination, as well.   MSDF It sounds like it may even have applicability to not only neurodegeneration but in development where you may have miswiring such as potentially an autism or something like that.   Dr. Kennedy Yeah. An exciting thing is that a lot of the mechanisms that I'm thinking about and we're thinking about in the lab is that the insights that got us working on myelin, that brought us to work on myelin really came from neural development and better understanding neural development; the studies of neural development identified proteins and gene families that have very, very potent actions in the nervous system. When we then looked at expression, we saw that they were expressed in the mature CNS, and that brought forth a whole other group of questions related to the function of the normal adult nervous system and also the degeneration of the adult nervous system in neurodegenerative disease. The exciting thing about that is that as we understand the molecular biology of the central nervous system better that's going to be applicable to development, to normal function, to enhanced function, and also promoting function in degenerative conditions.   MSDF I appreciate it. Thank you.   Dr. Kennedy You're very welcome.   [transition music]   Thank you for listening to Episode Twenty-Five 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 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.    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.   [outro music]

[intro music] Host – Dan Keller Hello, happy new year, and welcome to Episode Twenty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features an interview with Tim Kennedy about remyelination and neural development. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a>. According to a new clinical trial, azathioprine, or AZA, may be as effective as interferon beta. The generic immunosuppressant was effective in both reducing relapses and reducing new brain lesions in the multicenter trial. This may not be surprising since the drug has been used off-label to treat MS for several decades. If trials continue to go well, AZA may become the go-to alternative for patients who can’t afford brand name interferons. A pair of Canadian studies recently showed that both neurodegeneration and inflammation may start in the early stages of pediatric multiple sclerosis. One team found epitope spreading in the blood of children shortly after the onset of MS, suggesting a potential new diagnostic tool. Though children comprise only 2 to 10 percent of the MS population, data gleaned from them may provide insights into the disease as a whole. If you enjoyed our end-of-the-year interview with Alan Alda and find MSDF to be helpful, please consider supporting us with a donation. We share Mr. Alda’s philosophy that closing the gaps between scientific disciplines is key to improving scientific progress. To make a donation, visit <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a> and click on the green “Support MSDF” button next to “Research Resources”. [transition music] Now to the interview. Tim Kennedy is a researcher at the Montreal Neurological Institute. He met with MSDF to talk about the role of certain molecules and receptors necessary for oligodendrocyte development, maintenance, and function and their implications for remyelination. Interviewer – Dan Keller Welcome, Dr. Kennedy. Let's talk about the life of oligodendrocytes. These are important for myelination and probably play a role in remyelination. What is the life of an oligodendrocyte? How does it start out? And what does it react to? Interviewee – Tim Kennedy Many labs around the world have been studying the life history of an oligodendrocyte and also the lineage of the cells and how they differentiate during normal development. One of the reasons for doing this is that oligodendrocyte precursor cells are present in the mature nervous system and almost certainly contribute to remyelination in demyelinating diseases like MS. Oligodendrocyte precursors are born in the early embryonic CNS, and from the very restricted regions where they're born they then migrate away to populate all of the regions of the mature CNS where myelin occurs. In the lab here, we've been very interested in the molecular cues that direct and influence oligodendrocyte precursor migration. These include a family of proteins called netrins that we work on. And receptors for netrin like a protein called DCC. DCC stands for deleted in colorectal cancer. It was originally identified in cancer, and we now know that it has a critical role in the central nervous system in the migration, maturation, and maintenance of myelin by mature oligodendrocytes. MSDF Some of these molecules take on different functions as the oligodendrocytes mature. How do they react, or what do these molecules do over time? Dr. Kennedy When an oligodendrocyte precursor is born, it makes the netrin receptor DCC, but it doesn't make netrin. What the cell does is it responds to netrin in the environment, and through DCC reacts to it, and the netrin directs the cells to migrate. It tells them to initially migrate away from the position where they're born and sends them in the direction of axon tracks that require myelination. In mature myelinating oligodendrocytes, one of the huge surprises we had is that both of these proteins are made. Now, both netrin and DCC are required for normal neural development. If we examine a conventional knockout mouse that lacks either netrin-1 or DCC, those mice die within a few hours of being born, and there's a massive disorganization of the nervous system. So these are essential for normal neural development. When we look at the mature nervous system, we see that every single oligodendrocyte, every single mature myelination oligodendrocyte, makes readily detectable levels of netrin-1 and also the receptor for netrin-1, DCC. And a very simple statement of the question that we wanted to answer is what's the point of that? Why do these cells make these proteins that are essential for normal neural development but make them in the adult nervous system? In every adult human that we encounter, every single person, we're making netrin-1 and DCC in our brains right now. So what's the point? One of the functions that we've recently identified is that DCC produced by oligodendrocytes is required for the maintenance of myelin. Now what that means is that initially when we looked at the distribution of netrin-1 and DCC in relation to myelin we see that they're enriched at paranodal junctions. Paranodes are at the ends of internodes that are the regions of compact myelin that wrap and insulate an axon. The paranodes are a specialization that's made by the oligo that then connects it and ties it down to the surface of the axon. The paranodes flank the node of Ranvier, which is the key point, the specialized region along an axon that regenerates the action potential. So if we think of the internode of compact myelin as the region where the oligodendrocyte insulates the axon and allows the action potential to jump from node to node, the paranodes are the specializations at the end that tie it down. Now, the paranode is where we see the netrin and DCC enriched. If we take away either netrin-1 or DCC from oligodendrocytes, what we see is that the paranodes begin to come apart. Now in a very recent publication, what we did was use a genetic trick called cre-lox recombination to selectively take DCC out of mature myelinating oligodendrocytes. In these mice, the mice develop perfectly normally, the nervous system develops normally, the myelin develops normally. But then, at two months of age, we induce the deletion of DCC only from oligodendrocytes. Now having taken DCC out of oligodendrocytes, what we see is that first the paranodal junctions start to come apart, and then as we let the mice age the compact myelin itself starts to become disorganized. Now, that's interesting because what we're able to document in these mice is a progressive disorganization of the myelin produced by the oligodendrocyte. The progression is interesting, obviously, because we believe that this has identified a new mechanism that maintains myelin, and we would then relate that to the progression of demyelinating disorders like multiple sclerosis. A consequence of having lost DCC is that the action potential conduction velocity in the nervous system is delayed, and when we look at the mice themselves – and look at their behavior, put them through behavioral tests – what we see is that they become uncoordinated and slower in their movements. So again, this would all be consistent with this disruption of the myelin along the axons in the central nervous system due to the loss of DCC. And it's an indication that DCC being made by oligodendrocytes is absolutely essential to maintain the appropriate organization of myelin. MSDF That explains why myelin may become disorganized. Now, if there is a state in which it's already disorganized, which we look at someone with MS, is there any indication here how to remyelinate knowing what you now know about what's required for maintenance of myelin? Dr. Kennedy Certainly. What's really exciting having found that DCC is essential to maintain myelin is that this is a new biochemical mechanism that is required to organize and maintain the structural paranodal junctions, and that that's critical for the integrity and the maintenance of compact myelin. Now, DCC is a transmembrane receptor, and every single component of the signal transduction pathway downstream of DCC is potentially a drug target that could be manipulated to enhance the maintenance of myelin. So this is a new biochemical mechanism that exists in oligodendrocytes that promotes myelin maintenance. And that has enormous potential for trying to encourage the persistence of myelin in demyelinating disease. MSDF What about remyelination? I think you've said oligodendrocytes are born to myelinate. What's stopping them? Dr. Kennedy If we go back to the oligodendrocyte precursor in early development, what our studies of the developing nervous demonstrated was that oligodendrocyte precursors are repelled by netrin-1. The normal function of netrin-1 in the early embryo is to drive oligodendrocyte precursors away from where they're born so that they can go out into the rest of the central nervous system, find axons that need to be myelinated and myelinate them. That indicates that in the early embryo netrin-1 is a repellent for these cells. Again, we recently reported that in human MS plaques netrin-1 is present in those plaques. Where that's likely coming from is from the wreckage of cells that have died in those plaques. So I had said that mature myelinating oligodendrocytes express netrin-1. When those cells die and when the myelin is lost, the debris from those cells remains behind and potentially even builds up in plaques. There are a number of inhibitors of oligodendrocyte precursor migration that we now know are present in human MS plaques. These include proteins like chondroitin sulfate proteoglycans, semaphorins, and now netrin. What that strongly suggests is that when oligodendrocyte precursors are migrating in the adult brain to sites of demyelination with the intention of remyelinating an axon that has been demyelinated these inhibitors will very likely prevent those cells from entering the plaque and doing what they were born to do, which is to remyelinate. A very exciting thing about MS research today is that we know that the brain contains stem cells that produce oligodendrocyte precursor cells that readily give birth to these cells. So all of us have oligodendrocyte precursor cells in our head. Those cells are born to myelinate. They will migrate towards plaques where demyelination has happened, and if they're allowed to enter the plaque find the axon that needs to be remyelinated. And if they can be encouraged to overcome whatever it is that is blocking them from remyelinating, potentially that aspect of MS remyelination could be encouraged to happen. MSDF Do you have some ideas on how to overcome this blockage either clearing away the debris or making the oligodendrocytes insensitive to the inhibitors and the debris? Dr. Kennedy Both of those approaches would be very appropriate. So encouraging the nervous system to clear away the debris we would predict that that would encourage remyelination to happen. In addition, although I said there were multiple inhibitors present in MS plaques – and those inhibitors have different receptors – downstream of those receptors it's very likely that common signal transduction mechanisms are engaged. So targeting those common signal transduction mechanisms inside the migrating oligodendrocyte precursor cell could very potentially nullify all of the inhibitors at once. If it was possible to turn off the sensitivity to those inhibitors, then we would predict that the cells would enter the plaque more readily, and more of the cells would then be able to encounter the axons that require remyelination, and we would obviously predict that that would promote remyelination happening. MSDF What are some of the big questions now to look at, solve? Dr. Kennedy The oligodendrocyte is an absolutely fascinating cell type. It's a highly specialized cell type, critically clinically important. We still understand very little about these cells. The mechanisms that I've been talking about that regulate the maintenance of myelin, those have only very recently been discovered. And I think it's extremely exciting that this type of thing is being found in oligodendrocytes. But these are still very mysterious cell types. I think the more we understand about the cell biology of the oligo the more we'll be able to target pathways in the biochemistry of oligodendrocytes to try and promote things like myelin maintenance and the ability to remyelinate. Being able to do those things and essentially manipulate these cells in specific ways, we can then overcome specific clinical issues. MSDF Does this go beyond MS? Are there other conditions that it applies to? Dr. Kennedy I think there are two things built into that question. One is that there are many diseases for which the cause either isn't clear – and MS would be in that category – or there are also diseases that have many different causes, but they may manifest in similar ways. So by understanding oligodendrocytes and being able to encourage oligodendrocytes to remyelinate, that could have broad applicability for treating the symptoms of many different forms of demyelinating disease irrespective of the cause of those diseases. Beyond that, as we come to better understand how cells move in the nervous system, how they migrate, how they form attachments, how they connect to each other, and how they maintain those connections, those kinds of insights are going to have broad applicability for all sorts of neurodegenerative diseases where the basic problem in the neurodegenerative disease is that the networks that are the nervous system are coming apart. And if we can encourage those networks to just stay together or rebuild themselves, then I think that again has broad applicability to many types of neurodegenerative diseases in the myelinating field and outside of myelination, as well. MSDF It sounds like it may even have applicability to not only neurodegeneration but in development where you may have miswiring such as potentially an autism or something like that. Dr. Kennedy Yeah. An exciting thing is that a lot of the mechanisms that I'm thinking about and we're thinking about in the lab is that the insights that got us working on myelin, that brought us to work on myelin really came from neural development and better understanding neural development; the studies of neural development identified proteins and gene families that have very, very potent actions in the nervous system. When we then looked at expression, we saw that they were expressed in the mature CNS, and that brought forth a whole other group of questions related to the function of the normal adult nervous system and also the degeneration of the adult nervous system in neurodegenerative disease. The exciting thing about that is that as we understand the molecular biology of the central nervous system better that's going to be applicable to development, to normal function, to enhanced function, and also promoting function in degenerative conditions. MSDF I appreciate it. Thank you. Dr. Kennedy You're very welcome. [transition music] Thank you for listening to Episode Twenty-Five 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 Robert Finn. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. [outro music]

Multiple Sclerosis Discovery -- Episode 26 with Dr. Tim Kennedy

Philip De Jager

Multiple Sclerosis Discovery -- Episode 68 with Dr. Philip De Jager

Ellen Mowry

Transcript will be available Thursday, 24 Dec

Transcript will be available Thursday, 24 Dec

Multiple Sclerosis Discovery -- Episode 62 with Dr. Ellen Mowry 

Donna Osterhout

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. [transition music] 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]

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 <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a> 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 <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a>. 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. [transition music] 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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]

Multiple Sclerosis Discovery -- Episode 73 with Dr. Donna Osterhout

Gisela Kobelt

Multiple Sclerosis Discovery -- Episode 65 with Dr. Gisela Kobelt 

FULL TRANSCRIPT:[intro music]Host — Dan KellerHello, and welcome to Episode Seventy-six of MultipleSclerosisDiscovery, the podcast of the MS Discovery Forum. I’mDanKeller.Pregnancy presents special considerations for women withMS.Beyond the medical and pharmacological issues, there aresocial,socioeconomic, and parenting concerns. Dr. Dessa Sadovnick,aprofessor of medical genetics and neurology at the UniversityofBritish Columbia in Canada, spoke on issues ranging frompregnancyplanning through the postpartum period at the WorldCongress ofNeurology in Santiago, Chile, in November, where we metup.Interviewer – Dan KellerLet's talk about gender and hormonal issues in pregnancy.Whatare some of the things you're looking at now?Interviewee – Dessa SadovnickWell, in terms of gender, it's really been interesting thefactthat initially it was actually thought that men may have MSmoreoften than females. And now, of course, it's very wellestablished,as with many other autoimmune diseases, that femalesare affectedmuch more than males. The question is why? And there'sa lot ofresearch being done into hormones, especially theestrogens, theestradiols, to try to see how that relates to diseaseonset,clinical course, etc. But again, there's no reallyfirmanswers.We do know that the hormonal changes during pregnancy do seemtoreduce the number of relapses during gestation, and as soon asyoudeliver, the relapse rate goes up very high. So this is one areaofbig interest. There's been some recent work published onmenopause,and it does not seem that women who have MS havemenopause earlierthan other women or later than other women. Theredoesn'tnecessarily seem to be a direct effect between clinicalcourse andmenopause, other than to say that a lot of the symptomsdo overlap.So you have to be very careful, as a clinician, todecide whetheryou're talking about MS-related symptoms or symptomsthat might beamenable to treatment just for regular menopause.Puberty is a very key period in MS. We know that you can getMSprior to puberty, but it is recognized now in thepediatricpopulation that the group who have it prior to puberty dohave amore similar female to male ratio. It's only once pubertyhits thatyou have the excess in the females.MSDFDoes pregnancy permanently change physiology compared tothepre-pregnant state, or do people go back to their baselinerelapserisk after some point?Dr. SadovnickThere is no evidence to say that having a pregnancy willchangeyour long-term course or your outcome after a given period oftime.It seems like people on the whole, and everything is always onthewhole because there's always the exception, but in general,youtend to go back to what you were like before, taking intoaccountthat, after pregnancy, you'll have had a longer diseaseduration.Just an example, if it takes you a year to becomepregnant, thennine months pregnancy, three months postpartum, thenext time youlook at it you're two years since before you tried toget pregnant;so you're two years more into the disease. But there'sno evidencethat pregnancy harms the long-term outcome of MS, andthere's noevidence that not getting pregnant is beneficial forwomeneither.MSDFIs there a physiologic explanation for the higher relapserateafter pregnancy? Is it easily identified, or is itprettyhypothetical?Dr. SadovnickWell, it's thought to be related to the changes in hormonesassoon as a woman delivers. But there's nothing that can mark ittosay this woman's going to get it, this woman's not going tohaveit. You know, there's no marker that's going to say who's goingtohave a relapse after delivery, who isn't.MSDFEven though there's not much data right now about many ofthedrugs used in MS and pregnancy, women are advised oftentimes nottobe on the drugs, but they also don't immediately get pregnant.Sodo they have a long period potentially of risk of relapse, anddoesthat affect the long-term course eventually?Dr. SadovnickWell, there's been controversy in the literature aboutwhetherthe number of relapses a woman has while shehasrelapsing-remitting MS affects her emergence intosecondaryprogressive MS. So there's been controversy at thefindings aboutwhether the number of relapses predicts how soonyou're going to gointo a progressive phase or not. As far as I'maware, the mostrecent information suggests that they might be twoindependentfactors. So, it's a hard question to answer.Obviously, the drugs don't cure MS. So it's not that you'regoingto prevent MS by taking the drugs or stop MS dead in itscourse bytaking the drugs. You're taking a risk. [With] anyrelapse, youdon't know whether there's going to be a completerecovery or apartial recovery. The more relapses you have, theharder everythingis in day-to-day life and coping and recovery,and getting pregnantis not something that happens instantaneously.So it's a bigdecision that women do have to make. And there's noreal easy answerfor saying who will do well being off themedication for awhile, whowon't do well being off for awhile.It's an informed decision that people have to make. And wesayit's very important that if you're planning a pregnancy, toreallylook at all the information that's relevant to yourparticularsituation and make an informed decision about yoursituation.There's no general answer for everybody. And we've comeup withsome reproductive counseling models that deal with the wholeareaof reproduction and reproductive planning.Now, one thing that I find that people often don't tend tothinkabout is that they think of getting pregnant in termsofconceiving, having a pregnancy, delivering, and the threemonthspostpartum. But they forget the fact that once you do have achild,there's a lot of commitment you have for a long timemovingforward. It's not just your three-month postpartum relapseratethat you're concerned about. And people have to be verycognizantthat if they do have a chronic disorder, that this willhave someimpact on their socioeconomic status, on their ability toparent,on relationships; all this has to be taken into account. Andtwo ofthe things that we often say to people who are planning apregnancyis: One, remember that it's a long-term commitment; andtwo, as aparent, instead of focusing so much on what youcan't dobecause you're a parent who has MS, maybe youshould focus more onwhat you can do. And I think that's avery good attitudeto have.I remember many years ago we had a woman who was just soupset,because in the city she lived in there was a big annualfestivalfair every year. And she'd take her children there, and bythe endof the day she was hot, she was tired, she'd have a relapse,she'dbe in bed, but she felt it was her duty, as a parent, to takethechildren to this festival. So we just talked about it fromapractical point of view, nothing specifically medical oranythinglike that. And said, well, what would happen if you wentwith yourkids with someone else; you stayed in a nice shady place,you had,you know, something cold to drink. Your kids went off anddid allthe running around, and then they'd come back and report toyouwhat they're doing. And, you know, try a day like that insteadofyou're being the one to kill yourself running around with themtoall the activities. And she came back to the clinic a coupleofyears later, and she says, you know, it was such a difference.Thekids had a good time, and instead of my being in bed for thenexttwo weeks, we went out for dinner after, and lifecontinued.So I think that that's so important when you're talkingaboutplanning pregnancies is you have to think forward. You knowthatfor anybody having a baby in the newborn period, it's tiring,it'sstressful, not only for just the mother, but also for thefatherwhether he has MS or not. So if you know this is going tohappen,before you get to the point where you're in such a stateofexhaustion and relapses start happening, maybe plan ahead.Noteverybody can afford nannies or housekeepers or things likethat;that's a fact of life. But there's nothing to say you can'ttalk tofriends and work out a system where you get a bit of extrahelp inadvance, not just wait till you hit the crisis mode.MSDFAnd I suppose in the early postpartum period you could beverysleep-deprived.Dr. SadovnickYou can be very sleep-deprived, and then you have tostartthinking. If you're a father whose wife has just had a baby,maybeyou should try to sleep in a different room, not worryaboutgetting up when the baby gets up during the night. If you'reamother who has MS, maybe you want to reconsiderbreastfeeding.Maybe you want to consider expressing, so that you'renot upconstantly with the baby. You have to be practical. And Ithinkthat that is the big factor is: in theory there's so manythingsyou're supposed to do, but you actually have to be practical.Thefatigue component with a newborn is not going to go awayregardlessof if you have MS or not. So if you know in advance youhave MS,and it's going to be more of an issue, why not try to makesomepractical plans?MSDFYou had mentioned the changing sex ratio mainly becausemorewomen are being diagnosed with MS. Is it that there is more MSorbetter diagnosis or some other reason for this increase inthegender ratio with women predominating?Dr. SadovnickLooking at it in terms of a gender ratio, you're basicallytakingout factors, such as improved diagnostic techniques. So whatwe'restarting to think is that females react differently toenvironmentaltriggers than do males, and this could be a reasonfor the increasein females. Women are living a very different lifetoday than theydid even 30 years ago in terms of occupation, beingout of thehouse, exposures. Women react differently to vitamin D.Women havedifferent smoking habits in reacting. So we're thinkingthat what'shappening is that the female is actually responding toenvironmentalfactors in a different way now or being exposed morethan she wasmaybe a few decades ago.MSDFDo women live proportionately longer with MS? Could they justbegetting older, and the men aren't getting as old, and thatchangesthe ratio at that end of the spectrum?Dr. SadovnickLife expectancy does not really seem to be dramaticallyalteredin multiple sclerosis for males or for females. We've donestudieswith actuarians from life insurance companies looking atthis, andMS really doesn't kill you. So I don't think lifeexpectancy is afactor.MSDFAnything interesting or important to add?Dr. SadovnickWell, I think that a big difference is that there used to bealong lag time from the onset of the MS symptoms until youwerediagnosed. So a lot of life decisions, whether it wasdating,partnering, reproduction, or in that period when you reallydidn'tknow that you had a diagnosis, so in many ways ignorance wasbliss.You didn't really have to make decisions.Now, of course, with the new techniques, people aregettingdiagnosed so much earlier in the disease. And they're beingtoldthat you have MS, you'll do fine, you know, there are therapiesyoucan try. You're still a person who has a life to lead. You'renotan MS patient for your whole life. So but every decision theymakethey have to go out and decide disclosure and how to deal withthefact that they now have a diagnosis. It's not this periodofignorance is bliss. So let's just take, again, going back tothepediatric example: you're a teenage, you're in university,you'reon the dating scene. When do you tell someone you have MS, doyoutell them? Do you not tell them? You're someone who's in their20s:you have a diagnosis of MS, you're dating, you talk abouthaving apermanent relationship and going on to have childrentogether. Whendo you drop the bomb that you have MS? When do youtell it toemployers? When do you tell it to in-laws? You know, whendo yousay this? That period of being ignorant is really gone now.And so,how you react, how society reacts, is something that wereally haveto look at now. When do you disclose? When don't youdisclose? It'sa very big issue.MSDFVery good. Thank you.[transition music]MSDFThank you for listening to Episode Seventy-six ofMultipleSclerosis Discovery. This podcast was produced by the MSDiscoveryForum, MSDF, the premier source of independent news andinformationon MS research. MSDF’s executive editor is Carol CruzanMorton.Msdiscovery.org is part of the nonprofit Accelerated CureProjectfor Multiple Sclerosis. Robert McBurney is our President andCEO,and Hollie Schmidt is Vice President of ScientificOperations.Msdiscovery.org aims to focus attention on what is known andnotyet known about the causes of MS and related conditions,theirpathological mechanisms, and potential ways to intervene.Bycommunicating this information in a way that builds bridgesamongdifferent disciplines, we hope to open new routestowardsignificant clinical advances.[outro music]We’re interested in your opinions. Please join the discussiononone of our online forums or send comments, criticisms,andsuggestions to editor@msdiscovery.org.For Multiple Sclerosis Discovery, I'm Dan Keller.

