Aksel Siva's guest appearances

Aksel Siva

Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

Medyascope Podcast

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Alan Alda

Tim Kennedy

Richard Cohen

David Baker

Jeffrey Cohen

Michael Levy

Alan Thompson

David Holtzman

Oscar Fernandez

Paul Matthews

Raj Kapoor

Adam Kaplin

Bruce Cree

Lilyana Amezcua

Daniel Hartung

OwlTail

Meraklısına Bilim programının 67. bölümünde Şükran Şençekiçer’in konuğu Bilim Akademisi üyesi ve Cerrahpaşa Tıp Fakültesi Nörobiyoloji Anabilim Dalı öğretim üyesi Aksel Siva’ydı,  Multiple Skleroz hastalığı hakkında bildiklerimizi ve bilmediklerimizi konuştular. Aksel Siva programda MS hastalığı nedir? hastalığın demografisi, belirtiler, tanı koyulmasındaki zorluklar, MRI’ın tanıdaki yeri, hastalığın seyri, yeni ve umut verici tedavi yöntemlerini anlattı. https://sarkac.org/wp-content/uploads/2020/03/Multiple-Skleroz-Hastalığı-Hakkında-Neler-Biliyoruz-Prof.-Dr.-Aksel-Siva.mp3

Meraklısına Bilim programının 67. bölümünde Şükran Şençekiçer’in konuğu Bilim Akademisi üyesi ve Cerrahpaşa Tıp Fakültesi Nörobiyoloji Anabilim Dalı öğretim üyesi Aksel Siva’ydı,  Multiple Skleroz hastalığı hakkında bildiklerimizi ve bilmediklerimizi konuştular. Aksel Siva programda MS hastalığı nedir? hastalığın demografisi, belirtiler, tanı koyulmasındaki zorluklar, MRI’ın tanıdaki yeri, hastalığın seyri, yeni ve umut verici tedavi yöntemlerini anlattı. <a href="https://sarkac.org/wp-content/uploads/2020/03/Multiple-Skleroz-Hastalığı-Hakkında-Neler-Biliyoruz-Prof.-Dr.-Aksel-Siva.mp3" rel="nofollow" target="_blank">https://sarkac.org/wp-content/uploads/2020/03/Multiple-Skleroz-Hastalığı-Hakkında-Neler-Biliyoruz-Prof.-Dr.-Aksel-Siva.mp3</a>

Multiple Skleroz hastalığı hakkında neler biliyoruz? – 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

