Continuum Audio

• Diversity and Underserved Patient Populations in Epilepsy With Dr. Dave Clarke

  Despite advances in epilepsy management, disparities and lack of inclusion of many people with epilepsy are associated with increased morbidity and mortality. Improving awareness and promoting diversity in research participation can advance treatment for underserved populations and improve trust. In this episode, Teshamae Monteith, MD, PhD, FAAN speaks Dave F. Clarke, MBBS, FAES, author of the article “Diversity and Underserved Patient Populations in Epilepsy,” in the Continuum® February 2025 Epilepsy issue. Dr. Monteith is a Continuum® Audio interviewer and an associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida. Dr. Clarke is the Kozmetsky Family Foundation Endowed Chair of Pediatric Epilepsy and Chief or Comprehensive Pediatric Epilepsy Center, Dell Medical School at the University of Texas at Austin in Austin, Texas. Additional Resources Read the article: Diversity and Underserved Patient Populations in Epilepsy Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @HeadacheMD Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Monteith: This is Dr Teshamae Monteith. Today I'm interviewing Dr Dave Clarke about his article on diversity and underserved patient populations in epilepsy, which appears in the February 2025 Continuum issue on epilepsy. So why don't you introduce yourself to our audience? Dr Clarke: Sure. My name is Dr Dave Clarke, as alluded to. I'm presently at the University of Texas in Austin, originating from much farther south. I'm from Antigua, but have been here for quite a while working within the field in epilepsy surgery, but more and more getting involved in outreach, access to care, and equity of healthcare in epilepsy. Dr Monteith: And how did you get involved in this kind of work? Dr Clarke: That's an amazing question. You know, I did it in a bit of a inside out fashion. I initially started working in the field and trying to get access to persons in the Caribbean that didn't have any neurological care or investigative studies, but very quickly realized that persons around the corner here in Texas and wherever I’ve worked have had the exact same problems, getting access via fiscal or otherwise epilepsy care, or geographically getting access, with so few having neurologists close at hand. Therefore, I started working both on a regional, national, and it transcended to a global scale. Dr Monteith: Wow, so you're just everywhere. Dr Clarke: Well, building bridges. I've found building bridges and helping with knowledge and garnering knowledge, you can expand your reach without actually moving, which is quite helpful. Dr Monteith: Yeah. So why don't you tell us why you think this work is so important in issues of diversity, underserved populations, and of course, access to epilepsy care? Dr Clarke: Sure, not a problem. And I think every vested person in this can give you a different spiel as to why they think it's important. So, I'll add in a few facts pertaining to access, but also tell you about why I think personally that it's not only important, but it will improve care for all and improve what you believe you could do for a patient. Because the sad thing is to have a good outcome in the United States presently, we have over three hundred epilepsy centers, but they have about eight or nine states that don't have any epilepsy centers at all. And even within states themselves, people have to travel up to eight hours, i.e., in Texas, to get adequate epilepsy care. So that's one layer. Even if you have a epilepsy center around the corner, independent of just long wait times, if you have a particular race or ethnicity, we've found out that wait may be even longer or you may be referred to a general practitioner moreso than being referred to an epilepsy center. Then you add in layers of insurance or lack thereof, which is a big concern regardless of who you are; poverty, which is a big concern; and the layers just keep adding more. Culture, etcetera, etcetera. If you could just break down some of those barriers, it has been shown quite a few years ago that once you get to an epilepsy center, you can negate some of those factors. You can actually reduce time to access and you can improve care. So, that's why I'm so passionate about this, because something could potentially be done about it. Dr Monteith: That's cool. So, it sounds like you have some strategies, some strategies for us. Dr Clarke: Indeed. And you know, this is a growth and this is a learning curve for me and will be for others. But I think on a very local, one-to-one scale, the initial strategy I would suggest is you have to be a good listener. Because we don't know how, when, where or why people are coming to us for their concerns. And in order to judge someone, if they may not have had a follow-up visit or they may not have gotten to us after five medications, the onus may not have been on that person. In other words, as we learned when we were in medical school, history is extremely important, but social history, cultural history, that's also just as important when we're trying to create bridges. The second major thing that we have to learn is we can't do this alone. So, without others collaborating with us outside of even our fields, the social worker who will engage, the community worker who will discuss the translator for language; unless you treat those persons with respect and engage with those persons to help you to mitigate problems, you'll not get very far. And then we'll talk about more, but the last thing I'll say now is they have so many organizations out there, the Institute of Medicine or the International League Against Epilepsy or members of the American Epilepsy Society, that have ways, ideas, papers, and articles that can help guide you as to how better mitigate many of these problems. Dr Monteith: Great. So, you already mentioned a lot of things. What are some things that you feel absolutely the reader should take away in reading your article? You mentioned already listening skills, the importance of interdisciplinary work, including social work, and that there are strategies that we can use to help reduce some of this access issues. But give me some of the essential points and then we'll dive in. Dr Clarke: OK. I think first and foremost we have to lay the foundation in my mind and realize what exactly is happening. If you are Native American, of African descent, Hispanic, Latinx, geographically not in a region where care can be delivered, choosing one time to epilepsy surgery may be delayed twice, three, four times that of someone of white descent. If you are within certain regions in the US where they may have eight, nine, ten, fourteen epilepsy centers, you may get to that center within two to three years. But if you're in an area where they have no centers at all, or you live in the Dakotas, it may be very difficult to get to an individual that could provide that care for you. That's very, very basic. But a few things have happened a few years ago and even more recently that can help. COVID created this groundswell of ambulatory engagement and ambulatory care. I think that can help to mitigate time to get into that person and improving access. In saying that, there are many obstacles to that, but that's what we have to work towards: that virtual engagement and virtual care. That would suggest in some instances to some persons that it will take away the one-to-one care that you may get with persons coming to you. But I guarantee that you will not lose patients because