FULL TRANSCRIPT:[intro music]Host — Dan KellerHello, and welcome to Episode Seventy-six of MultipleSclerosisDiscovery, the podcast of the MS Discovery Forum. I’mDanKeller.Pregnancy presents special considerations for women withMS.Beyond the medical and pharmacological issues, there aresocial,socioeconomic, and parenting concerns. Dr. Dessa Sadovnick,aprofessor of medical genetics and neurology at the UniversityofBritish Columbia in Canada, spoke on issues ranging frompregnancyplanning through the postpartum period at the WorldCongress ofNeurology in Santiago, Chile, in November, where we metup.Interviewer – Dan KellerLet's talk about gender and hormonal issues in pregnancy.Whatare some of the things you're looking at now?Interviewee – Dessa SadovnickWell, in terms of gender, it's really been interesting thefactthat initially it was actually thought that men may have MSmoreoften than females. And now, of course, it's very wellestablished,as with many other autoimmune diseases, that femalesare affectedmuch more than males. The question is why? And there'sa lot ofresearch being done into hormones, especially theestrogens, theestradiols, to try to see how that relates to diseaseonset,clinical course, etc. But again, there's no reallyfirmanswers.We do know that the hormonal changes during pregnancy do seemtoreduce the number of relapses during gestation, and as soon asyoudeliver, the relapse rate goes up very high. So this is one areaofbig interest. There's been some recent work published onmenopause,and it does not seem that women who have MS havemenopause earlierthan other women or later than other women. Theredoesn'tnecessarily seem to be a direct effect between clinicalcourse andmenopause, other than to say that a lot of the symptomsdo <a href="http://overlap.So" rel="nofollow" target="_blank">overlap.So</a> you have to be very careful, as a clinician, todecide whetheryou're talking about MS-related symptoms or symptomsthat might beamenable to treatment just for regular menopause.Puberty is a very key period in MS. We know that you can getMSprior to puberty, but it is recognized now in thepediatricpopulation that the group who have it prior to puberty dohave amore similar female to male ratio. It's only once pubertyhits thatyou have the excess in the females.MSDFDoes pregnancy permanently change physiology compared tothepre-pregnant state, or do people go back to their baselinerelapserisk after some point?Dr. SadovnickThere is no evidence to say that having a pregnancy willchangeyour long-term course or your outcome after a given period <a href="http://oftime.It" rel="nofollow" target="_blank">oftime.It</a> seems like people on the whole, and everything is always onthewhole because there's always the exception, but in general,youtend to go back to what you were like before, taking intoaccountthat, after pregnancy, you'll have had a longer diseaseduration.Just an example, if it takes you a year to becomepregnant, thennine months pregnancy, three months postpartum, thenext time youlook at it you're two years since before you tried toget pregnant;so you're two years more into the disease. But there'sno evidencethat pregnancy harms the long-term outcome of MS, andthere's noevidence that not getting pregnant is beneficial forwomeneither.MSDFIs there a physiologic explanation for the higher relapserateafter pregnancy? Is it easily identified, or is itprettyhypothetical?Dr. SadovnickWell, it's thought to be related to the changes in hormonesassoon as a woman delivers. But there's nothing that can mark ittosay this woman's going to get it, this woman's not going tohaveit. You know, there's no marker that's going to say who's goingtohave a relapse after delivery, who isn't.MSDFEven though there's not much data right now about many ofthedrugs used in MS and pregnancy, women are advised oftentimes nottobe on the drugs, but they also don't immediately get pregnant.Sodo they have a long period potentially of risk of relapse, anddoesthat affect the long-term course eventually?Dr. SadovnickWell, there's been controversy in the literature aboutwhetherthe number of relapses a woman has while shehasrelapsing-remitting MS affects her emergence intosecondaryprogressive MS. So there's been controversy at thefindings aboutwhether the number of relapses predicts how soonyou're going to gointo a progressive phase or not. As far as I'maware, the mostrecent information suggests that they might be twoindependentfactors. So, it's a hard question to answer.Obviously, the drugs don't cure MS. So it's not that you'regoingto prevent MS by taking the drugs or stop MS dead in itscourse bytaking the drugs. You're taking a risk. [With] anyrelapse, youdon't know whether there's going to be a completerecovery or apartial recovery. The more relapses you have, theharder everythingis in day-to-day life and coping and recovery,and getting pregnantis not something that happens <a href="http://instantaneously.So" rel="nofollow" target="_blank">instantaneously.So</a> it's a bigdecision that women do have to make. And there's noreal easy answerfor saying who will do well being off themedication for awhile, whowon't do well being off for awhile.It's an informed decision that people have to make. And wesayit's very important that if you're planning a pregnancy, toreallylook at all the information that's relevant to yourparticularsituation and make an informed decision about yoursituation.There's no general answer for everybody. And we've comeup withsome reproductive counseling models that deal with the wholeareaof reproduction and reproductive planning.Now, one thing that I find that people often don't tend tothinkabout is that they think of getting pregnant in termsofconceiving, having a pregnancy, delivering, and the threemonthspostpartum. But they forget the fact that once you do have achild,there's a lot of commitment you have for a long timemovingforward. It's not just your three-month postpartum relapseratethat you're concerned about. And people have to be verycognizantthat if they do have a chronic disorder, that this willhave someimpact on their socioeconomic status, on their ability toparent,on relationships; all this has to be taken into account. Andtwo ofthe things that we often say to people who are planning apregnancyis: One, remember that it's a long-term commitment; andtwo, as aparent, instead of focusing so much on what youcan't dobecause you're a parent who has MS, maybe youshould focus more onwhat you can do. And I think that's avery good attitudeto have.I remember many years ago we had a woman who was just soupset,because in the city she lived in there was a big annualfestivalfair every year. And she'd take her children there, and bythe endof the day she was hot, she was tired, she'd have a relapse,she'dbe in bed, but she felt it was her duty, as a parent, to takethechildren to this festival. So we just talked about it fromapractical point of view, nothing specifically medical oranythinglike that. And said, well, what would happen if you wentwith yourkids with someone else; you stayed in a nice shady place,you had,you know, something cold to drink. Your kids went off anddid allthe running around, and then they'd come back and report toyouwhat they're doing. And, you know, try a day like that insteadofyou're being the one to kill yourself running around with themtoall the activities. And she came back to the clinic a coupleofyears later, and she says, you know, it was such a difference.Thekids had a good time, and instead of my being in bed for thenexttwo weeks, we went out for dinner after, and lifecontinued.So I think that that's so important when you're talkingaboutplanning pregnancies is you have to think forward. You knowthatfor anybody having a baby in the newborn period, it's tiring,it'sstressful, not only for just the mother, but also for thefatherwhether he has MS or not. So if you know this is going tohappen,before you get to the point where you're in such a stateofexhaustion and relapses start happening, maybe plan ahead.Noteverybody can afford nannies or housekeepers or things likethat;that's a fact of life. But there's nothing to say you can'ttalk tofriends and work out a system where you get a bit of extrahelp inadvance, not just wait till you hit the crisis mode.MSDFAnd I suppose in the early postpartum period you could beverysleep-deprived.Dr. SadovnickYou can be very sleep-deprived, and then you have tostartthinking. If you're a father whose wife has just had a baby,maybeyou should try to sleep in a different room, not worryaboutgetting up when the baby gets up during the night. If you'reamother who has MS, maybe you want to reconsiderbreastfeeding.Maybe you want to consider expressing, so that you'renot upconstantly with the baby. You have to be practical. And Ithinkthat that is the big factor is: in theory there's so manythingsyou're supposed to do, but you actually have to be practical.Thefatigue component with a newborn is not going to go awayregardlessof if you have MS or not. So if you know in advance youhave MS,and it's going to be more of an issue, why not try to makesomepractical plans?MSDFYou had mentioned the changing sex ratio mainly becausemorewomen are being diagnosed with MS. Is it that there is more MSorbetter diagnosis or some other reason for this increase inthegender ratio with women predominating?Dr. SadovnickLooking at it in terms of a gender ratio, you're basicallytakingout factors, such as improved diagnostic techniques. So whatwe'restarting to think is that females react differently toenvironmentaltriggers than do males, and this could be a reasonfor the increasein females. Women are living a very different lifetoday than theydid even 30 years ago in terms of occupation, beingout of thehouse, exposures. Women react differently to vitamin D.Women havedifferent smoking habits in reacting. So we're thinkingthat what'shappening is that the female is actually responding toenvironmentalfactors in a different way now or being exposed morethan she wasmaybe a few decades ago.MSDFDo women live proportionately longer with MS? Could they justbegetting older, and the men aren't getting as old, and thatchangesthe ratio at that end of the spectrum?Dr. SadovnickLife expectancy does not really seem to be dramaticallyalteredin multiple sclerosis for males or for females. We've donestudieswith actuarians from life insurance companies looking atthis, andMS really doesn't kill you. So I don't think lifeexpectancy is afactor.MSDFAnything interesting or important to add?Dr. SadovnickWell, I think that a big difference is that there used to bealong lag time from the onset of the MS symptoms until youwerediagnosed. So a lot of life decisions, whether it wasdating,partnering, reproduction, or in that period when you reallydidn'tknow that you had a diagnosis, so in many ways ignorance wasbliss.You didn't really have to make decisions.Now, of course, with the new techniques, people aregettingdiagnosed so much earlier in the disease. And they're beingtoldthat you have MS, you'll do fine, you know, there are therapiesyoucan try. You're still a person who has a life to lead. You'renotan MS patient for your whole life. So but every decision theymakethey have to go out and decide disclosure and how to deal withthefact that they now have a diagnosis. It's not this periodofignorance is bliss. So let's just take, again, going back tothepediatric example: you're a teenage, you're in university,you'reon the dating scene. When do you tell someone you have MS, doyoutell them? Do you not tell them? You're someone who's in their20s:you have a diagnosis of MS, you're dating, you talk abouthaving apermanent relationship and going on to have childrentogether. Whendo you drop the bomb that you have MS? When do youtell it toemployers? When do you tell it to in-laws? You know, whendo yousay this? That period of being ignorant is really gone now.And so,how you react, how society reacts, is something that wereally haveto look at now. When do you disclose? When don't youdisclose? It'sa very big issue.MSDFVery good. Thank you.[transition music]MSDFThank you for listening to Episode Seventy-six ofMultipleSclerosis Discovery. This podcast was produced by the MSDiscoveryForum, MSDF, the premier source of independent news andinformationon MS research. MSDF’s executive editor is Carol <a href="http://CruzanMorton.Msdiscovery.org" rel="nofollow" target="_blank">CruzanMorton.Msdiscovery.org</a> is part of the nonprofit Accelerated CureProjectfor Multiple Sclerosis. Robert McBurney is our President andCEO,and Hollie Schmidt is Vice President of ScientificOperations.<a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> aims to focus attention on what is known andnotyet known about the causes of MS and related conditions,theirpathological mechanisms, and potential ways to intervene.Bycommunicating this information in a way that builds bridgesamongdifferent disciplines, we hope to open new routestowardsignificant clinical advances.[outro music]We’re interested in your opinions. Please join the discussiononone of our online forums or send comments, criticisms,andsuggestions to editor@msdiscovery.org.For Multiple Sclerosis Discovery, I'm Dan Keller.