[intro music]   Hello, and welcome to Episode Twenty-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 Professor Aksel Siva about radiologically isolated syndrome. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   The role of diet in MS is a longstanding question, for which there many opinions, but few definitive answers. Researchers and clinicians know little about how diet may contribute to the risk of developing MS, and how it may help or hurt the progress of the disease once it starts. Nevertheless, patients are pushing for answers, hoping that there is more they can do to help slow their disease. We recently published a story looking into all the facts and myths of diet. We also covered what makes diet so difficult to study in a clinical setting, and where the field is going from here.   2015 is just around the corner, and deadlines are looming for submitting meeting abstracts and funding applications. Abstract submission deadlines for the Keystone Symposia are coming up in December, and ECTRIMS and the National MS Society have deadlines for funding opportunities early in January. For more details on the deadlines and how to submit your materials, go to the professional resources tab on our website and click on either “meetings and events” or “funding opportunities.”   We have also posted several exciting new job opportunities on our website. Go to the “jobs” section under professional resources to view them. And, if you’re looking for a neurologist, a laboratory technician, a post-doc, or any other position—let us know. We’ll help spread the word on our jobs section and in our weekly newsletter, and it won’t cost you a dime to reach a very choice group of MS professionals. Simply go to the “jobs” section and click on the “submit new item” button under the “Job Listings” header.   [transition music]   Now to the interview. Professor Aksel Siva is a professor of neurology at Istanbul University in Turkey. His work spans areas from clinical neuroimmunology to neuro-epidemiology to research in headaches.    Interviewer – Dan Keller When we met he discussed radiologically isolated syndrome or RIS and he starts by describing what it is.   Interviewee – Aksel Siva It is by definition an individual who gets an MRI for another reason such as migraine headache or whatever. Then, it turns out that they have MS looking like lesions in their brains. You cannot explain those lesions with any other pathology. They are not related to the patient's cause of referral for an MRI. Their neurological examination is normal, and these people never have experienced any neurological symptom, which might be consistent with past history of MS whatsoever.   It is an MRI diagnosis actually. It is not a clinical diagnosis. The question is whether these people do really have subclinical MS or asymptomatic MS and are they going to develop the disease. So the question is what to do when you see these patients. And this has been recently described as radiologically isolated syndrome by Okuda et al. At that time, there were acute CSF and now Darin is in Texas and at that time his mentor Daniel Pelletier is at Yale. So they have introduced this term. There have been, I would say, three pivotal papers by the French group, Christine Lebrun and her colleagues, and from our center together with Mayo Clinic in Rochester. Then this group came together and we have formed the Radiologically Isolated Syndrome Consortium, which has been later on joined by some other centers from Europe and the U.S.    MDSF So if you don’t know whether these people will go on to MS or where they stand, what do you do about it? How do you follow them and how many of these people do go on to MS?   Professor Siva The Radiologically Isolated Syndrome Consortium, we have conducted a study, which was published earlier this year in PLoS ONE and we have collected 451 cases with this syndrome. When they were followed, about 34% developed a neurological event consistent with either CIS or primary progressive MS. This means that about one-third of these people, who receive a diagnosis of radiologically isolated syndrome, in five years’ time, will develop clinical MS. And 10% of this group will develop primary progressive MS, which is very similar to what we see in two clinical cohorts. When statistically you follow these up to ten years and this is statistical, it turns out that around 55% will develop the disease. So at ten years’ time, still half of these people will not develop clinical MS. What does this mean? It is not clear, but on the other side, it seems that some people, who do have radiologically lesions consistent with multiple sclerosis and may continue to get new ones, still will not the clinical disease. We have known this from some autopsy studies started to be published in the 1960s, 70s, 80s, that there were cases, autopsy cases, where people turned out to have changes in their brains consistent with multiple sclerosis, but they never had the disease in their lifetime. We have to consider this subpopulation in both understanding the disease and when we should consider to start treatment, or whether we should really treat all people with MS or not.   MDSF There has been a feeling that you don't treat the image, but you treat the disease, but a lot of these people do go on to get the disease. Is it time for a randomized trial to see if you treat these people, some of them who would statistically go on, will not go on to get the disease?   Professor Siva It is time to start a treatment trial in RIS and our EOS colleagues, mainly Darin Okuda and Daniel Pelletier and Orhun Kantarci will be starting such a study in the U.S. later this year. There is also another probable trial that might start in Europe by Christine Lebrun. Yes we have come to this era, and probably within let's say a few years, we will have more evidence regarding who should be treated or who should not be when they present with RIS.   MDSF In the study that you looked at people for five years, what did you see were some of the risk factors for going on to MS?   