of this, because there's too big a vacuum. Only 22% of persons that should actually get to epilepsy centers actually get to epilepsy centers. So, I think we can start with that foundation, and you can go to the article and learn a lot more about what the problems are. Because if you don't know what the problems are, you can't come up with solutions. Dr Monteith: Just give us a few of the most persistent inequities and epilepsy care? Dr Clarke: Time to seeing a patient, very persistent. And that's both a disparity, a deficiency, and an inequity. And if you allow me, I'll just explain the slight but subtle difference. So, we know that time to surgery in epilepsy in persons that need epilepsy surgery can be as long as seventeen years. That's for everyone, so that's a deficiency in care. I just mentioned that some sociodemographic populations may not get the same care as someone else, and that's a disparity between one versus the other. Health equity, whether it be from NIH or any other definition, suggests that you should get equitable care between one person and the other. And that brings in not only medical, medicolegal or potential bias, that we may have one person versus the other. So, there's a breakdown as to those different layers that may occur. And in that I'm telling you what some of the potential differences are. Dr Monteith: And so, you mentioned, it comes up, race and ethnicity being a major issue as well as some of the geographic factors. How does that impact diagnosis and really trying to care for our patients? Dr Clarke: So again, I'm going to this article or going to, even. prior articles. It has been shown by many, and most recently in New Jersey, that if you're black, Hispanic, Latin- Latinx, it takes you greater than two times the time to surgery. Reduced time to surgery significantly increases morbidity. It potentially increases mortality, as has been shown by a colleague of mine presently in Calgary. And independent of that, we don't look at the other things, the other socially related things. Driving, inability to work, inability to be adequately educated, the stigma related to that in various cultures, various countries. So, that deficit not only increased the probability of having seizures, but we have to look at the umbrella as to what it does. It significantly impacts quality of life of that individual and, actually, the individuals around them. Dr Monteith: So, what are some of these drivers, and how can we address them, or at least identify them, in our clinic? Dr Clarke: That's a question that's rather difficult to answer. And not because there aren't ideas about it, but there’s actually mitigating those ideas or changing those ideas we're just presently trying to do. Although outlines have been given. So, in about 2013, the federal government suggested outlines to improve access and to reduce these inequities. And I'll just give you a few of them. One of those suggestions was related to language and having more improved and readily available translators. Something simple, and that could actually foster discussions and time to better management. Another suggestion was try to train more persons from underserved populations, persons of color. Reason being, it has been shown in the social sciences and it is known in the medical sciences that, if you speak to a person of similar culture, you tend to have a better rapport, you tend to be more compliant, and that track would move forward, and it reduces bias. Now we don't have that presently, and I'm not sure if we'll have that in the near future, although we're trying. So then, within your centers, if you have trainings on cultural sensitivity, or if you have engagements and lectures about how you can engage persons from different populations, those are just some very simple pearls that can improve care. This has been updated several times with the then-Institute of Medicine in 2012, 2013, they came out with, in my mind, a pretty amazing article---but I'm very biased---in which they outline a number of strategic initiatives that could be taken to improve research, improve clinical care, improve health equity through health services research, to move the field forward, and to improve overall care. They updated this in 2020, and it's a part of the 2030 federal initiative not only for epilepsy, but to improve overarching care. All of this is written in bits and pieces and referenced in the article. To add icing on top, the World Health Organization, through advocacy of neurological groups as well as the International League Against Epilepsy and the AES, came out with the Intersectoral Action Plan on Epilepsy and Other Neurological Diseases, which advocates for parallel improvement in overall global care. And the United States have signed on to it, and that have lit a fire to our member organizations like the American Epilepsy Society, American Academy of Neurology, and others, trying to create initiatives to address this here. I started off by saying this was difficult because, you know, we have debated epilepsy care through 1909 when the International League against Epilepsy was founded, and we have continually come up with ways to try and advance care. But this have been the most difficult and critical because there's social dynamics and social history and societal concerns that have negated us moving forward in this direction. But fortunately, I think we're moving in that direction presently. That's my hope. And the main thing we have to do is try to sustain that. Dr Monteith: So, you talked about the importance of these global initiatives, which is huge, and other sectors outside of neurology. Like for example, technology, you spoke about telemedicine. I think you were referring to telemedicine with COVID. What other technologies that are more specific to the field of epilepsy, some of these monitorings that maybe can be done? Dr Clarke: I was just going to just going to jump on that. Thank you so much for asking. Dr Monteith: I have no disclosures in this field. I think it's important and exciting to think how can we increase access and even access to monitoring some of these technologies. That might be expensive, which is another issue, but…. Dr Clarke: So, the main things in epilepsy diagnosis and management: you want to hear from the patient history, you want to see what the seizures look like, and then you want to find ways in which to monitor those seizures. Hearing from the patient, they have these questionnaires that have been out there, and this is local, regional, global, many of them standardized in English and Spanish. Our colleagues in Boston actually created quite a neat one in English and Spanish that some people are using. Ecuador has one. We have created someone- something analogous. And those questionnaires can be sent out virtually and you can retrieve them. But sometimes seeing is believing. So, video uploads of seizures, especially the cell phone, I think has been management-changing for the field of epilepsy. The thing you have to do however, is do that in a HIPAA-compliant way. And several studies are ongoing. In my mind, one of the better studies here was done on the East Coast, but another similar study, to be unnamed, but again, written out in the articles. When you go into these apps, you can actually type in a history and upload a video, but the feed is not only going to you, it may be going to the primary care physician. So, it not only helps in one way in you educating the patient, but you educate that primary care physician and they become extenders and providers. I must add here