Multiple Sclerosis Discovery -- Episode 76 with Dr. Dessa Sadovnick

John Hart

Full transcript: [intro music] Host – Dan Keller Hello, and welcome to Episode Eighty-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. You may have heard of transcranial magnetic stimulation, a treatment for migraine, neuropathic pain, and treatment-resistant depression using an electromagnet positioned on the scalp. Dr. John Hart, a professor of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas, is now testing another electrical technique called transcranial direct current stimulation, or tDCS, as well as alternating current to improve cognition in brain disorders, potentially including MS. An even more directed form, called high definition tDCS, allows more precise targeting of brain areas. The experimental procedure involves placing electrodes strategically on the outside of the head. We spoke in his office about how he's going about developing the technique and how it may eventually be combined with other therapeutic modalities. Interviewer – Dan Keller You're working in transcranial direct current stimulation. Basically, what is it; how does it work or be applied? Interviewee – John Hart tDCS is short for that. You'll have an electrode – actually it's a sort of small doughnut, so it's not such electrodes that people think of tiny little electrodes – and you place one on one part of the scalp area, and then another part, and you're basically going to pass current through the head in a sort of diffuse, generalized way, not very specific, from that one electrode to the other. Recently, a new sort of area has been developed, a new cap system approach called high definition transcranial direct current stimulation. It's an EEG cap with EEG electrodes on them, and you can pass current out one electrode and draw it in a variety of other electrodes. So you can target it to specific areas where it's coming out, and you can also direct it as to where it goes through to multiple, depending on how specific or not, brain regions that you're going to have the electrode come out. So if you want to hit one spot, you can go out one and bring it in its surrounders and keep all the current there, or you can go from one place to another. And in some instances, we're able to throw it – sort of like throwing your voice – down the deep structures and sort of hit those as a way of stimulating. The other part about it is the direct current part. We also do alternating currents, or HD TACS, and we can do frequencies and other things, too. So I feel that this has got a fair amount of promise and flexibility as a way to externally stimulate brain areas pretty safely. It does a little tingling to your scalp kind of side effects in terms of application. MSDF What kind of currents and voltages does it involve? Dr. Hart Right now normally in tDCS in the big things, we do 2 milliamps ballpark. We find that 1 milliamp is about where we're functioning now at the high definition, and right now we're doing studies with it where we're playing around with the amps and different frequencies to see – since it's relatively a new technique – what sort of effects you get. So … it's so new there's not a ton of papers out about it for me to tell you where we're going to land, will there be a dose-response curve? We're doing those studies right now.   MSDF You've said that you’re interested, in general, in cognition across all sorts of brain disorders—Alzheimer's, MS, others. What's the hypothesis for using this kind of stimulation? Dr. Hart Well, in my primary research area I do word retrieval and knowledge retrieval and storage, so we've mapped out in that example a circuit of the pre-SMA, the pre-supplementary motor area, and the caudate and the thalamus that's involved in retrieving a memory. So when I say desert and humps, does that make you think of a specific object? When camel pops into your head, we mapped out with fMRI, EEG depth, and electrodes this sort of electrical pattern of that retrieval circuit to effectively pull up that memory. So the way we've been doing it, we came up with this circuit in normal people, and we've seen certain disease states where it's dysfunctional, and MS happens to be one of them. So we're directing, right now, our current to the pre-SMA and trying to stimulate that circuit to hopefully have a less functional circuit become more functional, where it can pull out the signal to noise and fire off the right rhythms or get their rhythms in a correct pattern that are not there. Psychiatry's done a lot better in terms of treatments, because a lot of the disorders are based on neurotransmitters and neurotransmitter states, that a drug will affect those neurotransmitters, and it hits all the areas, because it's more the transmitter than the place. Cognition has a lot to do with place and connectivity. Drugs, we've not got a ton of them as the primary cognitive treatment because they don't go to a specific place, and they don't effectively change that specific area's connectivity and/or its links. I have a big study we just finished with RTMS [repetitive transcranial magnet stimulation] in PTSD [posttraumatic stress disorder]. I look at the fact that having worked as an electrician of cognition for years, that that's what the circuit is, and the best way for me to change cognitive status in the way that it's lined up its focal networks is probably not showering a brain with drug that won’t go to specific areas but maybe targeting things like electrical and magnetic current. MSDF In terms of MS or other diseases, have you done any clinical studies so far? Dr. Hart So we're right in the middle of doing some MS patients preliminarily. And I don't get excited easily – I'm normally a pessimist, I think, at heart for these things. We've had some encouraging results in having people not on meds or who have failed meds or not had a response to meds that we've looked at retrieving memory in both word retrieval and in episodic memory retrieval and seen some improvements that have been relatively reasonably long-lasting from my point of view, lasting over months. But we've only at this point done about 5 or 6 people and we're enrolling more folks. We had a grant proposal in and we needed to get more folks to do a bigger trial. We're doing some placebo and then add people later to also see how much of this is a fair sort of setup as a placebo effect versus not. So we're advancing getting more and more folks into those stages now. And we've tried a few folks with TBI [traumatic brain injury]. MSDF How long do you apply the treatment. Is it a one-shot deal and what's the residual effect? You said you've had benefit up to months, is that from a series or from just once? Dr. Hart We're doing one-shot now as a way of figuring out dosing and effectiveness, since it's a relatively new device. The way we're doing the treatments for folks is to do 20-minute sessions and 10 of those over a 2-week period. So once a day, 20 minutes, for a total of 10 sessions. And that has seem to have been from animal studies and some other folks in the literature reasonable time and reasonable number of sessions at this point. We're going to figure out and look at more about adjusting dose, dose response, will we need boosters if it starts fading, and things like that. Its affect fades, because in essence these folks are not treated with modafinil or stimulants that we're doing this, so we're not doing it in conjunction with that. So they're not receiving what are typical cognitive treating medications in MS. So that's a plus side, and that we haven't had any serious any sort of residual side effect things at this point. So if it lasted several months and you had to reapply a booster thing, compared to taking amphetamines or some of the other pro-amphetamine drugs, I think the upside is reasonable enough to say that compared to that, it would be a reasonable issue if you came in 4 times a year if that's what we need to do. But we'll see as we keep following folks. MSDF If it works as you said, kind of separates out the signal from noise, essentially boosts the signal, the signal is gone when you turn it off or when someone leaves the treatment room. So what do you think, something's happening biochemically, or what's it doing that gives you a long-lasting effect? Dr. Hart When we just finish our RTMS trial for post-traumatic stress disorder, one of our interesting findings was the length of time, or the time when the effect lasts, or how long it lasts and continues. So there are some studies on electrical stimulation in animal models that suggests that what it does is set up a state called meta-plasticity. And the meta-plasticity in the animal models support the fact that long-term potentiation and synaptic potentials that can be set up down the road are actually benefited from the electrical stimulation. And that's what's encouraged us a little bit looking at stuff to see why these things last, because the first thing always like a single-shot, it fades off, it fades away. Luckily, for some of this stuff we have some guidance from animal models. And this meta-plasticity phenomena has been noted for a continue – or delayed almost – effect of when you see improvement because of this. I think it's a state potential change that long-term potentiation can occur down the road. That's our best guess at this point. MSDF You said besides direct current stimulation, you're also trying alternating current. With a direct current, you probably would not get anything analogous to a magnetic stimulation because you wouldn’t set up a magnetic field. Do you see differences between your direct current stimulation and your alternating current stimulation? Dr. Hart We sure have – and I must admit none of this has been published yet because we're trying to set parameters. Initially, the enthusiasm for alternate current stimulation waned a lot, I think, for folks for any of these things, because it didn't seem to be nearly as effective as direct current. And I think as a lot of this stuff initially was done in normals. And I'm not so sure that when you have patients with a disease state, depending on what the disease state is, that I'm willing to sort of say that alternating current is not necessarily going to be useful or not. Also, this is very directional, so here's anode and cathode. So you can take the same current, same electrodes, change the directionality and get different effects. And typically people that found those things in the motor system were pretty noticeable. In cognitive systems, we haven't seen that as much, that when we flip the direction of the current, that we're getting the opposite effects—so instead of enhancing a performance in something, that we're knocking it out. So I think once we look at sort of these things, every new approach has to be taken really as a start from scratch, do the hard work of just what we're doing, change the amplitudes, change the parameters, change the direction in a nice, safe way in single shots, and which we've been doing, and then record pre- and post. We do a lot of electophys measures, but also cognitive measures and other sorts of measures to see how each one of these effects things, and do we have something that I would hope one day I'll be writing electrical prescriptions. And I'll say you should get F4 to CZ current at 1 milliamp or 0.5 milliamps, or whatever I wind up doing, for 10 sessions, 20 minutes. Or, no, my god, look at this, we've got to go from here to here at a different milliamp. Once we start looking at that, I think to me also frequencies are very important; can I send different frequencies instead of milliamps. We're going to discover a lot of different things work differently, especially in diseases that are not a homogeneous thing. Brain disease is not like liver cancer. Hepatocytes, it's like how many hepatocytes are not working and how big is the tumor? No, not having a good thalamus is very different than not having a functional motor cortex, you just see entirely different results. So I think it's going to be a lot more complicated, but I think doing it in a systematic way in normals, and then applying it to certain disease states gives us our best chance at coming up with primary or as adjunct treatments to other ways we're going to be treating diseases that have cognitive problems. MSDF It doesn't seem surprising that the polarity wouldn't matter, because not all the neurons, dendrites, and synapses are lined up in one direction; they're going in all different directions, so even their polarity is different. It seems like zapping it in one direction for one, but the opposite direction for the other anyway. Dr. Hart We've actually done stuff with EEG measures and fMRI measures, and done these things called Granger causality models. So how much does, say, one time point predict an activation or a change in the other time point? And in an area that we thought was really this guy is telling that guy what to do, we found that most of those were predominantly a lot of two-way interactions that are constantly going on, and there's a lot of feedback between these systems. And I always try to think like neurons and think electrically, and I can do it for about a couple hours and then my head starts really hurting. And in reality, I think the simplistic: Turn this light switch on and that you have a serial processing circuit is not really how electrically two neurons are always working together, or talking to each other, or keeping a tone or a level up. So I think you're right, I learn a lot every day. It's been sort of a cool job to figure out, yeah, that makes sense, because really it's an interactive set of neuronal firings. MSDF Do you see any role for combining it with drugs that have ionotropic effects? Dr. Hart Yeah, I do. And the other part of that is going to be really, to me, which I think has been a problem with a lot of approaches to cognition and treating them, the timing of when and how you add different therapies together are going to be very, very important. Even now to say, all right, let's say I want to do a behavioral therapy with HD [high definition?] tDCS, well do you do it during it, do you do the HD tDCS continually? Do you pre-prep the brain by doing that first, and then doing cognitive rehabilitation strategies and therapies? I think we glibly just put things together without thinking that there might be an order to this. So right now we're looking at what's called state changes. We're not the first folks to do this, but some people say before you do tDCS, and that's before this HD stuff, you do a little RTMS first to set the state of the neurons in that area so they're more receptive to whatever you're going to do with the tDCS. MSDF Just to be clear on it, RTMS is repetitive transcranial magnet stimulation. Dr. Hart So I think we're looking at kind of like, you know what, you get your pre-meds before you get your chemo so you don't vomit or do this or that. We might be finding ways that electrically how we're going to, or even you use meds prior to a treatment electrically, or vice versa, that that timing is going to be where the money is in terms of working out what are going to be the most effective therapies. MSDF What have we missed? I realize it's still pretty early, but is there anything important to add? Dr. Hart I think the way we've done it is not going to always be available, in that we came from a circuit that we worked out, and we have an idea as to what we were trying to do. And we're measuring all these brain rhythms as outcome measures, so I know when I'm supposed to see alpha and beta rhythms to do that. And I think what's going to happen is we're not always going to have these circuits, we're going to have a spot. Like we've talked a little bit, shall we try to hit the hippocampus? And what other diseases would you do these things in? And the question's going to be when you're doing that, or doing that as a general approach, how do you smartly do it, when you really are not sure about the circuit? We don't have a ton of really well worked out cognitive circuits in an active state of doing things. We have a lot of functional connectivity rest states, and you say I'd like to amp up that connectivity. I don't know what that does functionally, if you electrically take a rest state that normally is when your eyes close and add current to it. So I think while we've targeted this in the two areas that we're using electrical therapy in, post-traumatic stress disorder and this, and the things we've chosen, we built it off of normal studies. The things we've got to be careful about, thoughtful about, and open-minded to at the same time about, is what if we want to treat something different than this? We want to do working memory, we want to do episodic memory, we want to do frontal behavioral problems. And if we don't have a circuit, try our best to get the most reasonable pre/post measures. Do single shots just to see what it does in a transient state, and then sort of work our way through the fact that at least a reasonable pre/post model and start thinking of this not as one-size-fits-all, but may be 0.5 milliamps, maybe TACS, maybe pink noise, maybe whatever sort of way you want to deal with it. It's going to take a lot more thought, I think, than people might casually say, hey, got some electrodes? I mean, what bugs me right now is you can set up your own tDCS device off the internet, one of them using a car battery – 2 pieces of metal and some wire. And I highly would tell all those out there, which I know none of your listeners, don't do that. So when people started sort of exploring around in what they're going to do, I hope as we take this field further that we need to do it in a systematized fashion and a thoughtful way, because there's a lot of information you can get when something doesn't work. So you know what, I didn't change a thing here when I did this. Well, I would like to know that, you know, is somebody else trying to do it, and try to collect this information that might be useful to other people trying to do things. Saying, you know what, we did this electrodes, these are these things in normals or whatevers and didn't get a response, to try to come up with a way that we've got to take it for the fact that it's like a med. It's going to have schedules, it's going to have doses. So if you're taking it twice a day at 5 mg or 6 times a day at 40 mg, working all that out is going to clearly need to be done in a reasonable, thoughtful way. MSDF I appreciate it, thanks. Dr. Hart Oh, thank you so much, I really appreciate your interest. [transition music] MSDF Thank you for listening to Episode Eighty-eight 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] 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.

Multiple Sclerosis Discovery -- Episode 88 with Dr. John Hart

Annette Langer-Gould

Full transcript: [intro music] Host — Dan Keller Hello, and welcome to Episode Seventy-seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Pregnancy and the postpartum period present special concerns to women with MS. Dr. Annette Langer-Gould, a neurologist and epidemiologist at Kaiser Permanente in Los Angeles, investigates ways to lessen the risk of relapses in these women. We discussed the effects of breastfeeding, among other topics, when we met at the ECTRIMS meeting last fall in Barcelona. Interviewer – Dan Keller In terms of pregnancy and breastfeeding in MS, what are you looking at? Interviewee – Annette Langer-Gould We're studying modifiable risk factors for postpartum relapses in women with multiple sclerosis. And specifically, we are looking at starting therapy shortly after delivery, whether that can reduce the risk of postpartum relapses, whether breastfeeding, particularly breastfeeding exclusively, could reduce the risk of postpartum relapses, and whether vitamin D levels play any role in increasing or decreasing the risk of postpartum relapses. MSDF And are these women who are on disease-modifying therapy throughout pregnancy or not? Dr. Langer-Gould No. In our population, a little over 60% were treated prior to pregnancy. But we do have a decent number of women who had decided to never go on disease-modifying therapies before, and almost all of them stopped disease-modifying therapies either shortly before or when they find out that they're pregnant. MSDF In terms of each of those outcomes, what are you finding? Dr. Langer-Gould We haven't analyzed the data for the vitamin D yet, but in the German pregnancy registry, we just published the data in exclusive breastfeeding, and once again showed that exclusive breastfeeding does protect against postpartum relapses. In that population, actually 96% of the women had been on some sort of DMT prior to pregnancy, and none of them were treated throughout pregnancy. We also found that resuming DMTs does not seem to have a big effect on reducing the risk of relapses, particularly in the first six months postpartum. MSDF Is that in women who are exclusively breastfeeding or not? Dr. Langer-Gould Ah, so that's a good question. So there is no good safety data on taking the medications during breastfeeding. And therefore, many clinicians and most patients are concerned about potential theoretical risks. So behaviors are actually mutually exclusive. Women typically will either breastfeed or resume medications early in the postpartum course. The other thing we find in the Kaiser population is that there are still a fair number of women who neither breastfeed exclusively or resume their medications, which presents sort of an interesting opportunity. If we could show that one or the other behaviors is protective, perhaps we could encourage either exclusive breastfeeding or resuming DMT. MSDF If women are not breastfeeding, do you have an idea of the time course of resumption of risk for relapse? Dr. Langer-Gould Yes, so the concern about postpartum relapses really is about having a relapse in the first three to four months postpartum. If we look over at the whole pregnancy year, and that's about 30% to 40% of women. So this is actually still the best defined risk period for having a relapse and actually the only clear trigger—with perhaps the exception of upper respiratory tract infections—of relapses. So we know that having just had a baby or having an upper respiratory tract infection is a pretty strong predictor of having a relapse. So it presents sort of a unique opportunity to also look at other biological factors, like vitamin D, which is why we're interested in it, to see if any of these things have a strong role in relapses as well. MSDF If women are breastfeeding postpartum, what is the hormonal profile like? Is this almost like an extension of pregnancy? Dr. Langer-Gould For women who breastfeed exclusively, meaning that they breastfeed to the point of suppressing their ovaries and not resuming menstruation—so that essentially there's no regular meal that's being replaced by formula or by table food in the baby—they have very high prolactin levels. So it's actually a little bit different than being postmenopausal, in the sense that they have very high prolactin levels. And they have incredibly low nonpulsatile FSH and LH levels. In the postmenopausal period, there occurs a very high FSH and LH levels. The similarity, though, is that they both have bottomed-out estradiol and progesterone levels, in both women who are breastfeeding to the point of suppressing menses and also postmenopausal women. And of course the other similarity is that there's no ovulation occurring, either during pregnancy, during exclusive breastfeeding, or after menopause. MSDF So it sounds like breastfeeding is really a hypothalamic pituitary suppressant as opposed to in menopause, where you still have those cranking away, but just no response from the ovaries. Dr. Langer-Gould Correct. MSDF Can this be used in any clinical sense? Do you see an application? Dr. Langer-Gould The most obvious direct way to translate these findings is that that, if you have a woman with MS in front of you and she is pregnant and she tells you she'd like to breastfeed, we certainly have no good reason to discourage her. And that if anything, I would suggest that the data we've already published would point to the fact that we may want to encourage exclusive breastfeeding, provide them with lactation counseling, and also sort out exactly what the optimal duration of exclusive breastfeeding may be for these women. Is it really only eight weeks, which we had defined arbitrarily? Or does longer duration of exclusive breastfeeding have additional suppressive properties? And that would, of course, have implications in the United States for things like maternity leave and work accommodations to allow that to continue, if it has a strong therapeutic effect for the mother. MSDF What's the relapse rate among postmenopausal women compared to postpartum women? Dr. Langer-Gould So relapse rate declines with age. And so it typically in postmenopausal women, although there's not great data, we would expect them to have relapse rates of less than 0.3 per year, Annualized relapse rates of less than 0.3 per year. And in postpartum women, that first three to four months, the annualized relapse rate exceeds one. MSDF But men also have a decline in relapse rate as they age, too. So you can't attribute it to lower estradiol. Dr. Langer-Gould Exactly. Yeah, I think it's far more complicated than just a simple sex hormone effect. You know, that was sort of our first instinct from pregnancy or the reason pregnancy must be protective. It has to have something to do with estradiol or the very high progesterone levels. And that's what prompted the postpartum study and also the estradiol randomized control trial. And both of those, of course, disappointingly have been negative. In isolation, the sex hormones associated with the protective effect of pregnancy don't really have a protective effect on inflammation. It's probably more of a combination of factors that play into modulating the immune response. MSDF Where do you go from here? Dr. Langer-Gould I think that if we are able to reproduce the findings, looking at this population-based source, that early resumption of DMTs is not particularly helpful, but perhaps it may be later in the postpartum year, and that exclusive breastfeeding is, again, protective, then I think the next step really is to establish the safety of some of these medications during lactation. For several of them, there's really no biologically plausible reason to think that they would have an effect on the baby, as they're not likely to be absorbed through the gut or enter into the baby's bloodstream. Examples of that would be the large molecules like Copaxone, the interferons, and also the infusion medications, Tysabri (natalizumab), and rituximab as well. Although you may be able to detect them in breast milk, they are such large molecules that they would not diffuse across the baby's stomach and into the bloodstream. Think about it. If the mom has to take it as a pill, it is very likely to be transmitted to the baby. If the mom has to take it as an infusion or injection, very unlikely that oral route through the baby would have any effect. MSDF How sensitive is this effect to, as you said, exclusive breastfeeding? Can you start introducing formula, or it's all or none? Dr. Langer-Gould That's a really good question. So we did look at that also in the German pregnancy registry. So first of all, women tend to have very defined behavior. They tend to decide to supplemental feed with formula very, very early, before they've even established their full milk supply. So to back up even further, a healthy woman gives birth to her child. Usually menstruation will resume two months after delivery, not one month. So it does take the HPA gonadal axis a little chance to recover from those high-circulating hormones of pregnancy. And in women who introduce supplemental feedings, particularly early, we also see the very same thing; that they will resume their period at two months postpartum. Actually, most of the work done in this field has been done by nutritionists who are in developing countries who are interested in knowing what you should do if you see a starving mother and a starving baby. Who should you feed? It turns out that if you feed the baby, the mother's ovarian function will resume. So any regular supplemental feedings and very quickly their prolactin levels will drop. The pulsatility of the FSH and LH secretion will return. Ovulation returns, and so does menses. It's essentially sending the mother's body a signal that the baby no longer needs nutrition from the mom to survive, so she's ready to have another child. So the right thing to do in that situation would be feed the mom, and let her nurse the child. Biologically, it's very interesting. Even though some breastfeeding is better than none for the baby, in terms of the effect on the mother's HP [hypothalamic-pituitary] ovarian axis, some supplemental feeding is just like all supplemental feeding. MSDF Have we missed anything or anything interesting to add? Dr. Langer-Gould So I guess I would say just in general, women's, and now even men's, desire to have naturally-born children has taken on a new significance with a lot of the small molecule agents, because we need to consider family planning and discuss it much earlier, as small molecules are likely to have an effect even if they get pregnant accidentally on the developing fetus. This is a challenge we haven't had before, because large molecules won't cross the placenta in the first trimester. And the first trimester is the critical period for organ development. So it's sort of new era for MS neurologists, where we really, really have to think carefully about which medication we put them on if they're planning on having children soon. So I’d strongly encourage that you have that conversation very early and have it with every followup visit. I typically will ask them, are you planning on having children within the next two years? And if they say, no, I ask what kind of birth control they're on, or in some cases they're in same-sex couples. That's obviously an exception. And if they are not on a reliable form of birth control, I think you need to think twice about giving the small-molecule agents—so the pills, basically. MSDF Should MS neurologists work with high-risk OB/GYNs? Dr. Langer-Gould I think for the most part it's not necessary, because women with MS, they don't have abnormal complications at pregnancy. I think there are certainly situations that we're running into now. If they get pregnant accidentally on fingolimod, teriflunomide, or Tysabri, we do need to work with them, mostly for the baby. So you may want to do more intense early screening if the mother is culturally open to the idea of having an abortion. You may want to do more fetal ultrasounds, perhaps even a fetal MRI, if there's suspicion of major malformations early on in pregnancy. And also for the Tysabri, really, it's not so much about organogenesis, but if they've had later exposure to Tysabri during pregnancy, which unfortunately on occasion has been necessary to control rebound disease activity during pregnancy, that, you know, we have seen hematological abnormalities in some of these children, so far none with clinical complications. Only one child had a subclinical intraventricular hemorrhage that resolved. It's still concerning. Our experience is very small, and we would certainly highly recommend that those women give birth in a hospital that has a neonatal intensive care unit available and a pediatrician on call to examine the child and also make sure that the child doesn't have a severe thrombocytopenia or anemia at birth. MSDF Do the different drugs have different risks for fetal malformations or other dysfunctions? Dr. Langer-Gould Yes. So teriflunomide, or Aubagio, is the most concerning medication because if a woman gets pregnant on that accidentally, it is, you know, a category X drug because it can interfere with neural tube development. And although you can chelate to get the medication out very quickly, the safety data from other indications, you know, the rheumatoid arthritis and lupus literature, is not particularly reassuring in terms of fetal outcomes. So I think that's sort of the number one to stay away from if a woman is planning on getting pregnant. And it's also one where, you know, there is some concern, although not strong evidence, that it may also affect the offspring of men with MS who are on the medication. In terms of the other ones, of course, again, small molecules in fingolimod has about a 15% to 16% major fetal malformation risk with early pregnancy exposure. It has a very long half-life. So even if they stop the medicine the minute they find out they're pregnant, it takes over two months for it to be cleared, which means that the baby has seen it now through the entire first trimester. That can have significant effects, both on cardiac and brain development. And then with dimethyl fumarate, we haven't seen—now of course, this is a very new drug, so we don't have nearly as much experience—we have not seen any major malformations, but there was concern in the animal models that it could interfere with cognitive development. In particular, the rats had maze-finding difficulty. MSDF Is alemtuzumab indicated at all? It seems to have a long tail. Dr. Langer-Gould I'm not sure what the half-life of alemtuzumab, but it's probably similar to other monoclonal antibodies, which is usually around 15 to 20 days. So monoclonal antibodies don't cross the placenta in the first trimester, because it's a very large molecule. So large molecules only get across if there's an active transport system. For antibodies, there is an active transport system, because it's very important that the child be born with a high dose of antibodies received from the mother to help protect them during the early part of their infancy while their own immune system is still developing. So we see maternal antibodies being transported, and of course, monoclonal antibody medications would be dragged along with that during second trimester. And it goes up in elliptical fashion, with very, very high amounts being pumped across the placenta in third trimester. And they also, of course, have a very delayed clearance mechanism, both the fetus really has no clearance mechanism, and then even the neonate has a very slow clearance mechanism. So in TNF alpha studies, if the drug is given during third trimester, it's typically not cleared until about six to nine months postpartum. So you also have to be concerned that a baby exposed would have some of that medication hanging around during the early neonatal period and give some thought to whether or not their immunization scheme would need to be adjusted, as the cautionary tale there would be TNF alpha exposure during pregnancy. There was a case reported of a woman who had very severe rheumatological disease, had discussed with her rheumatologist the potential risks and benefits of taking it throughout pregnancy, opted to take it throughout pregnancy. And then living in an endemic area for tuberculosis, the baby got the BCG vaccine and got disseminated mycobacterium and died. And that, you know, was probably directly related to impaired immunity from the TNF alpha antagonist. And sure enough, the baby was born with fairly high cord levels and also had very high levels still remaining in the blood in the neonatal period. So it's not just once the baby's born, it's like the drug is out. So drugs like alemtuzumab and rituximab, the way in which they work, even though the drug could be long gone, but the effect of the medication works very long time. So those are actually good choices for women with highly active disease who are planning on getting pregnant. And you have concerns about rebound. I mean, we typically use rituximab because it's obviously much safer than alemtuzumab and seems to do a fairly good job. But you know, these aren't medications we should be giving while they're pregnant, but probably not a big effect in crossing the placenta and on the baby if they're used prior to pregnancy. MSDF If they can plan that well and get a pulse of that early, and then get pregnant a few months later. Dr. Langer-Gould Yes. Yeah, that's always the trick, right? And they do get pregnant accidentally on just about everything we put them on. So the infrequent infusion medications is the easiest because you can ask about last menstrual period. And you can ask about birth control use, and you can do a pregnancy test the day of, a quick urine dipstick and find out so that you don't accidentally infuse a pregnant woman. Of course with Tysabri, when you're giving them an infusion every month, it gets a little tricky. Usually people just kind of get tired of it. The nurses forget. The doctor forgets to order it, although it's not necessarily bad practice if you know you have a patient who is not on a reliable form of birth control. MSDF Very good. I appreciate it. Thank you. Dr. Langer-Gould You're welcome. [transition music] MSDF Thank you for listening to Episode Seventy-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. 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.