Professor Siva There were some clear-cut risk factors and this was, as already shown by Darin and their group in EOS [?] a couple of years ago, having a spinal cord lesion at the time of the RIS diagnosis is a predictive factor to develop MS. Other factors are male gender and younger age; because when we have looked in this RIS cohort of the 450 or so cases, the mean age of diagnosis was 37, which is older than the general mean age that we diagnose MS. So this should be also taught whether this is because we have just by coincidence we get these incidental lesions in some people who will never develop the disease.    MDSF Now this study started a while ago to be able to be published recently. In that amount of time people have been looking at a lot of biomarkers. Did you consider biomarkers at that time? Can you find something that is predictive of going on to MS?   Professor Siva Not yet. Actually this study was a retrospective study, but in part it was prospective because in our center we have been interested in this for more than ten years now, almost 15 years. I should say that in Turkey we have a lot of MRIs and the cost is very low. It is very practical for, let's say general neurologists to refer patients for headaches, for not otherwise you would refer for a MRI, to refer them to MRIs, and then suddenly you started to see this MS looking-like lesions. As we have in MS center, we had a lot of referrals and then we started to follow these people. It’s been more or less the same in the other centers. It is yes, a retrospective data collection, but most of this cohort has been prospectively followed in those centers from the time of their admittance. And your question was whether there was a biomarker other than imaging, not really. Not yet, let's put it that way.   MDSF So is it advisable to follow them with imaging and if so, how often?   Professor Siva It is what we are doing now. There have been some suggested algorithms, but what we do in our center, we ask those patients to have a followup MRI in six months. Then within another six months, unless they develop something clinical, and then if they continue to have changes or not in their MRIs, that depends on how frequently we start to follow them up by MRI. Our tendency is twice for the first six months and then yearly for the next two years and then three years or two years later, unless they develop a clinical event consistent with MS or whatever.   MDSF Necessarily these interval MRIs are really snapshots, even in MS lesions come and go. I suppose it would be possible to miss a lesion that was there and that isn't there at the time of the MRI.   Professor Siva Definitely. But it has been shown, again in our study, that about two-thirds of these people continue to have new MRI lesions, but only one-third of the whole population develop a CIS or other event consistent with MS. Having new lesions doesn't really mean that the risk is much higher. Developing new MRI lesions is not always equal to develop the disease or having a much higher risk. It has been shown by the Queen Square Group many years ago when they have followed people who were admitted with CIS for up to 20 years. Ten to 15 % of these populations who presented with CIS, mostly optic neuritis continued to have new lesions, but they never developed a second clinical attack. It is more or less, I believe, for RIS some of those people will continue to have maybe one or two lesions when you do a followup MRI, but that doesn't mean that they necessarily will develop the disease. Even having positive oligoclonal bands is not a much higher risk by itself.   MDSF It would be quite a burden to treat 100% of the RIS population to be able to avert a progression to MS in about a third or over ten years about 55%. I guess, what you really need to do is be able to figure out who will progress. I guess a subpart of that question is, how do you know, or do you know, who will go on to primary progressive MS?   Professor Siva Well we cannot say this when they don't have any clinical symptoms and signs, because in our center we had three such patients who developed primary progressive MS after a period of four to eight years, when we have followed them radiologically. Probably another question is, whether all primary progressive MSs are really primary progressive, or are let's say secondary progressive MS, the diagnosis was done when they have gone through all of the let's say CIS, relapsing-remitting MS subclinically, and when they have entered in the secondary progressive phase, then, the disease became clinically surfaced and because of this we thought that this was people who were primary progressive. Because when you look at these people and we had those…well the whole group, the RIS we have more such cases, which is now prepared for publication. These people continue to have new lesions and they are not really any different than the relapsing-remitting cases. This is another issue that we should consider.   MDSF So in essence asymptomatic MS might really be MS and what looks like primary progressive is really secondary progressive.   Professor Silva Could be. That is a possibility. If I am not wrong, it was the late Charles Poser who had suggested that a number of MS patients the disease goes subclinically for a certain period of time, but they continue to have axonal degeneration and after a certain threshold they become only clinically symptomatic. It might be an analogy between this view and what we have observed.   MDSF Is there anything important to add on the subject of RIS?   Professor Silva Our approach is on an individual basis. Yes, we do have some evidence, we do have some findings, but that doesn't mean that when you see an individual with RIS they will do how it is expected according to the present evidence. When I am with my patients, or I shouldn't call them patients, but the individuals with RIS, my approach is on an individual basis. If they continue to have new MRI lesions and it is really high T2 load on the MRI, we ask for a CNS study, if they have positive oligoclonal bands, they have but normal visual evoked potentials; they have family members and so on. The way I approach those individuals is a little bit different than someone who has a few lesions, just enough to make a diagnosis of RIS, but don't have really other risk factors, no spinal cord and so on. When it comes to the patients we should make our decisions on an individual basis. I do not treat people RIS, but there might be some exceptions.   MDSF Very good, I appreciate it.   [transition music]   Thank you for listening to Episode Twenty-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 Twenty-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 Professor Aksel Siva about radiologically isolated syndrome. 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>. The role of diet in MS is a longstanding question, for which there many opinions, but few definitive answers. Researchers and clinicians know little about how diet may contribute to the risk of developing MS, and how it may help or hurt the progress of the disease once it starts. Nevertheless, patients are pushing for answers, hoping that there is more they can do to help slow their disease. We recently published a story looking into all the facts and myths of diet. We also covered what makes diet so difficult to study in a clinical setting, and where the field is going from here. 2015 is just around the corner, and deadlines are looming for submitting meeting abstracts and funding applications. Abstract submission deadlines for the Keystone Symposia are coming up in December, and ECTRIMS and the National MS Society have deadlines for funding opportunities early in January. For more details on the deadlines and how to submit your materials, go to the professional resources tab on our website and click on either “meetings and events” or “funding opportunities.” We have also posted several exciting new job opportunities on our website. Go to the “jobs” section under professional resources to view them. And, if you’re looking for a neurologist, a laboratory technician, a post-doc, or any other position—let us know. We’ll help spread the word on our jobs section and in our weekly newsletter, and it won’t cost you a dime to reach a very choice group of MS professionals. Simply go to the “jobs” section and click on the “submit new item” button under the “Job Listings” header. [transition music] Now to the interview. Professor Aksel Siva is a professor of neurology at Istanbul University in Turkey. His work spans areas from clinical neuroimmunology to neuro-epidemiology to research in headaches.  Interviewer – Dan Keller When we met he discussed radiologically isolated syndrome or RIS and he starts by describing what it is. Interviewee – Aksel Siva It is by definition an individual who gets an MRI for another reason such as migraine headache or whatever. Then, it turns out that they have MS looking like lesions in their brains. You cannot explain those lesions with any other pathology. They are not related to the patient's cause of referral for an MRI. Their neurological examination is normal, and these people never have experienced any neurological symptom, which might be consistent with past history of MS whatsoever. It is an MRI diagnosis actually. It is not a clinical diagnosis. The question is whether these people do really have subclinical MS or asymptomatic MS and are they going to develop the disease. So the question is what to do when you see these patients. And this has been recently described as radiologically isolated syndrome by Okuda et al. At that time, there were acute CSF and now Darin is in Texas and at that time his mentor Daniel Pelletier is at Yale. So they have introduced this term. There have been, I would say, three pivotal papers by the French group, Christine Lebrun and her colleagues, and from our center together with Mayo Clinic in Rochester. Then this group came together and we have formed the Radiologically Isolated Syndrome Consortium, which has been later on joined by some other centers from Europe and the U.S.  MDSF So if you don’t know whether these people will go on to MS or where they stand, what do you do about it? How do you follow them and how many of these people do go on to MS? Professor Siva The Radiologically Isolated Syndrome Consortium, we have conducted a study, which was published earlier this year in PLoS ONE and we have collected 451 cases with this syndrome. When they were followed, about 34% developed a neurological event consistent with either CIS or primary progressive MS. This means that about one-third of these people, who receive a diagnosis of radiologically isolated syndrome, in five years’ time, will develop clinical MS. And 10% of this group will develop primary progressive MS, which is very similar to what we see in two clinical cohorts. When statistically you follow these up to ten years and this is statistical, it turns out that around 55% will develop the disease. So at ten years’ time, still half of these people will not develop clinical MS. What does this mean? It is not clear, but on the other side, it seems that some people, who do have radiologically lesions consistent with multiple sclerosis and may continue to get new ones, still will not the clinical disease. We have known this from some autopsy studies started to be published in the 1960s, 70s, 80s, that there were cases, autopsy cases, where people turned out to have changes in their brains consistent with multiple sclerosis, but they never had the disease in their lifetime. We have to consider this subpopulation in both understanding the disease and when we should consider to start treatment, or whether we should really treat all people with MS or not. MDSF There has been a feeling that you don't treat the image, but you treat the disease, but a lot of these people do go on to get the disease. Is it time for a randomized trial to see if you treat these people, some of them who would statistically go on, will not go on to get the disease? Professor Siva It is time to start a treatment trial in RIS and our EOS colleagues, mainly Darin Okuda and Daniel Pelletier and Orhun Kantarci will be starting such a study in the U.S. later this year. There is also another probable trial that might start in Europe by Christine Lebrun. Yes we have come to this era, and probably within let's say a few years, we will have more evidence regarding who should be treated or who should not be when they present with RIS. MDSF In the study that you looked at people for five years, what did you see were some of the risk factors for going on to MS? Professor Siva There were some clear-cut risk factors and this was, as already shown by Darin and their group in EOS [?] a couple of years ago, having a spinal cord lesion at the time of the RIS diagnosis is a predictive factor to develop MS. Other factors are male gender and younger age; because when we have looked in this RIS cohort of the 450 or so cases, the mean age of diagnosis was 37, which is older than the general mean age that we diagnose MS. So this should be also taught whether this is because we have just by coincidence we get these incidental lesions in some people who will never develop the disease.  