my colleagues, because we can't do without them. Arguably in some instances, some of the most important persons to refer patients, that's the APPs, the PAs and the nurse practitioners out there, that help to refer patients and share patients with us. So, that's the video uploads they're seeing. But then the other really cool part that we're doing now is the ambulatory world of EEGs. Ceribell, Zeto, to name of few, in which you could potentially put the EEG leads on persons with or without the EEG technologist wirelessly and utilize the clouds to review the EEGs. It's not perfect just yet, but that person that has to travel eight hours away from me, if I could do that and negate that travel when they don't have money to pay for travel or they have some potential legal issues or insurance-related issues and I could read the EEG, discuss with them via telemedicine their care, it actually improves access significantly. I'm going to throw in one small twist that, again, it’s not perfect. We're now trying to monitor via autonomic features, heart rate movement and others, for seizures and alert family members, parents, because although about 100,000 people may be affected with epilepsy, we're talking about 500,000 people who are also affected that are caregivers, affiliates, husbands, wives, etcetera. Just picture it: you have a child, let's say three, four years old and every time they have a seizure- or not every time, but 80% of times when they have a seizure, it alerts you via your watch or it alerts you in your room. It actually gives that child a sense of a bit more freedom. It empowers you to do something about it because you can understand here. It potentially negates significant morbidity. I won't stretch it to say SUDEP, but hopefully the time will come when actually it can prevent not only morbidity, but may prevent death. And I think that's the direction we are going in, to use technology to our benefit, but in a HIPAA-compliant way and in a judicious way in order to make sure that we not only don't overtreat, but at the end of the day, we have the patient as number one, meaning everything is vested towards that patient and do no harm. Dr Monteith: Great. One thing you had mentioned earlier was that there are even some simple approaches, efficiency approaches that we can use to try and optimize care for all in our clinics. Give me what I need to know, or do. Give me what I need to do. Dr Clarke: Yeah, I'll get personal as to what we're trying to do here, if you don't mind. The initial thing we did, we actually audited care and time to care delivery. And then we tried to figure out what we could do to improve that access and time to care, triaging, etcetera. A very, very simple thing that can be done, but you have to look at costs, is to have somebody that actually coordinates getting persons in and out of your center. If you are a neurologist that works in private practice, that could potentially be a nurse being associated directly one-and-one with one of the major centers, a third- or fourth-level center. That coordination is key. Educate your nurses about epilepsy care and what the urgent situations are because it will take away a lot of your headache and your midnight calls because they'll be able to know what to do during the day. Video uploads, as I suggested, regardless of the EMR that you have, figure out a way that a family could potentially send a video to you, because that has significantly helped in reducing investigative studies. Triaging appropriately for us to know what patients we can and cannot see. Extenders has helped me significantly, and that's where I’ll end. So, as stated, they had many neurologists and epileptologists, and utilizing appropriately trained nurse practitioners or residents, engaging with them equally, and/or social workers and coordinators, are very helpful. So hopefully that's just some low-hanging fruit that can be done to improve that care. Dr Monteith: So why don't you give us some of your major takeaways to how we can improve epilepsy care for all people? Dr Clarke: I've alluded to some already, but I like counts of threes and fives. So, I think one major thing, which in my mind is a major takeaway, is cultural sensitivity. I don't think that can go too far in improving care of persons with epilepsy. The second thing is, if you see a patient that have tried to adequately use medications and they're still having seizures, please triage them. Please send them to a third- or fourth-level epilepsy center and demand that that third- or fourth-level epilepsy center communicate with you, because that patient will eventually come back and see you. The third thing---I said three---: listen to your patients. Because those patients will actually help and tell you what is needed. And I'm not only talking about listening to them medication-wise. I know we have time constraints, but if you can somehow address some of those social needs of the patients, that will also not only improve care, but negate the multiple calls that you may get from a patient. Dr Monteith: You mentioned a lot already. This is really wonderful. But what I really want to know is what you're most hopeful about. Dr Clarke: I have grandiose hopes, I'll tell you. I'll tell you that from the beginning. My hope is when we look at this in ten years and studies are done to look at equitable care, at least when it comes to race, ethnicity, insurance, we'll be able to minimize, if not end, inequitable care. Very similar to the intersectoral action plan in epilepsy by 2030. I'll tell you something that suggests, and I think it's global and definitely regional, the plan suggests that 90% of persons with epilepsy should know about their epilepsy, 80% of persons with epilepsy should be able to receive appropriate care, and 70% of persons with epilepsy should have adequately controlled epilepsy. 90, 80, 70. If we can get close to that, that would be a significant achievement in my mind. So, when I'm chilling out in my home country on a fishing boat, reading EEGs in ten years, if I can read that, that would have been an achievement that not necessarily I would have achieved, but at least hopefully I would have played a very small part in helping to achieve. That's what I think. Dr Monteith: Awesome. Dr Clarke: I appreciate you asking me that, because I've never said it like that before. In my own mind, it actually helped with clarity. Dr Monteith: I ask great questions. Dr Clarke: There you go. Dr Monteith: Thank you so much. I really- I really appreciate your passion for this area. And the work that you do it's really important, as you mentioned, on a regional, national, and certainly on a global level, important to our patients and even some very simple concepts that we may not always think about on a day-to-day basis. Dr Clarke: Oh, I appreciate it. And you know, I'm always open to ideas. So, if others, including listeners, have ideas, please don't hesitate in reaching out. Dr Monteith: I'm sure you're going to get some messages now. Dr Clarke: Awesome. Thank you so much. Dr Monteith: Thank you. I've been interviewing Dr Dave Clarke about his article on diversity and underserved patient populations in epilepsy, which appears in the most recent issue of Continuum on epilepsy. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

  --------  

  28:16
• A Multidisciplinary Approach to Nonepileptic Events With Dr. Adriana Bermeo-Ovalle