Multiple Sclerosis Discovery --  Episode 77 with Dr. Annette Langer-Gould

Joseph Berger

[intro music]   Hello, and welcome to Episode Thirty-Eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features part one of a two-part interview with Joseph Berger of the University of Pennsylvania. But to begin, we’d like to tell you about MSDF’s Drug-Development Pipeline.   Twelve drugs are currently approved in the US for the treatment of MS, but there are many more drugs in various stages of clinical and pre-clinical development. We’re keeping daily track of 44 of them in our Drug Development Pipeline.   To visit the pipeline just go to msdiscovery.org and click on Research Resources, and then Drug-Development Pipeline. You’ll find a finely detailed, fully referenced, and easily searchable database of all 44 of those drugs. The database includes details on each drug candidate’s physiology, its progress through pre-clinical and clinical trials, and its regulatory and commercial status.   Science journalist Heather McDonald has managed this database since its inception, and she updates it continuously, whenever new information becomes available. In just the last week, for example, she added one new clinical trial to the database, she updated information on two other clinical trials, and she added 5 other pieces of information. The drugs with important additions and changes were dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, mitoxantrone, natalizumab, and RPC1063.   [transition music]   Now to the interview. Dr. Joseph P Berger is a professor of neurology and Chief of the MS Division at the University of Pennsylvania in Philadelphia. In part one of our discussion with Dr. Berger, we’re talking about the risk of progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection that occasionally arises in people being treated for multiple sclerosis.   Interviewer – Dan Keller The topic of quantifying risk and mitigating risk comes up with certain immunosuppressive drugs, notably natalizumab in MS but also with other drugs as well in other conditions. What are some of the confounding factors? Why is this not an easy thing to approach?   Interviewee – Joseph Berger Well, it’s not easy because it’s so unpredictable. Nobody would have thought that natalizumab would have uniquely predisposed to the development of progressive multifocal leukoencephalopathy. In fact, when natalizumab was introduced, if one would have attempted to predict what would have happened, you might have said, well, we’ll see a wide variety of opportunistic infections of the central nervous system, since this is a drug that prevents the neural immunosurveillance that is necessary to prevent these diseases from occurring. However, that’s not what we see. We don’t see the opportunistic infections of the central nervous system that we see in the AIDS patient; for instance, things like cryptococcal meningitis and toxoplasma and tuberculous meningitis, it simply doesn’t happen. What we see, on the other hand, is this unique increased risk for the development of progressive multifocal leukoencephalopathy. This was an entirely, in my mind, unpredictable event. I suspect that this is true of many of the other drugs that are now coming to market; that our experience with them is limited, they have what we think is a well-defined effect on the immune system – they’re not broadly immunosuppressant – yet our knowledge of the immune system is such that we don’t understand fully the downstream effects they have. And it’s only after we’ve used these drugs for a number of years do we have a comfort level with what sort of risks that are engendered by their use.   MSDF But it’s not unique to natalizumab; other drugs can induce this whether in neurologic conditions or even rheumatologic conditions. Is that right?   Dr. Berger Yes. In talking about PML, that is true that there are other drugs that carry black box warnings for the development of PML; however, there’s something unique about natalizumab and another drug that is somewhat related to it and now off the market called efalizumab, which was a drug which went by the name of Raptiva and was used for the treatment of psoriasis. So there are drugs that uniquely increase the risk of PML and there are those that marginally increase the risk of PML, and one shouldn’t conflate them. And though a drug carries a black box warning for PML, it doesn’t necessarily mean that the risk is the same as it is with another drug that may also carry such a warning.   And let me explain this a little further. If you look at natalizumab and you look at efalizumab, those are drugs that have been used for conditions that had never previously been associated with progressive multifocal leukoencephalopathy. So despite the fact… And natalizumab, as you know, is used in the treatment of MS and used in the treatment of inflammatory bowel disorders, in particular Crohn’s disease, efalizumab used in the treatment of psoriasis; these are autoimmune diseases. And prior to the availability of these compounds, we did some aggressive immunosuppressive therapies in the treatment of these diseases. We would treat them with drugs like Cytoxan and azathioprine and high-dose steroids; a wide variety of things were employed. Yet until the PML experience with natalizumab and efalizumab, we had never seen PML in the setting of multiple sclerosis, in the setting of inflammatory bowel disease, or in the setting of psoriasis. So that tells you that there’s something unique about the drugs that we’re using and that it’s not necessarily the underlying condition that is responsible.   The second is when you start the drug, you do not see PML develop immediately; it takes some time. So the experience with efalizumab was three or more years, the experience with natalizumab is typically 12 months; actually the vast majority of cases – over 80% - have been on natalizumab for 24 months, so they’re on the drug for a long time. The shortest latency from initiation to the development of PML has been a single case in which it developed within eight months; everything else is 12 or more months. So what is that telling you? That tells you that the drug is doing something fundamentally to overcome the barriers to the development of this disease and that it’s not simply opening up a gate and letting the horses out; it’s doing something to the pathobiology of the disease.   And then lastly, the incidence with which we see PML with natalizumab – and presumably with efalizumab, although the numbers were much smaller – is extraordinarily high in the appropriate context. So for natalizumab, the risk of developing PML, provided you’re on the drug for two years, you’ve seen prior immunosuppressive therapy, and you’re JC virus antibody-positive so that you have been exposed to the virus that causes this disease, if you have all three of those, your risk is on the order of 1 in 90 or thereabouts. That is a risk that is commensurate with what we see with HIV-associated PML, so it’s very, very high.   However, if one looks at these other drugs which I have called Class 2 agents in several papers now; drugs like rituximab, also a monoclonal antibody though directed against CD20, drugs like brentuximab vedotin or mycophenolate mofetil – which is CellCept – those drugs, too, carry black box warnings for the development of PML; however, the setting in which PML occurs with their use is almost always with a condition that already predisposes you to the development of PML. So with rituximab, for instance, it’s seen with lymphoproliferative disorders, or with transplantation, or with autoimmune diseases in which PML had already been described long before the use of rituximab for the condition. And the same is true with these other drugs.   The second is there’s no latency to the development of the disease, so this is strictly a stochastic event; you may start rituximab today and in two weeks’ time develop PML. There’s no way that somebody’s developed PML in two weeks’ time. What that indicates is that individual was predisposed to developing PML, that virus was already in their brain, it was percolating there, your immune system was suppressing it adequately so it wasn’t expressing itself. And now you’ve done something, you’ve tweaked it a bit and the PML is now expressing itself because you’ve introduced the drug, but the drug fundamentally is not changing the pathobiology of the disease.   Lastly, although we do not have good figures on this, but the best data that I have is that we’re talking about orders of magnitude lower risk with these other drugs. So rituximab, for instance, the risk is probably on the order of 1 in 30,000, or something to that effect. That compared to 1 in 90 when you have all the risk factors that I described with natalizumab. So we’re talking orders of magnitude difference. So I’d suggest that we avoid conflating these drugs when talking about PML risks, and I think that this is something that is generalizable for other risks; I mean, PML is just one risk, but we see other infections and other things that have occurred with other drugs that we’ve employed tweaking the immune system, and I don’t think that one should necessarily put all these drugs that cause these things in the same boat.   MSDF These drugs that are used in other conditions that do in themselves predispose to PML, when they’re used in MS which as a disease does not, on its own, predispose to PML, these same drugs – azathioprine, cyclophosphamide, mycophenolate – add to the risk when you give natalizumab?   Dr. Berger That’s what it looks like. So when Biogen looked at the data that they had available from the initial cases of natalizumab-associated PML, one of the risks that they identified was the increased risk of the development of PML in those individuals that had previously received immunosuppressive therapy. And it really didn’t seem to matter which immunosuppressive therapy it was, it was any immunosuppressive therapy. However, it may be different with the different immunotherapies, it’s simply that the numbers weren’t large enough for one to say that this was particularly associated with azathioprine. People in Europe like to use azathioprine often very early in the course of the disease, so they were seeing a bit more PML than we had seen in the United States at least initially. And it wouldn’t surprise me if there aren’t certain immunosuppressive agents that increase the risk significantly compared to others, but we simply don’t have that data. And what is known is that it really doesn’t matter, any of them can do that.   MSDF Without really having a firm understanding of the pathogenesis of PML – you know the risks but maybe not exactly why it’s occurring – how do you come up with a framework for mitigating risk; is it purely empiric?   Dr. Berger That’s an excellent question. So it turns out that this was a back-of-the-textbook disease; this was the disease that occurred very, very rarely. Between 1958 and 1984 in a review published by Ben Brooks and Deward Walker, there were only 230 cases that they were able to come up with; 1958, of course, is when the disease was first described. So this was a very, very rare disease until the AIDS pandemic where people developed some interest in it, and then it really became interesting when we saw it with natalizumab. And there’s been more resources put into the study of this disease since then, so that we do have a better understanding of the pathogenesis. But in identifying these risks, we’ve worked backwards; you know, we say, alright, what does natalizumab do? So why is it that we see this increased risk?   So in getting back to your question, we know that immunosurveilling the brain is important; so if you have a drug that prevents appropriate immunosurveillance of the central nervosus system, it should not surprise you that the risk of PML is increased. And we do think that the alpha-4 beta-1 integrin inhibition that occurs preventing the entry of JC virus-specific cytotoxic T lymphocytes into the brain is in a large measure – but not completely – contributing to the development of PML. We also know other things. For instance, the virus that we are likely infected with – and the infection occurs very early in our lives; seroepidemiologic studies indicate that most individuals that are infected are infected before the age of 20 – that that virus is a virus that is ubiquitous but incapable of growing effectively in glial tissues; it is a virus found in urine and found in the urinary tract, it’s found in kidney and renal pelvis and bladder, and it’s found in high concentrations in some people’s urine. That virus will not grow in the brain. So something has to happen to the virus.   Does natalizumab change that in some way? Well, we think it does. We think it does that by causing the release of immature B cells; these immature B cells can harbor JC virus, and that virus as these B cells mature there is an upregulation of transcriptional factors that transactivate the virus, it is occurring in a milieu that may uniquely predispose to a genetic rearrangement of the virus enabling it to become a form of the virus referred to as a prototype strain or a neurotropic strain that can grow in the brain. So we think that there are at least two very large barriers that prevent PML that are affected by natalizumab; there may be others. And as we investigate this disease further, our understanding may improve and these explanations I’m telling you will likely be expanded. And, in fact, it may be that some of the thoughts that we have are wrong, because the story with the B cells is actually somewhat hypothetical; there’s some preliminary evidence supportive of it, and that’s why I tell people that I’m fond of Ralph Waldo Emerson’s comment, that consistency is the hobgoblin of small minds. If I stand before you a year from today and tell you something different, it’s only because we’ve learned more about it.   MSDF So how do you mitigate risk and how do you get the point across to patients to let them make informed decisions with you?   Dr. Berger So this is difficult, but we lay the facts out to them. And the facts are that there is this risk of PML, the risk in individuals that are JC virus antibody-negative are very small, the product label puts the risk at less than 1 in a thousand; the belief is that it’s significantly less than that. The fact is that we do see individuals who are JC virus antibody-negative months before the development of PML – it’s rare but it occurs – and there have been studies, including my own, that have indicated that the antibody study doesn’t necessarily mean you’ve never been infected by the virus. So one shouldn’t conflate JC virus antibody negativity with never having been infected, but it is a very good marker for the development of PML, and it is one that needs to be monitored carefully at six month intervals.   So we lay out to the patients that if you’re antibody-negative your risk is infinitesimal and an acceptable risk, and that we monitor you carefully. The second is this is a disease that can be life-threatening, and if not life-threatening certainly severely debilitating – multiple sclerosis I’m talking about – and there are people that have very aggressive disease and will accept the risk of developing PML, knowing that the risk may be 1 in 100, but their risk of developing something that was going to leave them wheelchair-bound and totally disabled is very, very high, and they say I’d rather take the risk of the development of PML.   So we do know what the numbers are. There’s a table that’s been published and gets revised periodically that puts into it JC virus antibody positivity, duration of therapy broken up into 24-month epochs, and prior immunosuppressive use. So we know what the risks are; the highest are in individuals that are treated more than 24 months with the drug, are JC virus antibody-positive, and had previously received immunosuppressive therapies.   MSDF What about monitoring for signs and symptoms of PML if someone does choose to go on some of these drugs?   Dr. Berger Yes, so that’s very, very important. And we do have patients that even in the face of JC virus antibody positivity, we and the patient elect to continue them on the drug. And patients on natalizumab need to be monitored very carefully for the development of PML, and that is a combination of both clinical screening – there is a TOUCH program that queries for the development of symptoms that may be concordant with PML – unfortunately, you also see symptoms of that nature develop in MS patients, as well, so it’s sometimes difficult to tell whether it’s MS or PML – and at that point in time you definitely want to survey them with an MRI. And, in fact, many of us do MRIs at regular intervals in patients on Tysabri attempting to identify the disease – PML – when it is asymptomatic. And those people seem to do best; the prognosis both in terms of disability and in terms of survival is better when you pick the disease up while they’re still asymptomatic, and they have what one would refer to as radiographically isolated PML.   So it’s a combination of vigilance, asking the right questions, performing your physical examination, and obtaining period MRIs, and in those that are JC virus antibody-negative – or even the antibody-positive – repeating that study periodically. And the reason I say that repeating it periodically even in the positive patients is because what’s been demonstrated is that the higher your antibody titer, the greater the risk of developing PML. So there’s a threshold now that’s been identified and individuals above that range have a significantly higher risk of developing PML than individuals who are seropositive but below that level.   MSDF And just to clarify; the TOUCH program is the Tysabri Outreach Unified Commitment to Health? This is what you’re referring to in terms of monitoring for signs and symptoms of PML?   Dr. Berger That is correct. That is the risk mitigation strategy that is FDA-approved and that Biogen has implemented in an effort to decrease the likelihood of PML developing.   MSDF Very good, thank you.   Dr. Berger My pleasure.   [transition music]   Thank you for listening to Episode Thirty-Eight 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 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.   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.      [outro music]

Multiple Sclerosis Discovery -- Episode 38 with Dr. Joseph Berger

Paul Matthews

[intro music]   Hello, and welcome to Episode Twenty-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. Paul Matthews about the Optimize project in the United Kingdom. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Some good news came from the pharmaceutical company Genzyme. On November 14th at 9 pm Eastern time, the FDA approved the drug alemtuzumab – trade name Lemtrada – for relapsing forms of MS. The FDA previously rejected the drug in 2013 due to concerns about study design and side effects. There is still some concern over safety, though, so the company is releasing it to only a limited number of patients. The prescription will also come with a host of other drugs to protect against harmful side effects. Researchers aren’t quite sure how the drug works, but it appears to target monocytes, T cells, and B cells.   Researchers announced a new mouse model for fatigue at the 2014 Society for Neuroscience meeting in Washington, D.C. The model works by enhancing expression of the pro-inflammatory cytokine, interleukin-1-beta. The model caused mice to reduce physical activity, without showing other signs of illness such as fever or anhedonia. Middle-aged and aged female mice were most affected by the treatment, whereas young mice showed no difference in signs of fatigue. The model gives credence to the idea that fatigue is not produced from dysfunction in the arousal system, but rather is a result of inflammation. The researchers said that they hoped the model will help illuminate the neurobiology of fatigue, the most common and debilitating symptom of MS.   If you would like to keep up with all things MSDF, please consider subscribing to our weekly newsletter. We keep our newsletter up-to-date with all of our news stories, blogs, and items from our professional and research resource sections. We’re also on Twitter; follow us at msdforum. And on Facebook, you can like us at facebook.com/ms discovery forum.   [transition music]   Now to the interview. Professor Paul Matthews is at Imperial College London in brain sciences. Last week he talked with MSDF about imaging in MS. This week we’re discussing his involvement in a UK-based project intended to optimize and personalize MS treatment.   Interviewer – Dan Keller Welcome, Professor Matthews. You’re participating in the Optimize project in the UK. Can you tell me about that?   Interviewee – Paul Matthews Well, thanks, Dan. Optimize has been an exciting journey and we’re still at the early stages, but let me tell you a little bit about it. Over three years ago, a number of us got together to discuss what the barriers to development of stratified or personalized medicine for multiple sclerosis was. We all recognized what the potential could be if we could really figure out how to target medicines to responders, we would have a way of most appropriately staging the introduction of different medicines across patient populations, not exposing people who didn’t need them to drugs of higher risk and insuring that those who did need them got them early. This is a particular problem in the United Kingdom where there is a much more formal process for progressing from first-line DMTs to more powerful agents. And, in fact, there’s also – dare I say it – I mean, a frank therapeutic nihilism and a surprisingly small number of MS patients receive treatment because of the perceived lack of benefit to many of these first-line therapies.   Now how to change this. I think what we realized is that we need to have much more granular data on the characteristics of patients being treated and how they fared after their treatment over the long-term. The data provided within the usual clinical context is not only limited, but it ends up being rather patchy over time. In order to enable that, we needed tools that would both collect data and incentivize collection of complete data of high quality. Now a note about this. We all know how to do this within the context of clinical trials, but it’s hugely expensive; it’s expensive because there are multiple people always involved to crosscheck that the data is completely acquired in each paper, and secondarily, there are audit procedures in place in retrospect to insure that this is being done. This really isn’t feasible in routine clinical practice.   A colleague of mine, Rory Collins, who has specialized in setting up very large-scale clinical trials in areas like China and India, has shown how very simple electronic tools can help both insure that data is acquired completely and that there is an electronic audit trail to follow-up on data that isn’t. What they showed is that by creating simple electronic questionnaires that wouldn’t let the questionnaire be closed unless data of an appropriate type was entered in the field, and then automatically interrogating the data for quality from center to center and following up where there were potential lapses, one could begin to incentivize acquisition of the right data and actually make it flow faster.   So how could we make this happen within the MS space in the UK? Well, what we realized is that the toolkits were all there. The EU IMI program already has funded my colleague, Yike Guo, who’s head of the Imperial College Data Science Institute, to create a tool built around a platform called eTRIKS. This is a data management environment that allows links to apps or iPads or any other peripheral electronic tool for very powerful distributed data capture. We then, in gathering together a number of stakeholder meetings which involved people with MS, the MS societies, a number of industry representatives, and what I’m really pleased to say is leads from fully 18 of the major MS centers across the United Kingdom pretty much ringing the country, together created the vision of building such an electronic tool, distributing the types of input devices across the different centers, and beginning to create a database that could be held centrally or in a distributed fashion using all the new tricks of modern IT.   The first thing is acquiring the data, the second is doing useful with it. The second thing that’s rather neat about the eTRIKS platform is that we have shown how it can be built to allow different levels of access, so that there can be access by high-level users who get to see the whole dataset, but also by specialized users who might want to see only a part of it – like a doctor interrogating it for his or her patient – or, importantly, a person with MS interrogating it to see how the data that they have entered stands relative to that that’s entered across the country by all patients; it allows people with MS to begin to gauge how they’re doing relative to others with their disease.   Now, I think the latter point is worth building on, because I think all of us have been hugely impressed by the power of sites like Patients Like Me to engage people with the disease in the dialog about their disease and make them full participants in capturing data information. With this kind of distributed data platform where doctors and people with MS can enter data whenever and wherever they are to a central database which can organize it and allow it then to be interrogated as needed, means that we can begin to think about asking patients to enter data on the fly from home. Why is this important? Well, this actually completely transforms the way in which we understand the disease, it really gives us a much deeper sense of the patient experience. Rather than sampling a patient once every month or once every six months, we can actually capture how they’re doing through a day. And if we add to this some extra sensor technologies – say, for example, about movement – we can literally do this from moment to moment.   So the vision thus is that if we can use these modern IT tools to capture data from distributed sources – from doctors using iPads, from patients using apps, from sensors that people with MS wear – we can capture data in a central resource that can be distributed to those for the purposes that they need it in near real-time, and in turn provide a common environment for its analysis. I think it’s exciting. Now we’re at the early stages, the basic tools have been designed, we’re starting to build the sensor technology. And our genuine hope is with the completion of the first set of agreements with one of the companies who’s been the first to really take a plunge with us, we’re going to be able to create a beta form of the tool in 6-9 months.   Now before closing, I do want to add one thing. This is an exciting vision but the notion of building a database is hardly a new one and many people have had it. There is something that’s special about this vision and it’s the thing that I’m most proud of that’s come together from all of these stakeholders. It’s the vision of creating a database that will be an open database; open to all researchers once it’s built, not held privately by those who built it. And I think this is what could become a game-changer. Moreover, we see that the tools that we’re building in order to create this – the IT tools, the distributed apps, and so on – are tools that the community should own and should be able to improve on. So our intention is fully, as this program develops, to release a software for open-access use as well as the data. Our hope is that even if this doesn’t provide the solution of the future, it will begin to incentivize this kind of practice where we all share this important data to work together to find solutions to this disease.   MSDF Besides collecting MS-specific data, will it also look at general health and comorbidities to see how that affects outcomes?   Dr. Matthews No. That’s a really good question. Like so many doctors now, we’re very much focused on the progressive forms of the disease. Our belief is that comorbidities make major contributions to this, and that by influencing these comorbidities we may have the biggest short-term impact on our patients’ lives. So one of the advantages of a big data capture tool is that we can capture data on all of the other disorders that afflict people with MS, as well, and begin with, again, greater granularity because of contributions from people with as well as their doctors to look at this in ways that wonderful databases like NARCOMS haven’t been able to do. This is an important task for the future and one that we really want to grasp. We’re hoping with further funding to be able to link this to bioresources, as well, and the ability to access a patient’s fluid samples for Omics analyses certainly can add greatly to this.   MSDF Very good, I appreciate it.   Dr. Matthews You’re welcome, Dan, it’s been good speaking to you.   [transition music]   Thank you for listening to Episode Twenty-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 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.   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.    [outro music]