MDSF Now this study started a while ago to be able to be published recently. In that amount of time people have been looking at a lot of biomarkers. Did you consider biomarkers at that time? Can you find something that is predictive of going on to MS? Professor Siva Not yet. Actually this study was a retrospective study, but in part it was prospective because in our center we have been interested in this for more than ten years now, almost 15 years. I should say that in Turkey we have a lot of MRIs and the cost is very low. It is very practical for, let's say general neurologists to refer patients for headaches, for not otherwise you would refer for a MRI, to refer them to MRIs, and then suddenly you started to see this MS looking-like lesions. As we have in MS center, we had a lot of referrals and then we started to follow these people. It’s been more or less the same in the other centers. It is yes, a retrospective data collection, but most of this cohort has been prospectively followed in those centers from the time of their admittance. And your question was whether there was a biomarker other than imaging, not really. Not yet, let's put it that way. MDSF So is it advisable to follow them with imaging and if so, how often? Professor Siva It is what we are doing now. There have been some suggested algorithms, but what we do in our center, we ask those patients to have a followup MRI in six months. Then within another six months, unless they develop something clinical, and then if they continue to have changes or not in their MRIs, that depends on how frequently we start to follow them up by MRI. Our tendency is twice for the first six months and then yearly for the next two years and then three years or two years later, unless they develop a clinical event consistent with MS or whatever. MDSF Necessarily these interval MRIs are really snapshots, even in MS lesions come and go. I suppose it would be possible to miss a lesion that was there and that isn't there at the time of the MRI. Professor Siva Definitely. But it has been shown, again in our study, that about two-thirds of these people continue to have new MRI lesions, but only one-third of the whole population develop a CIS or other event consistent with MS. Having new lesions doesn't really mean that the risk is much higher. Developing new MRI lesions is not always equal to develop the disease or having a much higher risk. It has been shown by the Queen Square Group many years ago when they have followed people who were admitted with CIS for up to 20 years. Ten to 15 % of these populations who presented with CIS, mostly optic neuritis continued to have new lesions, but they never developed a second clinical attack. It is more or less, I believe, for RIS some of those people will continue to have maybe one or two lesions when you do a followup MRI, but that doesn't mean that they necessarily will develop the disease. Even having positive oligoclonal bands is not a much higher risk by itself. MDSF It would be quite a burden to treat 100% of the RIS population to be able to avert a progression to MS in about a third or over ten years about 55%. I guess, what you really need to do is be able to figure out who will progress. I guess a subpart of that question is, how do you know, or do you know, who will go on to primary progressive MS? Professor Siva Well we cannot say this when they don't have any clinical symptoms and signs, because in our center we had three such patients who developed primary progressive MS after a period of four to eight years, when we have followed them radiologically. Probably another question is, whether all primary progressive MSs are really primary progressive, or are let's say secondary progressive MS, the diagnosis was done when they have gone through all of the let's say CIS, relapsing-remitting MS subclinically, and when they have entered in the secondary progressive phase, then, the disease became clinically surfaced and because of this we thought that this was people who were primary progressive. Because when you look at these people and we had those…well the whole group, the RIS we have more such cases, which is now prepared for publication. These people continue to have new lesions and they are not really any different than the relapsing-remitting cases. This is another issue that we should consider. MDSF So in essence asymptomatic MS might really be MS and what looks like primary progressive is really secondary progressive. Professor Silva Could be. That is a possibility. If I am not wrong, it was the late Charles Poser who had suggested that a number of MS patients the disease goes subclinically for a certain period of time, but they continue to have axonal degeneration and after a certain threshold they become only clinically symptomatic. It might be an analogy between this view and what we have observed. MDSF Is there anything important to add on the subject of RIS? Professor Silva Our approach is on an individual basis. Yes, we do have some evidence, we do have some findings, but that doesn't mean that when you see an individual with RIS they will do how it is expected according to the present evidence. When I am with my patients, or I shouldn't call them patients, but the individuals with RIS, my approach is on an individual basis. If they continue to have new MRI lesions and it is really high T2 load on the MRI, we ask for a CNS study, if they have positive oligoclonal bands, they have but normal visual evoked potentials; they have family members and so on. The way I approach those individuals is a little bit different than someone who has a few lesions, just enough to make a diagnosis of RIS, but don't have really other risk factors, no spinal cord and so on. When it comes to the patients we should make our decisions on an individual basis. I do not treat people RIS, but there might be some exceptions. MDSF Very good, I appreciate it. [transition music] Thank you for listening to Episode Twenty-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 23 with Professor Aksel Siva