  Nonepileptic events are prevalent and highly disabling, and multiple pathophysiologic mechanisms for these events have been proposed. Multidisciplinary care teams enable the efficient use of individual expertise at different treatment stages to address presentation, risk factors, and comorbidities.   In this episode, Kait Nevel, MD, speaks with Adriana C. Bermeo-Ovalle, MD, an author of the article “A Multidisciplinary Approach to Nonepileptic Events,” in the Continuum® February 2025 Epilepsy issue. Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana. Dr. Bermeo-Ovalle is a professor and vice-chair for Faculty Affairs in the Department of Neurological Sciences at Rush University Medical Center in Chicago, Illinois. Additional Resources Read the article: A Multidisciplinary Approach to Nonepileptic Events Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @IUneurodocmom Full episode transcript available here Dr. Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Nevel: Hello, this is Dr Kait Nevel. Today I'm interviewing Dr Adriana Bermeo about her article on a multidisciplinary approach to nonepileptic events, which she wrote with Dr Victor Petron. This article appears in the February 2025 Continuum issue on epilepsy. Welcome to the podcast, and please introduce yourself to our audience. Dr Bermeo-Ovalle: Hello Dr Neville, it's a pleasure to be here. Thank you very much for inviting me. My name is Adriana Bermeo and I'm an adult epileptologist at Rush University Medical Center in Chicago, and I am also the codirector of the NEST clinic, which is a treatment clinic for patients with nonepileptic seizures within our level four epilepsy center. Dr Nevel: Wonderful. Well, thank you so much for being here, and I can't wait to talk to you about your article and learn a little bit about NEST, maybe, during our conversation, and how you approach things. To start us off talking about your article today, could you share with us what you think is the most important takeaway from your article for the practicing neurologist? Dr Bermeo-Ovalle: Wonderful. There's some messages that I would like people to get from working with patients with functional neurologic disorders in general. The first one is that functional neurologic disorders are very common in presentation in the neurologic clinic, almost no matter what your practice of self-specialty care is. The second is that for people who treat patients primarily with seizures or epilepsy, they account for between 5 to 10% of our patients in the clinic, but about 30% of our patients in our epilepsy monitoring unit because the seizures typically do not respond to anti-seizure medication management. Also, that in order to diagnose them, you don't need to have a neuropsychological stress already be available for the patient or the clinician. And the most important thing is that there are available treatments for these patients and that there are options that we can offer them for them to have less seizures and to be more integrated to whatever activities they want to get integrated. Dr Nevel: Wonderful. What do you think a practicing neurologist might find surprising after reading your article? Dr Bermeo-Ovalle: I think still many neurologists feel very hopeless when they see patients with these conditions. They do not have very good answers right away for the patients, which is frustrating for the neurologist. And they don't think there's too much they can do to help them other than send them somewhere else, which is very difficult for the neurologist and is crushing to the patients to see these doctors that they're hoping to find answers to and then just find that there's not much to do. But what I want neurologists to know is that we are making strides in our understanding of the condition and that there are effective treatments available. And I hope that after reading this and engaging with this conversation, they will feel curious, even hopeful when they see the next patient in the clinic. Dr Nevel: Yeah, absolutely. I find the history of nonepileptic seizures really interesting and I enjoyed that part of your article. How has our understanding of nonepileptic seizures evolved over the centuries, and how does our current understanding of nonepileptic seizures inform the terminology that we use? Dr Bermeo-Ovalle: Yeah. The way we name things and the way we offer treatment goes along to how we understand things. So, the functional seizures and epileptic seizures were understood in ancient times as possession from the spirits or the demons or the gods, and then treatments were offered to those kind of influences and that continues to happen with functional seizures. So, we go through the era when this was thought to be a women-only condition that was stemming from their reproductive organs and then treatments accordingly were presented. And later on with Charcot and then Freud, they evolved to even conversion disorders, which is one understanding the most conversion disorders, which is one of the frameworks where this condition has been treated with psychotherapy, psychoanalytic psychotherapy. And in our current understanding, we understand functional neurologic disorders in general as a more like a connection, communication network disorder, between areas of the brain that modulate emotional processing and movement control. And therefore, our approach these days is much more geared towards rehabilitation. You know, I think that's the evolution of thinking in many different areas. And as we learn more, we will be acquiring more tools to help our patients. Dr Nevel: Yeah, great. Thanks so much for that answer. Just reading the historical information that you have in your article, you can imagine a lot of stigma with this diagnosis too over time, and that- I think that that's lessening. But I was wondering if you could talk about that a little bit. How do we approach that with our patients and loved ones, any stigma that they might feel or perceive from being diagnosed with nonepileptic seizures? Dr Bermeo-Ovalle: Thank you for asking that question. Stigma is actually an important problem even for people living with epilepsy. There's still a lot of misunderstanding of what epilepsy is and how it affects people, and that people living with epilepsy can live normal, healthy lives and do everything they want to do with appropriate treatment. And if a stigma is still a problem with epilepsy, it is a huge problem for patients living with functional neurologic symptoms in general, but particularly with functional seizures or nonepileptic seizures. Because the stigma in this population is even perpetuated by the very people who are supposed to help them: physicians, primary care doctors, emergency room doctors. Unfortunately, the new understanding of this condition has not gotten to everybody. And these patients are often even blamed for their symptoms and for the consequences of their symptoms and of their seizures in their family members, in their job environment, in their community. Living with that is really, really crushing, right? Even people talk about, a lot about malingering. They come back about secondary gain. I can tell you the patients I see with functional seizures gain nothing from having this condition. They lose, often, a lot. They lose employment, they lose ability to drive. They lose their agency and their ability to function normally in society. I do think that the fight- the fighting of stigma is one that we should do starting from within, starting from the healthcare community into our understanding of what these patients go through and what is causing their symptoms and what can we do to help them. So there's a lot of good work to be done. Dr Nevel: Absolutely. And it starts, like