[intro music] Hello, and welcome to Episode Twenty-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features an interview with Dr. Paul Matthews about the Optimize project in the United Kingdom. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a>. Some good news came from the pharmaceutical company Genzyme. On November 14th at 9 pm Eastern time, the FDA approved the drug alemtuzumab – trade name Lemtrada – for relapsing forms of MS. The FDA previously rejected the drug in 2013 due to concerns about study design and side effects. There is still some concern over safety, though, so the company is releasing it to only a limited number of patients. The prescription will also come with a host of other drugs to protect against harmful side effects. Researchers aren’t quite sure how the drug works, but it appears to target monocytes, T cells, and B cells. Researchers announced a new mouse model for fatigue at the 2014 Society for Neuroscience meeting in Washington, D.C. The model works by enhancing expression of the pro-inflammatory cytokine, interleukin-1-beta. The model caused mice to reduce physical activity, without showing other signs of illness such as fever or anhedonia. Middle-aged and aged female mice were most affected by the treatment, whereas young mice showed no difference in signs of fatigue. The model gives credence to the idea that fatigue is not produced from dysfunction in the arousal system, but rather is a result of inflammation. The researchers said that they hoped the model will help illuminate the neurobiology of fatigue, the most common and debilitating symptom of MS. If you would like to keep up with all things MSDF, please consider subscribing to our weekly newsletter. We keep our newsletter up-to-date with all of our news stories, blogs, and items from our professional and research resource sections. We’re also on Twitter; follow us at msdforum. And on Facebook, you can like us at <a href="http://facebook.com/ms" rel="nofollow" target="_blank">facebook.com/ms</a> discovery forum. [transition music] Now to the interview. Professor Paul Matthews is at Imperial College London in brain sciences. Last week he talked with MSDF about imaging in MS. This week we’re discussing his involvement in a UK-based project intended to optimize and personalize MS treatment. Interviewer – Dan Keller Welcome, Professor Matthews. You’re participating in the Optimize project in the UK. Can you tell me about that? Interviewee – Paul Matthews Well, thanks, Dan. Optimize has been an exciting journey and we’re still at the early stages, but let me tell you a little bit about it. Over three years ago, a number of us got together to discuss what the barriers to development of stratified or personalized medicine for multiple sclerosis was. We all recognized what the potential could be if we could really figure out how to target medicines to responders, we would have a way of most appropriately staging the introduction of different medicines across patient populations, not exposing people who didn’t need them to drugs of higher risk and insuring that those who did need them got them early. This is a particular problem in the United Kingdom where there is a much more formal process for progressing from first-line DMTs to more powerful agents. And, in fact, there’s also – dare I say it – I mean, a frank therapeutic nihilism and a surprisingly small number of MS patients receive treatment because of the perceived lack of benefit to many of these first-line therapies. Now how to change this. I think what we realized is that we need to have much more granular data on the characteristics of patients being treated and how they fared after their treatment over the long-term. The data provided within the usual clinical context is not only limited, but it ends up being rather patchy over time. In order to enable that, we needed tools that would both collect data and incentivize collection of complete data of high quality. Now a note about this. We all know how to do this within the context of clinical trials, but it’s hugely expensive; it’s expensive because there are multiple people always involved to crosscheck that the data is completely acquired in each paper, and secondarily, there are audit procedures in place in retrospect to insure that this is being done. This really isn’t feasible in routine clinical practice. A colleague of mine, Rory Collins, who has specialized in setting up very large-scale clinical trials in areas like China and India, has shown how very simple electronic tools can help both insure that data is acquired completely and that there is an electronic audit trail to follow-up on data that isn’t. What they showed is that by creating simple electronic questionnaires that wouldn’t let the questionnaire be closed unless data of an appropriate type was entered in the field, and then automatically interrogating the data for quality from center to center and following up where there were potential lapses, one could begin to incentivize acquisition of the right data and actually make it flow faster. So how could we make this happen within the MS space in the UK? Well, what we realized is that the toolkits were all there. The EU IMI program already has funded my colleague, Yike Guo, who’s head of the Imperial College Data Science Institute, to create a tool built around a platform called eTRIKS. This is a data management environment that allows links to apps or iPads or any other peripheral electronic tool for very powerful distributed data capture. We then, in gathering together a number of stakeholder meetings which involved people with MS, the MS societies, a number of industry representatives, and what I’m really pleased to say is leads from fully 18 of the major MS centers across the United Kingdom pretty much ringing the country, together created the vision of building such an electronic tool, distributing the types of input devices across the different centers, and beginning to create a database that could be held centrally or in a distributed fashion using all the new tricks of modern IT. The first thing is acquiring the data, the second is doing useful with it. The second thing that’s rather neat about the eTRIKS platform is that we have shown how it can be built to allow different levels of access, so that there can be access by high-level users who get to see the whole dataset, but also by specialized users who might want to see only a part of it – like a doctor interrogating it for his or her patient – or, importantly, a person with MS interrogating it to see how the data that they have entered stands relative to that that’s entered across the country by all patients; it allows people with MS to begin to gauge how they’re doing relative to others with their disease. Now, I think the latter point is worth building on, because I think all of us have been hugely impressed by the power of sites like Patients Like Me to engage people with the disease in the dialog about their disease and make them full participants in capturing data information. With this kind of distributed data platform where doctors and people with MS can enter data whenever and wherever they are to a central database which can organize it and allow it then to be interrogated as needed, means that we can begin to think about asking patients to enter data on the fly from home. Why is this important? Well, this actually completely transforms the way in which we understand the disease, it really gives us a much deeper sense of the patient experience. Rather than sampling a patient once every month or once every six months, we can actually capture how they’re doing through a day. And if we add to this some extra sensor technologies – say, for example, about movement – we can literally do this from moment to moment. So the vision thus is that if we can use these modern IT tools to capture data from distributed sources – from doctors using iPads, from patients using apps, from sensors that people with MS wear – we can capture data in a central resource that can be distributed to those for the purposes that they need it in near real-time, and in turn provide a common environment for its analysis. I think it’s exciting. Now we’re at the early stages, the basic tools have been designed, we’re starting to build the sensor technology. And our genuine hope is with the completion of the first set of agreements with one of the companies who’s been the first to really take a plunge with us, we’re going to be able to create a beta form of the tool in 6-9 months. Now before closing, I do want to add one thing. This is an exciting vision but the notion of building a database is hardly a new one and many people have had it. There is something that’s special about this vision and it’s the thing that I’m most proud of that’s come together from all of these stakeholders. It’s the vision of creating a database that will be an open database; open to all researchers once it’s built, not held privately by those who built it. And I think this is what could become a game-changer. Moreover, we see that the tools that we’re building in order to create this – the IT tools, the distributed apps, and so on – are tools that the community should own and should be able to improve on. So our intention is fully, as this program develops, to release a software for open-access use as well as the data. Our hope is that even if this doesn’t provide the solution of the future, it will begin to incentivize this kind of practice where we all share this important data to work together to find solutions to this disease. MSDF Besides collecting MS-specific data, will it also look at general health and comorbidities to see how that affects outcomes? Dr. Matthews No. That’s a really good question. Like so many doctors now, we’re very much focused on the progressive forms of the disease. Our belief is that comorbidities make major contributions to this, and that by influencing these comorbidities we may have the biggest short-term impact on our patients’ lives. So one of the advantages of a big data capture tool is that we can capture data on all of the other disorders that afflict people with MS, as well, and begin with, again, greater granularity because of contributions from people with as well as their doctors to look at this in ways that wonderful databases like NARCOMS haven’t been able to do. This is an important task for the future and one that we really want to grasp. We’re hoping with further funding to be able to link this to bioresources, as well, and the ability to access a patient’s fluid samples for Omics analyses certainly can add greatly to this. MSDF Very good, I appreciate it. Dr. Matthews You’re welcome, Dan, it’s been good speaking to you. [transition music] Thank you for listening to Episode Twenty-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 Robert Finn. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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.  [outro music]

Multiple Sclerosis Discovery -- Episode 22 with Dr. Paul Matthews

Adam Kaplin

Multiple Sclerosis Discovery -- Episode 82 with Dr. Adam Kaplin

Alessandra Solari

Transcript will be available soon.

Multiple Sclerosis Discovery -- Episode 69 with Dr. Alessandra Solari 

Aksel Siva

[intro music]   Hello, and welcome to Episode Twenty-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Professor Aksel Siva about asymptomatic MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   We just uploaded a new data visualization to our website. This one breaks down the design of MRI-related clinical trials in MS. It combines 88 trials conducted between 1998 and 2013 in a colorful, interactive dot plot. Each dot represents a point in time for a particular measurement, such as brain volume. You can sort trials by phase, and you can look at trials in aggregate or one at a time. To view this new visualization, go to the Data Viz section under the “Research Resources” tab and click on the top link.   Magnetic resonance imaging is a source of anxiety for many people with MS. Just getting into the machine is nerve-wracking, and waiting for the results is even scarier, says a recent study from PLOS One. The researchers conducting the study suggested that educating patients about MRIs might alleviate some of the dread. Even though MSer’s typically know a great deal about MRIs, understanding how to interpret their own results may help increase the bond of trust with their physicians, the researchers said. To read more about the study, visit our “News and Future Directions” section, and under “News Briefs” click on the article, “MRI Education May Benefit MSers.”   Have a burning question? A bone to pick? Something you want to get off your chest? Start a discussion! We invite you to participate in our discussion forums by making your own threads and commenting on others. Just click on the “Discussions” option under the “Forums” tab on our website to get started.   [transition music]   Now to the interview. Last week, we spoke with Professor Aksel Siva about radiologically isolated syndrome. This week he’ll be speaking to us about asymptomatic MS and approaches to medicine in Turkey.   Interviewer – Dan Keller Professor Siva, first of all, why is it MS if it’s asymptomatic?   Interviewee – Aksel Siva Well, that’s a very good question and very difficult. But now with the tools that we have in medicine, we probably diagnose people without developing the disease. And, again, if we look to some other neurological diseases, today we are now discussing whether we can really diagnose Alzheimer prior that the individual develop the disease with imaging, with biomarkers, and so on. So to see the same thing in MS, I think it’s not really something very different. The thing is that not all these people will develop the disease, so the way we have been trained as clinicians, to us it’s important to see clinical signs and symptoms.    But now we have to start seeing that not everybody will develop the disease even if they do have it biologically, morphologically, or whatever you name it, however you name it. And then when they develop, we know well that all people are not going to have the same course. So these individual differences based on genetic background, maybe environmental influence, or whatever, should put a light in the way we see individuals – not a disease, but the individual with the disease rather let’s to say than the disease affecting the individuals. So I think this concept of subclinical disease, which is not only for MS, should influence our practice or our approach to our patients, and also in understanding the diseases and how to manage them.    MSDF Can you tell me a little bit about some of the studies that show heightened susceptibility and that possibly invoke the idea of genetics or environment?   Professor Siva I don’t think that I am in a state of responding to this question, because this is not really my area of interest. But from the genetic studies, we know there are some people who have the susceptibility genes, some who have the protective genes, and also some genes that may probably affect the course and prognosis of the patients. But, again, to my knowledge, what we have today, the information we have, is not really unique for everybody. It’s also very heterogeneous. So we need more time, and I think that this time it’s not too far, and especially the Genetic Consortium in the US, their findings are going to bring a lot of new information in the very near future.     MSDF What about studies on twins or just siblings. Although it doesn’t really nail down whether it’s genetic or environmental, it does speak to heightened risk. What did those show? Who looked at them and what did they find?   Professor Siva Well, again, I’m not aware of really very new studies on twins; identical and non-identical twins, the risk is very different, it’s maybe 2 to 3% up to 5%, depending like if it’s Canada or France it changes. But when it is identical, it’s 25 to 30. To my knowledge, the Canada cohort went up to 37%, although this number, I guess, was not published, but we know this. So it’s about only one-third even in the highest identical twin studies. So the question is what happens to the two-thirds? Maybe some of them do have incidental lesions, but they don’t have the disease. What is the present state in this genetics or others, I’m not aware of.   MSDF Even siblings who show oligoclonal bands don’t necessarily have or get the disease, is that correct?   Professor Siva No, that’s correct. According to the Swedish study, these people did not have the disease. Maybe more important, there was a subsequent paper reported in the same cohort, they have looked in the CSF of these asymptomatic, or let’s say of these siblings with positive oligoclonal bands, and what they called immunopathic trait. They looked in some other issues, but let’s put it these people with positive oligoclonal bands and the immunopathic trait, and they have looked in some neuronal degeneration markers. And the sibling who had the disease had high levels, which shows that there was a CNS damage, and asymptomatic case it was normal. So that is very clear that, yes, if you get the disease you might have some, let’s say, the biological evidence of it together with CNS damage, whereas if you don’t get… you may have the same trait but not the disease, because you will not have CNS damage. And there might be some underlying mechanisms – immunogenetic, whatever – which controls the disease spread and clinical expression. So I think this is a major issue.    And in the Steffano study when he had studied, again, the relatives of people with MS who had lesions – these 4% or 10% of asymptomatic cases – he also looked in the normal-appearing white matter. And in the diseased individuals it was abnormal; whereas in the people who had just those, let’s say, T2 changes, the normal-appearing white matter was completely normal, which again shows us that the CNS damage is very, very limited in people who don’t get the disease. And from the early autopsy studies, again the people in whom the autopsy had shown brain lesions, they were mostly periventricular and probably in silent areas, and there was not widespread damage as we see in people who get the clinical disease.    MSDF It seems Turkey is a very good setting for looking at a lot of this, because people get a lot of MRIs.   Professor Siva That’s correct, that’s very correct, and that’s why we have so many cases. Today with contribution of another medical school from Ankara, Hacettepe Medical School, together now we have more than 86 RIS cases that we continue to follow up, some of who have converted now.    MSDF And RIS is radiological isolated syndrome. Do people pay for their MRIs, or why are they so apt to come in and get so many?   Professor Siva Not really, it’s reimbursed, mostly it’s reimbursed, or if they have their private insurance because, let’s say, physician is suspecting something. And I should also confess that in some hospitals – mainly state hospitals – there is an overload of patients. Let’s say neurologists in those institutions may not find time to listen and examine the patient as they should do. So in order not to miss something, even a patient who comes with a headache may get an MRI.   MSDF Is there a difference in Turkey of how you approach MS patients, or treat them, or follow them from in other countries that you’ve noticed?   Professor Siva Not really. It’s, I would say, very much the same. I have started our MS clinic in 1987 here, and today we have more than 7,000 registered patients, which is really quite a very large population. This doesn’t mean that we follow all the 7,000 and more patients because many of them had been referred for second opinions, but I would say we continue to see at least half of these people. And the way the practice is here is not any different than most major European and US centers. I had spent some time at Mayo many years ago and I had some of my other colleagues now who had spent some time. So it’s more or less the same. We have all the same drugs, most of them are reimbursed. So we have many alternatives for our MS patients, although there are some restrictions for reimbursement. We need to at least try the so-called injectables in order to go to orals, or, let’s say, the monoclonal antibody therapies, but almost all are available. And according to some rules, they are also reimbursed.    MSDF Are there good patient support services, psychosocial and other?   Professor Siva Not maybe so strong. That we may differ a bit from Europe and US. We do have Turkish MS Society where such services are tried to be provided, but that is not enough. We do have some MS Society chapters in some cities but not everywhere. But mostly the problem, I would say, is economical. All these services mostly are based on voluntary basis.   MSDF Do you think that patients react the same to their disease?   Professor Siva We do have some studies – psychologically, physically – and it’s at very similar to western theories. So actually Turks are Caucasians mostly, and therefore it’s what if we are going to call the western-type MS, that’s what we see here too.   MSDF Are there cultural differences in various parts of Turkey how people view their disease, or is it all about the same? I mean, Istanbul is really Europe, as you move farther east you get into more Asian and Middle Eastern.   Professor Siva I may say not really, because we get referrals from all around Turkey, and the behavior is not really much different. I should say either whether the patient is from Istanbul or from the east part of the country or the Mediterranean, it’s more or less the same.   MSDF  Anything important to add that we’ve missed or interesting topic points?   Professor Siva We have a large number of MS people in Turkey, probably prevalence rate is around 50 per 100,000 or more. There have been a number of prevalence studies, and this is about what we can really derive from all the studies – 50 or more even. But I have the impression that we are getting more and more MS in Turkey today, and more familial cases, which was not the case maybe 15 to 20 years ago.   MSDF Very good. Thanks a lot.   Professor Siva Thank you.   [transition music]   Thank you for listening to Episode Twenty-four 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 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.    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.    [outro music]