you said, with educating everybody more about nonepileptic seizures and why this happens. The neurobiology, neurophysiology of it that you outlined so nicely in your article, I'm going to encourage the listeners to look at Figure 1 and 4 for some really nice visualization of these really complex things that we're learning a lot about now. And so, if you don't mind for our listeners, kind of going over some of the neurobiology and neurophysiology of nonepileptic seizures and what we're learning about it. Dr Bermeo-Ovalle: Our understanding of the pathophysiology of functional neurologic seizure disorder is in its infancy at this point. The neurobiological processes that integrate emotional regulation and our responses to it, both to internal stimuli and to external stimuli and how they affect our ability to have control over our movement---it’s actually amazing that we as neurologists know so little about these very complex processes that the brain do, right? And for many of us this is the reason why we're in neurology, right, to be at the forefront of this understanding of our brain. So, this is in that realm. It is interesting what we have learned, but it's amazing all that we have to learn. There is the clear relationship between risk factors. So, we know patients with functional neurologic symptom disorder and with functional seizures, particularly in many different places in the world with many different beliefs, relationship to their body, to their expression of their body, have this condition no matter how different they are. And also, we know that they have commonalities. For example, traumatic experiences that are usually either very strong traumatic experiences or very pervasive traumatic experiences or recurrent over time of different quality. So, we are in the process of understanding how these traumatic experiences actually inform brain connectivity and brain development that result in this lack of connections between brain areas and the expression of them, and that result in this kind of disorder. I wish I can tell you more about it or that I would understand more about it, but I am just grateful for the work that has been done so that we can understand more and therefore have more to offer to these patients and their families and their communities that are support. Dr Nevel: Yeah, absolutely. That's always the key, and just really exciting that we're starting to understand this better so that we can hopefully treat it better and inform our patients better---and ourselves. Can you talk to us a little bit about the multidisciplinary team approach and taking care of patients with nonepileptic seizures? Who's involved, what does best practice model look like? You have a clinic there, obviously; if you could share with us how your clinic runs in the multidisciplinary approach for care of these patients? Dr Bermeo-Ovalle: The usual experience of patients dealing with functional seizures, because this is a condition that has neurological symptoms and psychiatric symptoms, is that they go to the neurologist and the neurologist does not feel sufficiently able to manage all the psychiatric comorbidities of the condition. So, the patient is sent to psychiatry. The psychiatry really finds themselves very hopeless into handling seizures, which is definitely not their area of expertise, and these patients then being- “ping-ponging” from one to the other, or they are eventually sent to psychotherapy and the psychotherapist doesn't know what they're dealing with. So, we have found with- and we didn't come up with this. We had wonderful support from other institutions who have done- been doing this for a longer time. That bringing all of this specialty together and kind of situating ourselves around the patient so that we can communicate our questions and our discrepancies and our decision between who takes care of what without putting that burden on the patient is the best treatment not only for the patient, who finally feels welcome and not burden, but actually for the team. So that the psychiatrist and the neurologist support the psychotherapist who does the psychotherapy, rehabilitation, mind the program. And we also have the support and the involvement of neuropsychology. So, we have a psychiatrist, a neurologist, social worker, psychotherapist and neuropsychology colleagues. And together we look at the patient from everywhere and we support each other in the treatment of the patient, keeping the patient in the middle and the interest of the patient in the middle. And we have found that that approach has helped our patients the best, but more importantly, makes our job sustainable so that none of us is overburdened with one aspect of the care of the patient and we feel supported from the instances that is not our most comfortable area. So that is one model to do it. There's other models how to do it, but definitely the interdisciplinary care is the way to go so far for the care of patients with functional neurologic symptom disorders and with functional seizures or nonepileptic seizures in particular. Dr Nevel: Yeah, I can see that, that everybody brings their unique expertise and then doesn't feel like they're practicing outside their, like you said, comfort zone or scope of practice. In these clinics---or maybe this happens before the patient gets to this multidisciplinary team---when you've established a diagnosis of nonepileptic seizures, what's your personal approach or style in terms of how you communicate that with the patient and their loved ones? Dr Bermeo-Ovalle: It is important to bring this diagnosis in a positive term. You know, unfortunately the terminology question is still out and there's a lot of teams very invested into how to better characterize this condition and how to- being told that you don't have something is maybe not that satisfying for patients. So, we are still working on that, but we do deliver the diagnosis in positive terms. Like, this is what you have. It's a common condition. It’s shared by this many other people in the world. It's a neuropsychiatric disorder and that's why we need the joint or collaborative care from neurology and psychiatry. We know the risk factors and these are the risk factors. You don't have to have all of them in order to have this condition. These are the reasons why we think this is the condition you have. There is coexisting epilepsy and functional seizures as well. We will explore that possibility and if we get to that conclusion, we will treat these two conditions independently and we- our team is able to treat both of them. And we give them the numbers of our own clinic and other similar clinics. And with that we hope that they will be able to get the seizures under better control and back to whatever is important to them. I tell my trainees and my patients that my goals of care for patients with functional seizures are the same as my patients with epileptic seizures, meaning less seizures, less disability, less medications, less side effects, less burden of the disease. And when we communicate it in that way, patients are very, very open and receptive. Dr Nevel: Right. What do you think is a mistake to avoid? I don't know if “mistake” is necessarily the right word, but what's something that we should avoid when evaluating or managing patients with nonepileptic seizures? What’s something that you see sometimes, maybe, that you think, we should do that differently? Dr Bermeo-Ovalle: I think the opportunity of engaging with these patients is probably the hardest one. Because neurologists have the credibility, they have