[intro music] Hello, and welcome to Episode Twenty-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features an interview with Professor Aksel Siva about asymptomatic MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a>. We just uploaded a new data visualization to our website. This one breaks down the design of MRI-related clinical trials in MS. It combines 88 trials conducted between 1998 and 2013 in a colorful, interactive dot plot. Each dot represents a point in time for a particular measurement, such as brain volume. You can sort trials by phase, and you can look at trials in aggregate or one at a time. To view this new visualization, go to the Data Viz section under the “Research Resources” tab and click on the top link. Magnetic resonance imaging is a source of anxiety for many people with MS. Just getting into the machine is nerve-wracking, and waiting for the results is even scarier, says a recent study from PLOS One. The researchers conducting the study suggested that educating patients about MRIs might alleviate some of the dread. Even though MSer’s typically know a great deal about MRIs, understanding how to interpret their own results may help increase the bond of trust with their physicians, the researchers said. To read more about the study, visit our “News and Future Directions” section, and under “News Briefs” click on the article, “MRI Education May Benefit MSers.” Have a burning question? A bone to pick? Something you want to get off your chest? Start a discussion! We invite you to participate in our discussion forums by making your own threads and commenting on others. Just click on the “Discussions” option under the “Forums” tab on our website to get started. [transition music] Now to the interview. Last week, we spoke with Professor Aksel Siva about radiologically isolated syndrome. This week he’ll be speaking to us about asymptomatic MS and approaches to medicine in Turkey. Interviewer – Dan Keller Professor Siva, first of all, why is it MS if it’s asymptomatic? Interviewee – Aksel Siva Well, that’s a very good question and very difficult. But now with the tools that we have in medicine, we probably diagnose people without developing the disease. And, again, if we look to some other neurological diseases, today we are now discussing whether we can really diagnose Alzheimer prior that the individual develop the disease with imaging, with biomarkers, and so on. So to see the same thing in MS, I think it’s not really something very different. The thing is that not all these people will develop the disease, so the way we have been trained as clinicians, to us it’s important to see clinical signs and symptoms.  But now we have to start seeing that not everybody will develop the disease even if they do have it biologically, morphologically, or whatever you name it, however you name it. And then when they develop, we know well that all people are not going to have the same course. So these individual differences based on genetic background, maybe environmental influence, or whatever, should put a light in the way we see individuals – not a disease, but the individual with the disease rather let’s to say than the disease affecting the individuals. So I think this concept of subclinical disease, which is not only for MS, should influence our practice or our approach to our patients, and also in understanding the diseases and how to manage them.  MSDF Can you tell me a little bit about some of the studies that show heightened susceptibility and that possibly invoke the idea of genetics or environment? Professor Siva I don’t think that I am in a state of responding to this question, because this is not really my area of interest. But from the genetic studies, we know there are some people who have the susceptibility genes, some who have the protective genes, and also some genes that may probably affect the course and prognosis of the patients. But, again, to my knowledge, what we have today, the information we have, is not really unique for everybody. It’s also very heterogeneous. So we need more time, and I think that this time it’s not too far, and especially the Genetic Consortium in the US, their findings are going to bring a lot of new information in the very near future. MSDF What about studies on twins or just siblings. Although it doesn’t really nail down whether it’s genetic or environmental, it does speak to heightened risk. What did those show? Who looked at them and what did they find? Professor Siva Well, again, I’m not aware of really very new studies on twins; identical and non-identical twins, the risk is very different, it’s maybe 2 to 3% up to 5%, depending like if it’s Canada or France it changes. But when it is identical, it’s 25 to 30. To my knowledge, the Canada cohort went up to 37%, although this number, I guess, was not published, but we know this. So it’s about only one-third even in the highest identical twin studies. So the question is what happens to the two-thirds? Maybe some of them do have incidental lesions, but they don’t have the disease. What is the present state in this genetics or others, I’m not aware of. MSDF Even siblings who show oligoclonal bands don’t necessarily have or get the disease, is that correct? Professor Siva No, that’s correct. According to the Swedish study, these people did not have the disease. Maybe more important, there was a subsequent paper reported in the same cohort, they have looked in the CSF of these asymptomatic, or let’s say of these siblings with positive oligoclonal bands, and what they called immunopathic trait. They looked in some other issues, but let’s put it these people with positive oligoclonal bands and the immunopathic trait, and they have looked in some neuronal degeneration markers. And the sibling who had the disease had high levels, which shows that there was a CNS damage, and asymptomatic case it was normal. So that is very clear that, yes, if you get the disease you might have some, let’s say, the biological evidence of it together with CNS damage, whereas if you don’t get… you may have the same trait but not the disease, because you will not have CNS damage. And there might be some underlying mechanisms – immunogenetic, whatever – which controls the disease spread and clinical expression. So I think this is a major issue.  And in the Steffano study when he had studied, again, the relatives of people with MS who had lesions – these 4% or 10% of asymptomatic cases – he also looked in the normal-appearing white matter. And in the diseased individuals it was abnormal; whereas in the people who had just those, let’s say, T2 changes, the normal-appearing white matter was completely normal, which again shows us that the CNS damage is very, very limited in people who don’t get the disease. And from the early autopsy studies, again the people in whom the autopsy had shown brain lesions, they were mostly periventricular and probably in silent areas, and there was not widespread damage as we see in people who get the clinical disease.  MSDF It seems Turkey is a very good setting for looking at a lot of this, because people get a lot of MRIs. Professor Siva That’s correct, that’s very correct, and that’s why we have so many cases. Today with contribution of another medical school from Ankara, Hacettepe Medical School, together now we have more than 86 RIS cases that we continue to follow up, some of who have converted now.  MSDF And RIS is radiological isolated syndrome. Do people pay for their MRIs, or why are they so apt to come in and get so many? Professor Siva Not really, it’s reimbursed, mostly it’s reimbursed, or if they have their private insurance because, let’s say, physician is suspecting something. And I should also confess that in some hospitals – mainly state hospitals – there is an overload of patients. Let’s say neurologists in those institutions may not find time to listen and examine the patient as they should do. So in order not to miss something, even a patient who comes with a headache may get an MRI. MSDF Is there a difference in Turkey of how you approach MS patients, or treat them, or follow them from in other countries that you’ve noticed? Professor Siva Not really. It’s, I would say, very much the same. I have started our MS clinic in 1987 here, and today we have more than 7,000 registered patients, which is really quite a very large population. This doesn’t mean that we follow all the 7,000 and more patients because many of them had been referred for second opinions, but I would say we continue to see at least half of these people. And the way the practice is here is not any different than most major European and US centers. I had spent some time at Mayo many years ago and I had some of my other colleagues now who had spent some time. So it’s more or less the same. We have all the same drugs, most of them are reimbursed. So we have many alternatives for our MS patients, although there are some restrictions for reimbursement. We need to at least try the so-called injectables in order to go to orals, or, let’s say, the monoclonal antibody therapies, but almost all are available. And according to some rules, they are also reimbursed.  MSDF Are there good patient support services, psychosocial and other? Professor Siva Not maybe so strong. That we may differ a bit from Europe and US. We do have Turkish MS Society where such services are tried to be provided, but that is not enough. We do have some MS Society chapters in some cities but not everywhere. But mostly the problem, I would say, is economical. All these services mostly are based on voluntary basis. MSDF Do you think that patients react the same to their disease? Professor Siva We do have some studies – psychologically, physically – and it’s at very similar to western theories. So actually Turks are Caucasians mostly, and therefore it’s what if we are going to call the western-type MS, that’s what we see here too. MSDF Are there cultural differences in various parts of Turkey how people view their disease, or is it all about the same? I mean, Istanbul is really Europe, as you move farther east you get into more Asian and Middle Eastern. Professor Siva I may say not really, because we get referrals from all around Turkey, and the behavior is not really much different. I should say either whether the patient is from Istanbul or from the east part of the country or the Mediterranean, it’s more or less the same. MSDF  Anything important to add that we’ve missed or interesting topic points? Professor Siva We have a large number of MS people in Turkey, probably prevalence rate is around 50 per 100,000 or more. There have been a number of prevalence studies, and this is about what we can really derive from all the studies – 50 or more even. But I have the impression that we are getting more and more MS in Turkey today, and more familial cases, which was not the case maybe 15 to 20 years ago. MSDF Very good. Thanks a lot. Professor Siva Thank you. [transition music] Thank you for listening to Episode Twenty-four 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 Robert Finn. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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.  <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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.  [outro music]

Multiple Sclerosis Discovery -- Episode 24 with Professor Aksel Siva

Elaine Kingwell

[intro music] Host – Dan Keller Hello, and welcome to Episode Seventy-five of Multiple SclerosisDiscovery, the podcast of the MS Discovery Forum. I’m DanKeller. Today's interview features Elaine Kingwell, a research associateat the University of British Columbia in Canada. She and hercolleagues have gathered and recently published incidence andprevalence figures for people with MS in the province. I spoke withDr. Kingwell at the ECTRIMS meeting in Barcelona in October to findout the reason for the study and to explore the changing trends shefound and their significance. Interviewer – Dan Keller What prompted you to do this study? Interviewee – Elaine Kingwell In British Columbia, we know that Canada has got a highincidence and prevalence rate of MS, but we don't actually have thenumbers, so we've been doing a lot of research on MS in BritishColumbia for many, many years. But we don't have the incidencenumbers for BC, and also the prevalence is out of date – theestimates that we have – so it really was time to get an idea onhow many people we have in BC. And also, we wanted to look atchange over time, and we have access to some amazing administrativedatabases in BC and also had some algorithms that we could use thathave been validated, so that we could identify people with MS inthe databases. MSDF Why are these numbers important? Dr. Kingwell It's important for lots of different reasons. For instance, it'simportant to monitor trends over time. We're able to do that in BC,because we have data going back several years. And so, it'simportant to see if populations are changing, so that we can getsome clues about whether environmental factors might be changing.And also, for the prevalence estimates, it's important to know howmany people have MS in the province, so that healthcare planningcan be done wisely and resources. MSDF How do you go about looking at this? Dr. Kingwell So as I mentioned, we did use the health administrativedatabases in BC, which are big databases that collect data on thewhole population. A number of different databases were combined,including hospital admissions and physician visits. It's all claimsdata, so that when someone goes to see their physician, a billingclaim gets put in with their diagnosis. So we use these codes toidentify people with MS. And we basically estimated the number ofpeople with MS [over] several years – one year at a time – so thatwe could look at change over time for prevalence. And we alsoestimated the incidence, the number of new cases each year,starting in '96 right up until 2008. MSDF What did you find in terms of incidence and prevalence? Dr. Kingwell Well we found the incidence and prevalence are both high. Theincidence was around 7.8 per 100,000 per year, and the prevalencewas around 180 to 200 per 100,000 in 2008. So they were both high,what is relatively high compared to other places in the world andsimilar to rates that have been found in Europe, in NorthernEurope, and other parts of Canada, as well. MSDF And the prevalence is increasing over time? Dr. Kingwell Yeah, we found that it increased quite significantly by about4.7% per year, so a big increase. It also shifted in thepredominant age of people, so that the peak prevalence age wasaround in the mid-40s in the 1990s, and it's now shifted up intothe mid-50s. So the population of people with MS is getting olderin BC. We also saw with incidence … quite differently, theincidence was not changing over time, so it stayed relativelystable; it did fluctuate as incidence always does. But over time,on average, it stayed the same. MSDF Are those two pieces combined—increasing prevalence and olderage—good news? Dr. Kingwell I don't know if any of it's good news. It means that we have anolder population that are probably requiring more care, as they getolder, for the MS, as well as, of course, comorbidities they mayhave. So, it's certainly something that healthcare planners need tobe aware of. And we have an aging population, in general, inCanada, as we do in other parts of the world, but we have a lotmore people with MS at an older age. MSDF But doesn't that mean they're surviving longer? Dr. Kingwell That's the good news part, yeah. And it does mean that, becausewe're not seeing a change in incidence, the most likely explanationis that the survival is better. People are surviving longer withMS. We're seeing an increase in survival for the whole population,but we're also seeing an increase in survival for people withMS. MSDF What about the gender ratio in terms of prevalence but also interms of survival? Dr. Kingwell We're seeing a gradual increase in the number of women relativeto men in prevalence. That's most likely due to the fact that womendo survive longer than men, on average, of course that's highlyvariable. But on average, they survive longer than men. And so, ifyou've got an aging population and three-quarters of the peoplewith MS are women, then you're going to find the number of womenare increasing. MSDF How did the socioeconomic status affect the findings? Dr. Kingwell Yeah, so we did actually look at socioeconomic status. It wasmeasured at the neighborhood level, so not the individual level.It's linked into the databases by postal code. We did find thatthere were more people with MS in the higher levels ofsocioeconomic status, but the absolute differences were not thatgreat. And, when we looked at this, it was not linked or adjustedfor other factors. So there's so many things that can be attachedto socioeconomic status and, of course, age is one of them, andyour age is greatly related to whether you have MS or not. And so,there are other possible explanations, so we don't put a lot ofemphasis on that. When we look at socioeconomic status, we reallythink that you need to design a study specifically to look atthat. MSDF Could you look at the use of disease-modifying drugs accordingto socioeconomic status? Dr. Kingwell We could, and we have actually looked at that in other studies.Again, as a kind of an adjustment factor or something to bear inmind when we're looking at lots of variables at once, we findthere's the same kind of trend that people in the higher levelstend to be on drug more often. But again, the absolute numbers arevery small, and it could totally be related to age or other factorsthat are not adjusted in. MSDF Were the data there to be able to look at early initiation ofdisease-modifying drugs and any effects it may have had? Dr. Kingwell Well for this particular study – in the incidence and prevalencestudy – we looked at just whether people had ever had drug. Welooked at the incident population to see if they'd had it in thelast three years or so—that's the three years from their firstclaim, which is close to when they're first diagnosed or recognizedas having MS. And for the prevalent population, we looked atwhether they'd ever had MS. So we were able to tell that about athird of the cases had had a disease-modifying drug. And this studydid start way back in the early 90s and then mid-90s for theincidence cases. So, you would expect it to be a lower rate becausethe drugs were just starting to become available in the mid-90s. Sowe didn't look at the actual start date of the drug for thisparticular study; we certainly are able to look at that because wehave access to the databases to look at those kinds of questions,and we are looking at those kinds of questions in otherstudies. MSDF Can you put your findings in context to other studies at otherlatitudes, locals, healthcare systems? Dr. Kingwell Yeah, that's a complicated question. Certainly as studies aresimilar to the findings from some other studies. In particular, inCanada, there's been some very similar studies done in Manitoba andNova Scotia where we've used exactly the same algorithm that wasvalidated in those provinces led by Dr. Ruth Ann Marrie from theUniversity of Manitoba. So, we found that prevalence and incidenceestimates are very similar, and the findings and the change overtime are also very comparable. When we look at some of the othercountries, there are some similar findings in other places, butthey vary a lot. When it comes to latitude, of course, we didn'thave a big latitude gradient in our study; we were just looking inBC, and most of the people in BC live in one area around they'reconcentrated in the south of the province. But certainly there's alot of variation in findings. But in order to get a look at thechange over time, you really need to look within the samepopulation on more than one occasion rather than comparing betweenpopulations over time. It's really difficult to make thatcomparison. MSDF Do you have a particularly good situation in BC in that you canlink databases of diagnostic codes, physician visits,hospitalizations, pharmacy benefits, things like that that may notexist in other places with a less coordinated system? Dr. Kingwell Yeah, definitely. We are in a situation where we have access tosome amazing databases. Many of the provinces in Canada have thesame or similar databases, so it is like that. We also have thegreat situation that we have a clinical database in BC too wherewe've been collecting data on MS patients over a very long periodof time. And we can link that data into the administrativedatabases, so we have the depth of the clinical data that we canlink in the breadth of the administrative data, which has reallyput us in a very strong position to look at these long-termfollowup studies. MSDF Is it pretty smooth to be able to delve into these databases, ordo you have any regulatory barriers like, in the US, we have allthese HIPAA things. Do you have a problem with de-identifying oranything like that? Dr. Kingwell It's certainly not smooth. It can actually take us several yearsto access this data. It's a long process. It's a lot of paperworkfor all of the reasons that…or some of the reasons you justmentioned. The data is actually all handled through…when we're atUBC, it's handled through Population Data BC, which is kind of thecenter between the Ministry of Health and the databases. And theystrip all the identifiers off, so that by the time we receive anydata … we, of course, have to go through a lot of privacy concernsand justification before we get any data sets. All the names andthe numbers are removed, so that we don't know who anybody is inour database. Even when we're linking our clinical data, of course,everything is completely anonymized by the time we work on anythinglike that. MSDF What kind of conclusions can you draw from what you've found sofar? Dr. Kingwell One of the main conclusions, I think, is that the incidentpopulation has leveled off, apparently, in BC. We started measuringincidence in 1996, and it's possible there were changes inincidence before that, but we can say that in the last 13 years –up to 2008 – that the number of cases has leveled off, which isgood news it's not increasing. We also can say that the number ofprevalent cases, on the other hand, is increasing a lot, so thatthe services need to be aware of that that there's going to be ademand on the healthcare system, there already is. And also thatour results are very similar to as seen in other parts of Canadaand comparable. The other main conclusion I would draw is that this study reallyshows how you can utilize these types of databases and reliablealgorithms and ways of identifying people with MS in order tomonitor the number of people and also changes over time. And alsocan give us some information about the people with MS and whatkinds of drugs they're taking because we're linked into thePharmaNet databases, and we can do that too. So there's lots ofquestions we can answer about the population in BritishColumbia. [transition music] MSDF Thank you for listening to Episode Seventy-five of MultipleSclerosis Discovery. This podcast was produced by the MS DiscoveryForum, MSDF, the premier source of independent news and informationon MS research. MSDF’s executive editor is Carol Cruzan Morton.Msdiscovery.org is part of the nonprofit Accelerated Cure Projectfor 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 notyet known about the causes of MS and related conditions, theirpathological mechanisms, and potential ways to intervene. Bycommunicating this information in a way that builds bridges amongdifferent disciplines, we hope to open new routes towardsignificant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion onone of our online forums or send comments, criticisms, andsuggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music] Host – Dan Keller Hello, and welcome to Episode Seventy-five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Today's interview features Elaine Kingwell, a research associate at the University of British Columbia in Canada. She and her colleagues have gathered and recently published incidence and prevalence figures for people with MS in the province. I spoke with Dr. Kingwell at the ECTRIMS meeting in Barcelona in October to find out the reason for the study and to explore the changing trends she found and their significance. Interviewer – Dan Keller What prompted you to do this study? Interviewee – Elaine Kingwell In British Columbia, we know that Canada has got a high incidence and prevalence rate of MS, but we don't actually have the numbers, so we've been doing a lot of research on MS in British Columbia for many, many years. But we don't have the incidence numbers for BC, and also the prevalence is out of date – the estimates that we have – so it really was time to get an idea on how many people we have in BC. And also, we wanted to look at change over time, and we have access to some amazing administrative databases in BC and also had some algorithms that we could use that have been validated, so that we could identify people with MS in the databases. MSDF Why are these numbers important? Dr. Kingwell It's important for lots of different reasons. For instance, it's important to monitor trends over time. We're able to do that in BC, because we have data going back several years. And so, it's important to see if populations are changing, so that we can get some clues about whether environmental factors might be changing. And also, for the prevalence estimates, it's important to know how many people have MS in the province, so that healthcare planning can be done wisely and resources. MSDF How do you go about looking at this? Dr. Kingwell So as I mentioned, we did use the health administrative databases in BC, which are big databases that collect data on the whole population. A number of different databases were combined, including hospital admissions and physician visits. It's all claims data, so that when someone goes to see their physician, a billing claim gets put in with their diagnosis. So we use these codes to identify people with MS. And we basically estimated the number of people with MS [over] several years – one year at a time – so that we could look at change over time for prevalence. And we also estimated the incidence, the number of new cases each year, starting in '96 right up until 2008. MSDF What did you find in terms of incidence and prevalence? Dr. Kingwell Well we found the incidence and prevalence are both high. The incidence was around 7.8 per 100,000 per year, and the prevalence was around 180 to 200 per 100,000 in 2008. So they were both high, what is relatively high compared to other places in the world and similar to rates that have been found in Europe, in Northern Europe, and other parts of Canada, as well. MSDF And the prevalence is increasing over time? Dr. Kingwell Yeah, we found that it increased quite significantly by about 4.7% per year, so a big increase. It also shifted in the predominant age of people, so that the peak prevalence age was around in the mid-40s in the 1990s, and it's now shifted up into the mid-50s. So the population of people with MS is getting older in BC. We also saw with incidence … quite differently, the incidence was not changing over time, so it stayed relatively stable; it did fluctuate as incidence always does. But over time, on average, it stayed the same. MSDF Are those two pieces combined—increasing prevalence and older age—good news? Dr. Kingwell I don't know if any of it's good news. It means that we have an older population that are probably requiring more care, as they get older, for the MS, as well as, of course, comorbidities they may have. So, it's certainly something that healthcare planners need to be aware of. And we have an aging population, in general, in Canada, as we do in other parts of the world, but we have a lot more people with MS at an older age. MSDF But doesn't that mean they're surviving longer? Dr. Kingwell That's the good news part, yeah. And it does mean that, because we're not seeing a change in incidence, the most likely explanation is that the survival is better. People are surviving longer with MS. We're seeing an increase in survival for the whole population, but we're also seeing an increase in survival for people with MS. MSDF What about the gender ratio in terms of prevalence but also in terms of survival? Dr. Kingwell We're seeing a gradual increase in the number of women relative to men in prevalence. That's most likely due to the fact that women do survive longer than men, on average, of course that's highly variable. But on average, they survive longer than men. And so, if you've got an aging population and three-quarters of the people with MS are women, then you're going to find the number of women are increasing. MSDF How did the socioeconomic status affect the findings? Dr. Kingwell Yeah, so we did actually look at socioeconomic status. It was measured at the neighborhood level, so not the individual level. It's linked into the databases by postal code. We did find that there were more people with MS in the higher levels of socioeconomic status, but the absolute differences were not that great. And, when we looked at this, it was not linked or adjusted for other factors. So there's so many things that can be attached to socioeconomic status and, of course, age is one of them, and your age is greatly related to whether you have MS or not. And so, there are other possible explanations, so we don't put a lot of emphasis on that. When we look at socioeconomic status, we really think that you need to design a study specifically to look at that. MSDF Could you look at the use of disease-modifying drugs according to socioeconomic status? Dr. Kingwell We could, and we have actually looked at that in other studies. Again, as a kind of an adjustment factor or something to bear in mind when we're looking at lots of variables at once, we find there's the same kind of trend that people in the higher levels tend to be on drug more often. But again, the absolute numbers are very small, and it could totally be related to age or other factors that are not adjusted in. MSDF Were the data there to be able to look at early initiation of disease-modifying drugs and any effects it may have had? Dr. Kingwell Well for this particular study – in the incidence and prevalence study – we looked at just whether people had ever had drug. We looked at the incident population to see if they'd had it in the last three years or so—that's the three years from their first claim, which is close to when they're first diagnosed or recognized as having MS. And for the prevalent population, we looked at whether they'd ever had MS. So we were able to tell that about a third of the cases had had a disease-modifying drug. And this study did start way back in the early 90s and then mid-90s for the incidence cases. So, you would expect it to be a lower rate because the drugs were just starting to become available in the mid-90s. So we didn't look at the actual start date of the drug for this particular study; we certainly are able to look at that because we have access to the databases to look at those kinds of questions, and we are looking at those kinds of questions in other studies. MSDF Can you put your findings in context to other studies at other latitudes, locals, healthcare systems? Dr. Kingwell Yeah, that's a complicated question. Certainly as studies are similar to the findings from some other studies. In particular, in Canada, there's been some very similar studies done in Manitoba and Nova Scotia where we've used exactly the same algorithm that was validated in those provinces led by Dr. Ruth Ann Marrie from the University of Manitoba. So, we found that prevalence and incidence estimates are very similar, and the findings and the change over time are also very comparable. When we look at some of the other countries, there are some similar findings in other places, but they vary a lot. When it comes to latitude, of course, we didn't have a big latitude gradient in our study; we were just looking in BC, and most of the people in BC live in one area around they're concentrated in the south of the province. But certainly there's a lot of variation in findings. But in order to get a look at the change over time, you really need to look within the same population on more than one occasion rather than comparing between populations over time. It's really difficult to make that comparison. MSDF Do you have a particularly good situation in BC in that you can link databases of diagnostic codes, physician visits, hospitalizations, pharmacy benefits, things like that that may not exist in other places with a less coordinated system? Dr. Kingwell Yeah, definitely. We are in a situation where we have access to some amazing databases. Many of the provinces in Canada have the same or similar databases, so it is like that. We also have the great situation that we have a clinical database in BC too where we've been collecting data on MS patients over a very long period of time. And we can link that data into the administrative databases, so we have the depth of the clinical data that we can link in the breadth of the administrative data, which has really put us in a very strong position to look at these long-term followup studies. MSDF Is it pretty smooth to be able to delve into these databases, or do you have any regulatory barriers like, in the US, we have all these HIPAA things. Do you have a problem with de-identifying or anything like that? Dr. Kingwell It's certainly not smooth. It can actually take us several years to access this data. It's a long process. It's a lot of paperwork for all of the reasons that…or some of the reasons you just mentioned. The data is actually all handled through…when we're at UBC, it's handled through Population Data BC, which is kind of the center between the Ministry of Health and the databases. And they strip all the identifiers off, so that by the time we receive any data … we, of course, have to go through a lot of privacy concerns and justification before we get any data sets. All the names and the numbers are removed, so that we don't know who anybody is in our database. Even when we're linking our clinical data, of course, everything is completely anonymized by the time we work on anything like that. MSDF What kind of conclusions can you draw from what you've found so far? Dr. Kingwell One of the main conclusions, I think, is that the incident population has leveled off, apparently, in BC. We started measuring incidence in 1996, and it's possible there were changes in incidence before that, but we can say that in the last 13 years – up to 2008 – that the number of cases has leveled off, which is good news it's not increasing. We also can say that the number of prevalent cases, on the other hand, is increasing a lot, so that the services need to be aware of that that there's going to be a demand on the healthcare system, there already is. And also that our results are very similar to as seen in other parts of Canada and comparable. The other main conclusion I would draw is that this study really shows how you can utilize these types of databases and reliable algorithms and ways of identifying people with MS in order to monitor the number of people and also changes over time. And also can give us some information about the people with MS and what kinds of drugs they're taking because we're linked into the PharmaNet databases, and we can do that too. So there's lots of questions we can answer about the population in British Columbia. [transition music] MSDF Thank you for listening to Episode Seventy-five 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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 <a href="mailto:editor@msdiscovery.org">editor@msdiscovery.org</a>. For Multiple Sclerosis Discovery, I'm Dan Keller.