the relationship, they have- even if they don't have a multi-disciplinary team all sitting in one room, they probably have some of the pieces of this puzzle that they can bring together by collaborating. So, I think that missing the opportunity, telling the patient, this is not what I do or this is not something that belongs to me, you need to go to a mental health provider only, I think is the hardest one and the most disheartening for patients because our patients come to us just like all patients, with hopes and with some information to share with us so that we can help them make sense of it and have a better way forward. We as neurologists know very well that we don't have an answer to all our patients, and we don't offer zero seizures to any of our patients, right? We offer our collaborative work to understand what is going on and a commitment to walk in the right direction so that we are better every day. And I do think wholeheartedly that that is something that we can offer to patients with functional seizures almost in any environment. Dr Nevel: Yeah, absolutely. And using that multidisciplinary approach and being there with your patient, moving forward in a longitudinal fashion, I can see how that's so important. What do you find most challenging and what do you find most rewarding about caring for patients with nonepileptic seizures? Dr Bermeo-Ovalle: The thing that I find more challenging are the systemic barriers that the system still places. We discuss with the patients, what is the right time to go to the emergency room or not? Because the emergency room may be a triggering environment for patients with functional seizures and it may be a place where not everybody is necessarily attuned to have this conversation. Having said that, I never tell any of my patients not to go to the emergency room because I don't know what's happening with them. As a matter of fact, we're getting a lot of information on high mortality rates in patients with functional seizures, and it’s not because of suicide and is probably not related to the seizure. Maybe this is---you know, this is speculation on my part---that is because they get to more severe conditions in other things that are not the functional seizures because they just experienced the healthcare system as very hostile because we are very in many instances. So, navigating that is a little bit difficult, and I try to tell them to have the doctors call me so that I can frame it in a different way and still be there for them. But I can tell you this clinic is the most rewarding clinic of all my clinical activities. And I love with all my heart being an epileptologist and seeing my patients with epilepsy. But the number of times my patients with functional seizures say, nobody had ever explained this to me, nobody had ever validated my experience in front of my family so that I'm not- like, feel guilty myself for having this episode, I can't tell you how many times. And obviously patients who come to the nonepileptic seizure clinic already know that they come to the nonepileptic seizure clinic, so that- you can say it's a selection of patients that are already educated in this condition to come to the clinic. But I would love everybody to know managing this population can be enormously, enormously satisfying and rewarding. Dr Nevel: Especially for, I imagine, patients who have been in and out of the ER, in and out of the hospital, or seen multiple providers and make their way to you. And you're able to explain it in a way that makes sense and hopefully reduces some of that stigma maybe that they have been feeling. Dr Bermeo-Ovalle: And along with that, iatrogenic interventions, unnecessary intubations, unnecessary ICUs; like, so much. And I think, I have no superpower to do that other than understanding this condition in a different way. And by I, I mean all the providers, because I'm not alone in this. There's many, many people doing excellent work in this state. And we just need to be more. Dr Nevel: Yeah, sure. Absolutely. So, on that note, what's next in research, or what do you think will be the next big thing? What's on the horizon in this area? Dr Bermeo-Ovalle: I think the community in the functional neurologic disorder community is really hopeful that more understanding into the neurobiology of this condition will bring more people over and more neurologists willing to take it on. There was an invitation from the NIH, I think, about four or five years ago to submit proposals for research in this area in particular. So, all of those studies must be ongoing. I'm much more a clinician than a researcher myself, but I am looking forward to what all of that is going to mean for our patients. And for- I think there's other opportunities in that further understanding of the clinical manifestations of many other conditions, and for our understanding of our relationship with our patients. I feel we are more attuned to align with a disease that, when the experience of the patient- and with a disease like this, a condition like this one, we have to engage with the personal experience of the patient. What I mean by that is that we are more likely to say,  I'm an epileptologist, I'm an MS doctor, you know, and we engage with that condition. This condition, like, just makes us engaging with the symptom and with the experience of the person. And I think that's a different frame that is real and rounded into the relationship with our patients. So, I think there's so much that we can learn that can change practice in the future. Dr Nevel: Yeah. And as your article, you know, outlines, and you've outlined today during our discussion, that- how important this is for the future, that we treat these patients and help them as much as we can, that comes with understanding the condition better, because wow, I was really surprised reading your article. The mortality associated with this, the healthcare costs, how many people it affects, was just very shocking to me. So, I mean, this is a really important topic, obviously, and something that we can continue to do better in. Wonderful. Well, thank you so much. It's been really great talking to you today. Dr Bermeo-Ovalle: Thank you, Katie, I appreciate it too. Dr Nevel: So again, today I've been interviewing Dr Adriana Bermeo about her article on a multidisciplinary approach to nonepileptic events, which she wrote with Dr Victor Petron. This article appears in the most recent issue of Continuum on epilepsy. Be sure to check out Continuum audio episodes from this and other issues. And thank you to our listeners for joining today.  Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

  --------  

  24:05
• Surgical Treatments, Devices, and Nonmedical Management of Epilepsy With Dr. Daniel Friedman

  Many patients with epilepsy are unable to acheive optimal seizure control with medical therapy. Palliative surgical procedures, neurostimulation devices, and other nonpharmalogical treatments can lead to a meaningful reduction in seizures and improved outcomes. In this episode, Teshamae Monteith, MD FAAN, speaks with Daniel Friedman, MD, MSc, author of the article “Surgical Treatments, Devices, and Nonmedical Management of Epilepsy,” in the Continuum® February 2025 Epilepsy issue. Dr. Montieth is a Continuum® Audio interviewer and an associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida. Dr. Friedman is a professor (clinical) of neurology at NYU Grossman School of Medicine and Director of NYU Langone Comprehensive Epilepsy Center at NYU Langone Health in New York, New York. Additional Resources Read the article: Surgical Treatments, Devices, and Nonmedical Management of Epilepsy Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @headacheMD Guest: @dfriedman36  Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Monteith: This is Dr Teshamae Monteith. Today, I'm interviewing Dr Daniel Friedman about his article on surgical treatments, devices, tools, and non-medication management of epilepsy, which appears in the February 2025 Continuum issue on epilepsy. Welcome to the podcast. How are you? Dr Friedman: I'm well, how are you? Dr Monteith: Thank you for your article. Dr Friedman: Thank you for the opportunity to talk today. Dr Monteith: Why don't you introduce yourself? Dr Friedman: So yeah, so I'm Dan Friedman. I am a professor of neurology here at NYU Grossman School of Medicine and I am the director of the NYU Comprehensive Epilepsy Center. I'm primarily an adult neurologist and I treat teens and adults with hard- difficult-to-treat epilepsy, including surgical treatments for epilepsy. Dr Monteith: And I know you see a lot of patients because I did my residency there. And so, when you graduate, you get a lot of it, like I think many, many residents. What inspired you to choose epilepsy as a profession? Dr Friedman: I came to neurology through my interest in neuroscience. I was a neuroscience undergraduate. I was very interested in the brain and brain function. Particularly, I was interested in how neurons communicate and organize to entrain and rhythms and that encode information. And through that interest and through my experiences in the laboratory, I actually became interested in how they do that in pathological circumstances like seizures. And so, I started reading about epilepsy, and then when I started seeing patients with epilepsy, you know, I decided this is the specialty for me for a lot of reasons. One is it combines inpatient and outpatient care. You get to establish long-term relationships with patients. For many of my patients, I'm probably the doctor that they see most often. You see people across the lifespan. And what I'm going to talk about today is for some people, you actually get to cure their disease, which at the time I was coming into neurology was something pretty rare. Dr Monteith: Yeah, that's great. Why don't you tell us, what were you thinking when you started writing the article? What did you set out to do? Dr Friedman: What I really wanted to do is to educate neurologists out there about the options that they have for their patients with epilepsy, especially those with difficult-to-treat or drug-resistant epilepsy, and give them the tools to communicate those options. Especially for them to understand the rationale, why we choose the interventions that we do as epileptologists, how to appropriately refer patients and have them be partners in that discussion with patients and families. One of the things that we have known for a long time is that the time to referral for things like epilepsy surgery is too long. You know, the average patient with drug resistant epilepsy who undergoes epilepsy surgery waits about twenty years. And for patients who could have curative therapy, you know, become seizure free, that's a lot of life years lost. If we can get patients to that potentially life-altering therapy earlier, that'd be great. Dr Monteith: Yeah, that is really impactful as you think about it. So why don't you tell us what the essential points of your article? Dr Friedman: The central point of my article is really that when patients have drug-resistant epilepsy, which means that our available anti-seizure medicines are not controlling their seizures to the degree that they need, there are other treatment options. Some of those are what we call curative, which means that they could stop their seizures entirely; and some of them are palliative, they could reduce the frequency or severity of seizures and improve quality of life and other outcomes. The other thing that I wanted to highlight was, in addition to these types of therapies, there are other tools we have at our disposal that can improve the quality of life and safety of our patients with epilepsy, including devices for seizure monitoring. Dr Monteith: And how do you define drug-resistant epilepsy? I feel like that could be a moving target. Dr Friedman: The International League Against Epilepsy actually set out to define it about a decade ago, and they defined it as patients who fail at least two appropriately selected anti-seizure medicines due to lack of efficacy. Then they're still having ongoing seizures. What does that mean? So, that means that the medicine that was chosen was appropriate for the type of seizures that they have, whether it's focal or generalized, and that it didn't work because of a lack of efficacy and not because of side effects. And we know from multiple studies that once patients fail two medications, the likelihood that the third, fourth, fifth, etcetera, medicine will control their seizures becomes smaller and smaller. It's not impossible, but the rates fall below five percent. And so we call those patients drug-resistant. Dr Monteith: So, it sounds like despite newer therapies, really things haven't changed in ten years. Dr Friedman: Yeah, unfortunately, at least when the concept was first investigated back in 2000 by Quan and Brody, they found that a third of patients were drug-resistant. When they went back in the mid-2010s to relook at these patients, despite the introduction of many new medications, the rate of patients who were drug-resistant was essentially unchanged. There may be therapies that are emerging or in development that may have better odds, but right now we don't really understand what makes people drug resistant and how we can target that. Dr Monteith: But you do raise a good point that this is about efficacy and not tolerability. And at least for some of the newer medications, they're better tolerated. If you stop the medicine because you had some side effect, that might change how that person has classified better-tolerated treatments. Dr Friedman: It's true. And better-tolerated treatments, you can potentially use higher doses. One of the things that is not in the definition of drug-resistant epilepsy, but as a practicing neurologist, we all know, is that the patients have to take the medicine for it to be effective. And unfortunately, they have to take it every day. And if the medicine makes them feel bad, they may choose not to take it, present to you as drug-resistant, when in reality they may be drug-sensitive if you got them on medicine that doesn't make them feel bad. Dr Monteith: So why don't we talk about patients that are ideal candidates for epilepsy surgery? Dr Friedman: The ideal candidates for epilepsy surgery… and I'll start by talking about curative epilepsy surgery, where the goal of the surgery is to make patients seizure-free. The best candidates are patients who have lesional epilepsy, meaning that there is a visible MRI abnormality like a focal cortical dysplasia, hippocampus sclerosis, cavernoma in a part of the brain that is safe to resect, non-eloquent, and where you can safely perform a wide margin of resection around that lesion. It helps if they have few or no generalized tonic-clonic seizures and a shorter duration of epilepsy. So the ideal patient, the patient that if they came to my office, I would say you should get surgery right now, are patients with non-dominant temporal lobe epilepsy of a few years’ duration. So as soon as they've shown that they're not responding to two medicines, those are the ideal