Multiple Sclerosis Discovery -- Episode 75 with Dr. Elaine Kingwell

Hans Lassmann

[intro music]   Host – Dan Keller Hello, and welcome to Episode Forty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features the second part of a two-part interview with Dr. Hans Lassmann, who discusses oxidative stress as a mechanism of tissue injury in progressive MS. But first, here are some of the new items in the MS Discovery Forum.   According to our curated list of the latest scientific articles related to MS, 56 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One of them includes revised guidelines from the Association of British Neurologists on prescribing disease-modifying treatments for MS. The other describes an international consensus on diagnostic criteria for neuromyelitis optica and related disorders.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of June, we added 10 new trials, we updated information on 6 other trials, and we’ve added 67 other pieces of information. The drugs with important additions and changes are alemtuzumab, cladribine, cyclophosphamide, daclizumab, dalfampridine, dimethyl fumarate, fingolimod, glatiramer acetate, idebenone, interferon beta-1a, interferon beta-1b, laquinimod, rituximab, natalizumab, and ocrelizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   [transition music]   Now to our interview with Dr. Hans Lassmann of the Medical University of Vienna in Austria. Last week we spoke about biomarkers, and this week we’ll discuss oxidative stress as a mechanism of tissue injury in progressive MS.   Interviewer – Dan Keller What's interesting there at this point?   Interviewee – Hans Lassmann The big problem in multiple sclerosis is that we have very good therapies for the early stage of multiple sclerosis, and they all interfere with the inflammation and the immune system. But when the patients have reached a progressive stage of the disease, then all these therapies are currently noneffective. So the key points were to define what are actually the mechanisms of inflammation and tissue injury in the progressive stage of multiple sclerosis, and there are still a lot of open questions. It is clear that even in the progressive stage there is an inflammatory process, and this inflammatory process is associated with active tissue damage. From that certainly we cannot definitely conclude that the inflammatory process drives the tissue damage; however, it's clearly associated.   Now, we were then very interested to see what are the mechanisms of tissue injury. And this involves, first of all, studies on the nature of the inflammatory process. And here what we found is that in the progressive stage of multiple sclerosis the inflammatory reaction is predominantly hidden within the central nervous system behind a repaired blood-brain barrier. So that means this inflammatory process is no longer really under control of the peripheral immune system. And also, the therapies which we have currently mainly interfere with immune functions in the periphery, and they have actually very little access to an inflammatory process which is taking place within the central nervous system.   So that means that new drugs have to be developed and tested which actually exert an antiinflammatory or some neuroprotective action directly within the central nervous system. And there are now a number of the large companies fully engaged in this process, and there are new candidates coming up, which will have to be tested in proper clinical trials in patients with progressive MS.   The second question, which we have mainly addressed during the last year, was the mechanisms how the tissue damage is induced. And in this regard, we concentrated on cortical lesions in multiple sclerosis, which are very, very specific for the disease. And we compared in gene expression studies these cortical lesions not only with normal controls but also with inflammatory controls. And we used here a disease which has very similar inflammatory infiltrates, as you see in multiple sclerosis brain, but doesn't lead to the MS typical demyelination, and this is tuberculous meningitis. And then we also used as a control for neurodegeneration Alzheimer's disease just to see what is a reaction in gene expression due to degeneration of neurons.   And when we did that, actually it was interesting to see that there were relatively few genes which were specifically changed in their expression in multiple sclerosis patients in comparison to these other disease controls. And these genes were, in part, associated with inflammatory processes. A large part of the genes were associated with a more or less single pathway of tissue injury, which includes oxidative injury leading to mitochondrial injury and its secondary consequences. And then, there were also some genes involved which were MS specifically related to tissue regenerative processes.   We have then looked in further detail, and it now turns out that this cascade of oxidative injury leading to mitochondrial dysfunction and with that to a state of energy deficiency is actually one of the major driving forces of neurodegeneration in the progressive stage of multiple sclerosis. So this oxidative injury is, in part, driven by the inflammatory process. But it is also augmented by factors which are related to age of the patients and to the accumulation of lesion burden due to the chronic disease.   So here the central portion is the activation of microglial cells which can, on the one hand, be activated in the inflammatory process, but they also get activated when tissue is damaged due to completely different causes. And they also get activated just simply in an aging process. And in this respect, then they get activated in a pro-oxidative form. And then, the tissue injury can further be propagated through additional age-related changes, including, for instance, the accumulation of iron in the central nervous system and also obviously the chronic microglia activation due to retrograded and anterograde degeneration when lesions already present within the central nervous system.   MSDF Are the microglia just overdoing what they normally would be expected to do? I mean macrophages use oxidative systems to get rid of pathogens.   Dr. Lassmann Yeah, this is absolutely true. That is a key element of microphage and microglia function. And this is exaggerated in both the aging process, as well as in the chronic inflammatory state like multiple sclerosis. The question only remains what is really driving this massive microglia activation in MS, which is even more and more pronounced than even in very severe other inflammatory diseases of the central nervous system.   MSDF Can you identify or has anyone identified factors that disappear with aging or are increased with aging that may lead to this state?   Dr. Lassmann That is also not really very clear now. I think one interesting aspect is that this massive microglia activation in the direction of oxidative stress you don't really see in rodents and even not in primate experimental models; you see it in humans. And the reason for that is not completely clear, but it may very well be that environmental factors actually play a major role. I think one of the major differences between humans and these experimental animals is that the experimental animals are genetically very homogenous; they are generally inbred strains. And the second is that they are kept under a very constant pathogen-free environment. And this is very different in a human situation, and these animals also have a very … standardized diet. Now this is completely different in human situations, and there are certainly many factors, including peripheral infections but also including diet changes, and many other factors can actually have an influence on microglia in the central nervous system.   MSDF And experimental animals also have optimized diets; people have figured out the nutrients they need I suppose. They're getting a good diet compared to people who knows how everybody is eating these days.   Dr. Lassmann Yes, that's absolutely the case. They have a standardized diet, and they certainly are not exposed to very much of the fats, for instance, which we take into when we eat fat pork meat.   MSDF Do any of the antiinflammatory agents modify the course? Things like lipoxygenase inhibitors and things like that? Not necessarily NSAIDs but now that you bring up fats?   Dr. Lassmann I think there is certainly an aspect behind that is that lifestyle control certainly has a beneficial effect. One can just see that in a way that environmental lifestyle factors, which actually also increase the risk for vascular injury or other things, will be certainly deleterious in a patient with progressive multiple sclerosis where the brain is already damaged due to the original disease process and where the functional reserve capacity of the brain is already partially exhausted. So in that case, even minor changes – which are related to lifestyle or aging – will have a more dramatic effect in such a brain than in a normal aging brain.   MSDF Finally, circling back to something you said at the beginning, in progressive MS I think you said that the immune system the cells have now entered the brain, but the blood-brain barrier has – once again – become a real barrier. So do you really have an immune response running autonomously in the brain no longer subject to any sort of peripheral control?   Dr. Lassmann Yeah, this is certainly a very important open question. We know that the inflammatory cells are present within the central nervous system in the progressive stage and that they are associated with the degenerative processes and the demyelination. We know currently very little about the exact phenotype and functional activation of the inflammatory cells within the central nervous system. This is actually a large research project, which is running currently in my lab, to try to define exactly the functional polarization of the cells within the MS lesions and to determine their activation state, their proliferation rate, and so on.   What we can say from our preliminary data on that is that they are present, they are in part activated. They also express certain transcription factors, which would be associated with a proinflammatory state in the central nervous system. However, overall all these changes are relatively small in comparison to an acute, for instance, virus-induced inflammatory process in the brain. So it seems to be that there is a slow and low-grade activation state which, however, could be completely sufficient to drive the degenerative process in the patients. But that is not the final answer yet.   [transition music]   MSDF Thank you for listening to Episode Forty-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 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.    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.   [outro music]

[intro music] Host – Dan Keller Hello, and welcome to Episode Forty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features the second part of a two-part interview with Dr. Hans Lassmann, who discusses oxidative stress as a mechanism of tissue injury in progressive MS. But first, here are some of the new items in the MS Discovery Forum. According to our curated list of the latest scientific articles related to MS, 56 such articles were published last week. To see the list, go to <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a> and click on Papers. We selected two of those papers as Editors’ Picks. One of them includes revised guidelines from the <a href="http://www.msdiscovery.org/papers/biblio/19772-association-british-neurologists-revised-2015-guidelines-prescribing-disease" rel="nofollow" target="_blank">Association of British Neurologists</a> on prescribing disease-modifying treatments for MS. The other describes an international consensus on diagnostic criteria for neuromyelitis optica and related disorders. Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of June, we added 10 new trials, we updated information on 6 other trials, and we’ve added 67 other pieces of information. The drugs with important additions and changes are alemtuzumab, cladribine, cyclophosphamide, daclizumab, dalfampridine, dimethyl fumarate, fingolimod, glatiramer acetate, idebenone, interferon beta-1a, interferon beta-1b, laquinimod, rituximab, natalizumab, and ocrelizumab. To find information on all 44 compounds, visit <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a> and click first on Research Resources and then on Drug-Development Pipeline. [transition music] Now to our interview with Dr. Hans Lassmann of the Medical University of Vienna in Austria. Last week we spoke about biomarkers, and this week we’ll discuss oxidative stress as a mechanism of tissue injury in progressive MS. Interviewer – Dan Keller What's interesting there at this point? Interviewee – Hans Lassmann The big problem in multiple sclerosis is that we have very good therapies for the early stage of multiple sclerosis, and they all interfere with the inflammation and the immune system. But when the patients have reached a progressive stage of the disease, then all these therapies are currently noneffective. So the key points were to define what are actually the mechanisms of inflammation and tissue injury in the progressive stage of multiple sclerosis, and there are still a lot of open questions. It is clear that even in the progressive stage there is an inflammatory process, and this inflammatory process is associated with active tissue damage. From that certainly we cannot definitely conclude that the inflammatory process drives the tissue damage; however, it's clearly associated. Now, we were then very interested to see what are the mechanisms of tissue injury. And this involves, first of all, studies on the nature of the inflammatory process. And here what we found is that in the progressive stage of multiple sclerosis the inflammatory reaction is predominantly hidden within the central nervous system behind a repaired blood-brain barrier. So that means this inflammatory process is no longer really under control of the peripheral immune system. And also, the therapies which we have currently mainly interfere with immune functions in the periphery, and they have actually very little access to an inflammatory process which is taking place within the central nervous system. So that means that new drugs have to be developed and tested which actually exert an antiinflammatory or some neuroprotective action directly within the central nervous system. And there are now a number of the large companies fully engaged in this process, and there are new candidates coming up, which will have to be tested in proper clinical trials in patients with progressive MS. The second question, which we have mainly addressed during the last year, was the mechanisms how the tissue damage is induced. And in this regard, we concentrated on cortical lesions in multiple sclerosis, which are very, very specific for the disease. And we compared in gene expression studies these cortical lesions not only with normal controls but also with inflammatory controls. And we used here a disease which has very similar inflammatory infiltrates, as you see in multiple sclerosis brain, but doesn't lead to the MS typical demyelination, and this is tuberculous meningitis. And then we also used as a control for neurodegeneration Alzheimer's disease just to see what is a reaction in gene expression due to degeneration of neurons. And when we did that, actually it was interesting to see that there were relatively few genes which were specifically changed in their expression in multiple sclerosis patients in comparison to these other disease controls. And these genes were, in part, associated with inflammatory processes. A large part of the genes were associated with a more or less single pathway of tissue injury, which includes oxidative injury leading to mitochondrial injury and its secondary consequences. And then, there were also some genes involved which were MS specifically related to tissue regenerative processes. We have then looked in further detail, and it now turns out that this cascade of oxidative injury leading to mitochondrial dysfunction and with that to a state of energy deficiency is actually one of the major driving forces of neurodegeneration in the progressive stage of multiple sclerosis. So this oxidative injury is, in part, driven by the inflammatory process. But it is also augmented by factors which are related to age of the patients and to the accumulation of lesion burden due to the chronic disease. So here the central portion is the activation of microglial cells which can, on the one hand, be activated in the inflammatory process, but they also get activated when tissue is damaged due to completely different causes. And they also get activated just simply in an aging process. And in this respect, then they get activated in a pro-oxidative form. And then, the tissue injury can further be propagated through additional age-related changes, including, for instance, the accumulation of iron in the central nervous system and also obviously the chronic microglia activation due to retrograded and anterograde degeneration when lesions already present within the central nervous system. MSDF Are the microglia just overdoing what they normally would be expected to do? I mean macrophages use oxidative systems to get rid of pathogens. Dr. Lassmann Yeah, this is absolutely true. That is a key element of microphage and microglia function. And this is exaggerated in both the aging process, as well as in the chronic inflammatory state like multiple sclerosis. The question only remains what is really driving this massive microglia activation in MS, which is even more and more pronounced than even in very severe other inflammatory diseases of the central nervous system. MSDF Can you identify or has anyone identified factors that disappear with aging or are increased with aging that may lead to this state? Dr. Lassmann That is also not really very clear now. I think one interesting aspect is that this massive microglia activation in the direction of oxidative stress you don't really see in rodents and even not in primate experimental models; you see it in humans. And the reason for that is not completely clear, but it may very well be that environmental factors actually play a major role. I think one of the major differences between humans and these experimental animals is that the experimental animals are genetically very homogenous; they are generally inbred strains. And the second is that they are kept under a very constant pathogen-free environment. And this is very different in a human situation, and these animals also have a very … standardized diet. Now this is completely different in human situations, and there are certainly many factors, including peripheral infections but also including diet changes, and many other factors can actually have an influence on microglia in the central nervous system. MSDF And experimental animals also have optimized diets; people have figured out the nutrients they need I suppose. They're getting a good diet compared to people who knows how everybody is eating these days. Dr. Lassmann Yes, that's absolutely the case. They have a standardized diet, and they certainly are not exposed to very much of the fats, for instance, which we take into when we eat fat pork meat. MSDF Do any of the antiinflammatory agents modify the course? Things like lipoxygenase inhibitors and things like that? Not necessarily NSAIDs but now that you bring up fats? Dr. Lassmann I think there is certainly an aspect behind that is that lifestyle control certainly has a beneficial effect. One can just see that in a way that environmental lifestyle factors, which actually also increase the risk for vascular injury or other things, will be certainly deleterious in a patient with progressive multiple sclerosis where the brain is already damaged due to the original disease process and where the functional reserve capacity of the brain is already partially exhausted. So in that case, even minor changes – which are related to lifestyle or aging – will have a more dramatic effect in such a brain than in a normal aging brain. MSDF Finally, circling back to something you said at the beginning, in progressive MS I think you said that the immune system the cells have now entered the brain, but the blood-brain barrier has – once again – become a real barrier. So do you really have an immune response running autonomously in the brain no longer subject to any sort of peripheral control? Dr. Lassmann Yeah, this is certainly a very important open question. We know that the inflammatory cells are present within the central nervous system in the progressive stage and that they are associated with the degenerative processes and the demyelination. We know currently very little about the exact phenotype and functional activation of the inflammatory cells within the central nervous system. This is actually a large research project, which is running currently in my lab, to try to define exactly the functional polarization of the cells within the MS lesions and to determine their activation state, their proliferation rate, and so on. What we can say from our preliminary data on that is that they are present, they are in part activated. They also express certain transcription factors, which would be associated with a proinflammatory state in the central nervous system. However, overall all these changes are relatively small in comparison to an acute, for instance, virus-induced inflammatory process in the brain. So it seems to be that there is a slow and low-grade activation state which, however, could be completely sufficient to drive the degenerative process in the patients. But that is not the final answer yet. [transition music] MSDF Thank you for listening to Episode Forty-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 Robert Finn. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. [outro music]

Multiple Sclerosis Discovery -- Episode 47 with Dr. Hans Lassmann (Part 2)

[intro music]   Hello, and welcome to Episode Forty-Three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. May Han, who discusses issues related to following patients with clinically isolated syndrome. But first, here are some new items on the MS Discovery Forum.   We recently posted an article on a surprisingly strong association between a certain gene variant and non-response to interferon beta in people with RRMS. The study is a meta-analysis of three independent cohorts in Italy, France, and the U.S., and it comes from the labs of Philip De Jager and Filippo Boneschi. You’ll find this article by clicking first on News &amp; Future Directions and then on New Findings.   This past week we published the latest in our series of data visualizations. This month’s visualization is a series of word clouds illustrating how key terms in the MS clinical-trial literature have changed between 1993 and 2014. To find this visualization, first click on Research Resources, then on Data Visualizations, and then on Word Cloud.   According to our curated list of the latest scientific articles related to MS, 30 such articles were published last week. To see last week’s list, go to msdiscovery.org and click on Papers. We selected one of those papers as an Editors’ Pick. It’s study of the association between depressive symptoms and walking ability in people with RRMS.   Are you attending the annual meeting of the Consortium of Multiple Sclerosis Centers in Indianapolis this week? If so, please come visit us at the Accelerated Cure Project’s booth. We’ll be demonstrating some of our latest data visualizations along with other features of the MS Discovery Forum. You’ll find the booth in the hallway close to the main entrance to the exhibit hall, and we look forward to meeting you.   [transition music]   Now to the interview. Dr. May Han is an assistant professor in Neurology and Neurological Sciences at Stanford University. I spoke with her about following patients with clinically isolated syndrome, as well as her approach to patients with MS across the course of their disease. But first, she addressed some unmet needs in MS.   Interviewer – Dan Keller Dr. Han, you told me that we’re good at the diagnosis of MS in general, but still there’s a vast area that we don’t know about. What are some of those unmet needs?   Interviewee – May Han So it’s been over 150 years since Charcot first described multiple sclerosis, and I have to say that we have come a long way in understanding and treating this disease. But as you have mentioned, there are still areas where we have no idea, there are gaps in our understanding of this disease. One of these areas that is clinically very relevant and is very challenging is in the day and age where we have a dozen disease-modifying therapies for MS patients, and yet we don’t have a good way, a scientific way of selecting the most effective therapy for a particular patient is what I find quite challenging in the clinics.   MSDF What gives you clues or how do you approach this essentially algorithm of deciding where to begin and how to move on to other medications if the first one’s not working well?   Dr. Han Currently, of course, we follow the guidelines. So for any relapsing-remitting patients, our logic is to go for the safest medication that we think are going to be most effective, which means we go with the first-line therapies. So we have the convention ABC drugs such as beta-interferon family of therapies and glatiramer acetate, plus the newer oral medications such as Tecfidera and fingolimod or Gilenya that we use for the first-line therapy; not a whole lot of science in choosing these medications for a particular patient, but what we would do is initially we would educate the patient about these disease-modifying therapies and then select the medication together with the patient to see what would be most appropriate and the patient could be most compliant for a particular medication.   To give you an example, certain patients have aversion to needles, in which case we go with the oral medications. We also have in mind what the preference of the patient, such as whether they could be able to follow it through for years on end with a particular medication. Ideally, we would like to have zero relapses or MRI activity when a patient is on a disease-modifying therapy, but as we all know none of these medications are 100% foolproof, and they can still have some degree of MRI activity or infrequent relapses on this medication. However, if a patient is clearly not responding to a therapy either in terms of not being compliant, being intolerant to the mode of administration, or if they’re having worsening disease activity, we would decide to go on to stronger medications or second-line of therapy.   MSDF Do you initially discuss a plan of action, a stepwise pattern of medication prescribing, or do you wait until something needs to be changed to bring it up with patients?   Dr. Han That is a very good question. I’m sure it varies among clinicians, but, however, I would like to paint the picture to the patient the best that I can. So, let’s say for example, if a patient who is a newly-diagnosed MS patient who has very few MRI lesions, I would discuss with them what the most appropriate medication could be. We would decide a medication and we would also give them an outline of what the followup plan would be and when we would be deciding to switch to a different therapy, and if so, which medications would be most likely appropriate for them, and also how we would monitor them. So by doing this, it gives the patient a better picture of their path and what to watch out for, and in my experience we have a better outcome with these patients.   MSDF Do you find that once you achieve success in limiting relapses and lesions that the medication is fairly stable for a long time, or do you have to have an armamentarium that you keep moving through?   Dr. Han So my model if a patient is responding to a medication, unless they have other side effects or reasons to switch, I would like to get the most mileage out of the medication as much as I can for a particular patient. However, if a patient, for example, has JC virus positivity, in which case even if they’re responding to Tysabri really well, there is a cutoff time point where we have to sit down and consider whether this patient should be switched onto a different medication to prevent the development of opportunistic brain inflammation such as PML, in which case what the next medication would be. And so we would sit down and talk the pros and cons; this conversation was started even before the patient was started on medication, but that would be the checkpoint.   MSDF I suppose another aspect is do medications start to fail patients even after a long period of stability, or do they usually continue to be stable if the medication is working for some period of time?   Dr. Han This is also a very pertinent question. MS patients, as we know, is very heterogeneous. Some of the patients, if they are stable on a medication, they would continue to do well on a medication for several years up to decades. However, some patients would have an initial improvement or stabilization of their disease, however in the later stages they would have worsening disease. And it is really unclear whether because their disease per se is getting worse or whether their body is rejecting the medication secondary to the immune response. And that is also one area that we should do research on to better understand this condition.   MSDF When you say reject the medication, are you actually referring to an immune rejection such as with, say, interferon; I would think it would be less likely they would actually mount an immune response to a small molecule. Am I clear on that or not?   Dr. Han I think we have quite a lot of information in terms of beta interferon therapies, because we clearly know that patients do tend to develop antibodies against beta interferon, especially the therapy. However, even that we don’t really know if all those antibodies are attacking the drug or whether they are just there. So just by finding the antibody alone is not enough to say that the patient is not responding to it; I think we need to use it hand-in-hand with the clinical response as well as the MRI activity.   Getting to the second part of your question whether there’ll be less intolerance or rejection to the therapy if it were small molecules, but I don’t think we understand at the cellular or molecular level. For small molecules there could be receptor down-regulation, there could be availability or cellular sequestration, or even the prodrug being converted to an active drug, or how the breakdown process occurs. So when a patient does not respond anymore to a medication, we just know that the clinical response is worse, and we don’t really know whether it is because the disease activity has worsened or other aspects, pharmacodynamic or kinetic aspects of the system has changed in such a way that they no longer respond. So, again, we do need to do more research to have a better understanding.   MSDF You have called it MS comes in many different flavors. Have you found that any medications are particularly good for different constellations of symptoms, or is everything about equal no matter how they present?   Dr. Han Very good question as well. I think in the experimental models people know that MS, or central system autoimmunity, can have a bias towards one type of inflammation as opposed to the other. For example, some would say that certain medications are better to treat Th1 as opposed to the Th17 type of inflammation, however in human beings there’s no clear-cut Th1 MS or Th17 MS. I don’t think people have done enough studies to clearly decipher the immune profiles of patients. So the answer is we don’t know.   MSDF Finally, let’s talk about the need for biomarkers especially very early in the disease when someone’s presenting with CIS which may or may not become MS. Where does that stand and how acute is the need?   Dr. Han The need is there, especially if you look at it from a patient who just had an initial attack. If you tell them that we don’t really know whether this is a one-time thing or whether you’re going to develop MS, and we’ll have to wait and see for three-plus years. So for these three years, the patient’s life is very much consumed by the “is it going to be MS” kind of question. And it does affect their physical-mental wellbeing as well as their quality of life.   I think we’ve come a long way with the advancement of the MRI studies in such a way that if a patient has MRI lesions together with the first-time attack, we could almost clearly say that this is going to blossom into MS. However, for patients who are radiographically clean and who just had one episode, it would be very, very helpful to have some kind of blood biomarkers to predict whether this could be a single event or whether it could be a central nervous system inflammatory disorder.   MSDF You picked three years as a period of waiting, watching. Are they out of the woods after that, or how late can it blossom into full MS?   Dr. Han It’s always a bell-shaped curve. There are patients who would declare themselves sooner than three years, there are also patients who would take several years before they have the second attack. I have one patient who had an initial attack of optic neuritis and nine years later she had the second attack. During that period, she had had MRI scans for three years which were clean. So, I guess, one is never completely out of the woods, but at the same time it is also not prudent to perform unnecessary tests on a patient.   So I think we have to focus on what is the safety net and pick a period of time, but at the same time it is very important to educate a patient to symptoms to watch out for, how to get help, and to work very closely with the primary care physician or a neurologist so in case the symptoms show up they will not be ignored or delayed to receiving treatment.   MSDF Is there anything we’ve missed or is important to add? I’m sure it’s a gigantic field, but is there anything glaring that should be added?   Dr. Han I would like to encourage people in the field to also focus on the secondary-progressive stage of MS. We know that relapsing-remitting MS patients with or without therapy eventually would end up having secondary-progressive MS, so it’ll be really important to decipher whether during the secondary-progressive stage there is no inflammation but only the early neurodegeneration, or how the immune system and the central nervous system interact and how we can change it, or at least modulate it, to either delay or to prevent neurodegeneration. The third area that I think is very important is to try to understand the regenerative aspects of the central nervous system.   As I have given you the example, if we have two patients who have had similar lesion burden or even lesions that are approximately the same in similar areas, a patient can be severely devastated, neurologically devastated, whereas the other may have minimal neurologic deficits. And we would always say that it depends on the brain reserve, or neural reserve, but we don’t quite know what it is. Is it the stem cells, is it the nervous system being more resistant to insult and how the immune system interacts with it? And I think this is also a big area that we should focus on, of course, to prevent further damage, but also once the damage is done to limit the damage and perhaps to regenerate it. And I think that people always have within themselves the ability to heal.   MSDF Good, thank you.   Dr. Han Thank you.   [transition music]   Thank you for listening to Episode Forty-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 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.   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.      [outro music]

[intro music] Hello, and welcome to Episode Forty-Three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features an interview with Dr. May Han, who discusses issues related to following patients with clinically isolated syndrome. But first, here are some new items on the MS Discovery Forum. We recently posted an article on a surprisingly strong association between a certain gene variant and non-response to interferon beta in people with RRMS. The study is a meta-analysis of three independent cohorts in Italy, France, and the U.S., and it comes from the labs of Philip De Jager and Filippo Boneschi. You’ll find this article by clicking first on News &amp; Future Directions and then on New Findings. This past week we published the latest in our series of data visualizations. This month’s visualization is a series of word clouds illustrating how key terms in the MS clinical-trial literature have changed between 1993 and 2014. To find this visualization, first click on Research Resources, then on Data Visualizations, and then on Word Cloud. According to our curated list of the latest scientific articles related to MS, 30 such articles were published last week. To see last week’s list, go to <a href="http://msdiscovery.org" rel="nofollow" target="_blank">msdiscovery.org</a> and click on Papers. We selected one of those papers as an Editors’ Pick. It’s study of the association between depressive symptoms and walking ability in people with RRMS. Are you attending the annual meeting of the Consortium of Multiple Sclerosis Centers in Indianapolis this week? If so, please come visit us at the Accelerated Cure Project’s booth. We’ll be demonstrating some of our latest data visualizations along with other features of the MS Discovery Forum. You’ll find the booth in the hallway close to the main entrance to the exhibit hall, and we look forward to meeting you. [transition music] Now to the interview. Dr. May Han is an assistant professor in Neurology and Neurological Sciences at Stanford University. I spoke with her about following patients with clinically isolated syndrome, as well as her approach to patients with MS across the course of their disease. But first, she addressed some unmet needs in MS. Interviewer – Dan Keller Dr. Han, you told me that we’re good at the diagnosis of MS in general, but still there’s a vast area that we don’t know about. What are some of those unmet needs? Interviewee – May Han So it’s been over 150 years since Charcot first described multiple sclerosis, and I have to say that we have come a long way in understanding and treating this disease. But as you have mentioned, there are still areas where we have no idea, there are gaps in our understanding of this disease. One of these areas that is clinically very relevant and is very challenging is in the day and age where we have a dozen disease-modifying therapies for MS patients, and yet we don’t have a good way, a scientific way of selecting the most effective therapy for a particular patient is what I find quite challenging in the clinics. MSDF What gives you clues or how do you approach this essentially algorithm of deciding where to begin and how to move on to other medications if the first one’s not working well? Dr. Han Currently, of course, we follow the guidelines. So for any relapsing-remitting patients, our logic is to go for the safest medication that we think are going to be most effective, which means we go with the first-line therapies. So we have the convention ABC drugs such as beta-interferon family of therapies and glatiramer acetate, plus the newer oral medications such as Tecfidera and fingolimod or Gilenya that we use for the first-line therapy; not a whole lot of science in choosing these medications for a particular patient, but what we would do is initially we would educate the patient about these disease-modifying therapies and then select the medication together with the patient to see what would be most appropriate and the patient could be most compliant for a particular medication. To give you an example, certain patients have aversion to needles, in which case we go with the oral medications. We also have in mind what the preference of the patient, such as whether they could be able to follow it through for years on end with a particular medication. Ideally, we would like to have zero relapses or MRI activity when a patient is on a disease-modifying therapy, but as we all know none of these medications are 100% foolproof, and they can still have some degree of MRI activity or infrequent relapses on this medication. However, if a patient is clearly not responding to a therapy either in terms of not being compliant, being intolerant to the mode of administration, or if they’re having worsening disease activity, we would decide to go on to stronger medications or second-line of therapy. MSDF Do you initially discuss a plan of action, a stepwise pattern of medication prescribing, or do you wait until something needs to be changed to bring it up with patients? Dr. Han That is a very good question. I’m sure it varies among clinicians, but, however, I would like to paint the picture to the patient the best that I can. So, let’s say for example, if a patient who is a newly-diagnosed MS patient who has very few MRI lesions, I would discuss with them what the most appropriate medication could be. We would decide a medication and we would also give them an outline of what the followup plan would be and when we would be deciding to switch to a different therapy, and if so, which medications would be most likely appropriate for them, and also how we would monitor them. So by doing this, it gives the patient a better picture of their path and what to watch out for, and in my experience we have a better outcome with these patients. MSDF Do you find that once you achieve success in limiting relapses and lesions that the medication is fairly stable for a long time, or do you have to have an armamentarium that you keep moving through? Dr. Han So my model if a patient is responding to a medication, unless they have other side effects or reasons to switch, I would like to get the most mileage out of the medication as much as I can for a particular patient. However, if a patient, for example, has JC virus positivity, in which case even if they’re responding to Tysabri really well, there is a cutoff time point where we have to sit down and consider whether this patient should be switched onto a different medication to prevent the development of opportunistic brain inflammation such as PML, in which case what the next medication would be. And so we would sit down and talk the pros and cons; this conversation was started even before the patient was started on medication, but that would be the checkpoint. MSDF I suppose another aspect is do medications start to fail patients even after a long period of stability, or do they usually continue to be stable if the medication is working for some period of time? Dr. Han This is also a very pertinent question. MS patients, as we know, is very heterogeneous. Some of the patients, if they are stable on a medication, they would continue to do well on a medication for several years up to decades. However, some patients would have an initial improvement or stabilization of their disease, however in the later stages they would have worsening disease. And it is really unclear whether because their disease per se is getting worse or whether their body is rejecting the medication secondary to the immune response. And that is also one area that we should do research on to better understand this condition. MSDF When you say reject the medication, are you actually referring to an immune rejection such as with, say, interferon; I would think it would be less likely they would actually mount an immune response to a small molecule. Am I clear on that or not? Dr. Han I think we have quite a lot of information in terms of beta interferon therapies, because we clearly know that patients do tend to develop antibodies against beta interferon, especially the therapy. However, even that we don’t really know if all those antibodies are attacking the drug or whether they are just there. So just by finding the antibody alone is not enough to say that the patient is not responding to it; I think we need to use it hand-in-hand with the clinical response as well as the MRI activity. Getting to the second part of your question whether there’ll be less intolerance or rejection to the therapy if it were small molecules, but I don’t think we understand at the cellular or molecular level. For small molecules there could be receptor down-regulation, there could be availability or cellular sequestration, or even the prodrug being converted to an active drug, or how the breakdown process occurs. So when a patient does not respond anymore to a medication, we just know that the clinical response is worse, and we don’t really know whether it is because the disease activity has worsened or other aspects, pharmacodynamic or kinetic aspects of the system has changed in such a way that they no longer respond. So, again, we do need to do more research to have a better understanding. MSDF You have called it MS comes in many different flavors. Have you found that any medications are particularly good for different constellations of symptoms, or is everything about equal no matter how they present? Dr. Han Very good question as well. I think in the experimental models people know that MS, or central system autoimmunity, can have a bias towards one type of inflammation as opposed to the other. For example, some would say that certain medications are better to treat Th1 as opposed to the Th17 type of inflammation, however in human beings there’s no clear-cut Th1 MS or Th17 MS. I don’t think people have done enough studies to clearly decipher the immune profiles of patients. So the answer is we don’t know. MSDF Finally, let’s talk about the need for biomarkers especially very early in the disease when someone’s presenting with CIS which may or may not become MS. Where does that stand and how acute is the need? Dr. Han The need is there, especially if you look at it from a patient who just had an initial attack. If you tell them that we don’t really know whether this is a one-time thing or whether you’re going to develop MS, and we’ll have to wait and see for three-plus years. So for these three years, the patient’s life is very much consumed by the “is it going to be MS” kind of question. And it does affect their physical-mental wellbeing as well as their quality of life. I think we’ve come a long way with the advancement of the MRI studies in such a way that if a patient has MRI lesions together with the first-time attack, we could almost clearly say that this is going to blossom into MS. However, for patients who are radiographically clean and who just had one episode, it would be very, very helpful to have some kind of blood biomarkers to predict whether this could be a single event or whether it could be a central nervous system inflammatory disorder. MSDF You picked three years as a period of waiting, watching. Are they out of the woods after that, or how late can it blossom into full MS? Dr. Han It’s always a bell-shaped curve. There are patients who would declare themselves sooner than three years, there are also patients who would take several years before they have the second attack. I have one patient who had an initial attack of optic neuritis and nine years later she had the second attack. During that period, she had had MRI scans for three years which were clean. So, I guess, one is never completely out of the woods, but at the same time it is also not prudent to perform unnecessary tests on a patient. So I think we have to focus on what is the safety net and pick a period of time, but at the same time it is very important to educate a patient to symptoms to watch out for, how to get help, and to work very closely with the primary care physician or a neurologist so in case the symptoms show up they will not be ignored or delayed to receiving treatment. MSDF Is there anything we’ve missed or is important to add? I’m sure it’s a gigantic field, but is there anything glaring that should be added? Dr. Han I would like to encourage people in the field to also focus on the secondary-progressive stage of MS. We know that relapsing-remitting MS patients with or without therapy eventually would end up having secondary-progressive MS, so it’ll be really important to decipher whether during the secondary-progressive stage there is no inflammation but only the early neurodegeneration, or how the immune system and the central nervous system interact and how we can change it, or at least modulate it, to either delay or to prevent neurodegeneration. The third area that I think is very important is to try to understand the regenerative aspects of the central nervous system. As I have given you the example, if we have two patients who have had similar lesion burden or even lesions that are approximately the same in similar areas, a patient can be severely devastated, neurologically devastated, whereas the other may have minimal neurologic deficits. And we would always say that it depends on the brain reserve, or neural reserve, but we don’t quite know what it is. Is it the stem cells, is it the nervous system being more resistant to insult and how the immune system interacts with it? And I think this is also a big area that we should focus on, of course, to prevent further damage, but also once the damage is done to limit the damage and perhaps to regenerate it. And I think that people always have within themselves the ability to heal. MSDF Good, thank you. Dr. Han Thank you. [transition music] Thank you for listening to Episode Forty-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 Robert Finn. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> 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.  [outro music]

Multiple Sclerosis Discovery -- Episode 43 with Dr. May Han

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