patients to say, you would have the most benefit and the least risk from epilepsy surgery. We know from studies that patients with temporal lobe epilepsy do a little better with surgery. We know patients who have a visible lesion on MRI do better with epilepsy surgery. We know that patients who have infrequent secondarily generalized seizures do better. But all patients with drug-resistant epilepsy should be considered for some form of surgery because even if they're not candidates for a curative surgery, there may be some palliative options, whether it's surgical resections that lessen the severity of their seizures or neurostimulation devices that reduce the frequency and severity of seizures. Ideal candidates, the ones that you would push through sooner rather than later, are those who have the likelihood of the best outcomes and the least risk of neurocognitive decline. Dr Monteith: So, you mentioned that there may be other candidates that still benefit, although maybe not ideal. You mentioned neuromodulation. What other interventions are available? Dr Friedman: For patients who are not candidates for resective surgery, there are several neurostimulation options. There's vagus nerve stimulation, which has been around the longest. It is a device that is implanted in- under the skin near the clavicle and has a lead that goes to the left vagus nerve and delivers stimulation, electrical stimulation to the nerve. For reasons we don't fully understand, it can reduce the both the frequency and severity of seizures. Seldom does it make people seizure free, but the reduction in seizure frequency for many patients is associated with improved quality of life, reduced risk of injury, and even reduced rates of SUDEP. We also have two intracranial neurostimulation devices we use for epilepsy. One is the responsive neurostimulator. So, this is a device that- it has leads that are implanted directly into the seizure focus and sense electrocortical brain activity and deliver electrical stimulation to attempt to abort abnormal brain activity. So functioning kind of like a cardiac defibrillator for the heart, but for seizures in the brain. And because these devices have two leads, they can be used to treat people with more than one seizure focus---so up to two---or be used in patients who are not candidates for resection because their seizure focus is in language cortex, motor cortex, things that would be unable to resect. And the RNS has somewhat better efficacy in terms of percent reduction in seizures compared to the VNS, but obviously because it's an intracranial device, it's also a little riskier. It has more potential for neurosurgical adverse effects. There's also a deep brain stimulator for epilepsies, the same exact device that we use to treat movement disorders. We can implant in the thalamus, in either the anterior nucleus of the thalamus or now, for some patients, into the central median nucleus of the thalamus, and deliver open loop stimulation to treat epilepsy and reduce the frequency and severity of seizures as well. Unlike the RNS, you don't have to localize the seizure focus, so you don't need to know exactly where the seizures are coming from. And you could treat patients with multifocal epilepsy with seizures coming from more than two locations or even generalized seizures. Dr Monteith: So, it sounds like there are a lot of options available to patients. I think one of the things I find challenging is when we have patients that may have some cognitive dysfunction, especially in the hospital, and they've had some seizures that are very obvious, but then there are these, maybe, events that you wonder are seizures. So, what is the utility of some of these seizure detection devices? Dr Friedman: The development of seizure detection devices started out primarily with the observation that a majority of cases of sudden unexpected death and epilepsy, or SUDEP, occurred following tonic-clonic seizures. And there was a need to be able to monitor for convulsive seizures, especially that occur at night when people were otherwise unattended. And so, the first generation of devices that were developed came on the market, essentially detected convulsive seizures, and they alerted caregivers nearby who are able to come to the bedside, provide basic seizure first aid, turn people on the side. And theoretically all this---this hasn't been shown in studies---prevents SUDEP. And so, the ones that are currently available on the market are focused on the detection of convulsive seizures, mostly generalized tonic-clonic seizures, but some devices can also detect other seizures with very prominent motor components. What we don't have yet available to us, and what people are working on, are devices that detect nonconvulsive seizures. We know that patients who have focal impaired aware seizures are often amnestic for their seizures. They don't know they had a seizure if family members aren't there to observe them. They may never report them, which makes treating these patients very difficult. How do you quantify disease burden in your headache patients, for instance? You say, how many headache days did you have since we last met in the clinic? Your patients will be able to report on their calendar, this many days. Well, imagine if the patients had no awareness of whether or not they had a headache day. You wouldn't know if your therapy is working or not. In epilepsy, we need those types of devices which can tell us whether patients are having seizures they're unaware of, and that may be more subtle than convulsions. Dr Monteith: Oh, that'd be great for headache, too. You just gave me an idea, but that's the next podcast. So, you mentioned SUDEP, really important. How good are surgical interventions at reducing what we would think the prevalence of SUDEP? Dr Friedman: For me that is one of the primary motivations for epilepsy surgery in patients who are drug-resistant, because we know that if patients who are candidates for epilepsy surgery have high SUDEP rates. Estimates range from six to nine per thousand patients per year. If surgery is successful, their mortality rates go down to the general population level. It literally can be lifesaving for some patients, especially when you're talking about curative epilepsy surgery. But we also know that the biggest driver for SUDEP risk is tonic-clonic seizures and the frequency of those tonic-clonic seizures. So even our palliative interventions, which can reduce the frequency and severity of seizures, may also reduce the risk of SUDEP. So, we know in study- observational studies of patients with VNS and with RNS, for instance, the rates of SUDEP in patients treated with those devices are lower than expected for the drug-resistant epilepsy population. Dr Monteith: Let's talk a little bit about some of these prediction models. And you have a lot of great work in your article, so I don't want to get into all the details, but how do you use that in the real world? Do you communicate that with patients? How do you approach these prediction factors? Dr Friedman: There are two places where, I think, clinical prediction tools for epilepsy surgery have a role. One is, for me, in my clinic where I'm talking to patients about the risks and benefits for surgery, right? You want to be able to accurately communicate the likelihood that the surgery is going to give you the desired outcome. So patients and their families can make educated decisions, be weighing the risks and benefits. I think it's important to be realistic with patients because surgery, like- you know, any surgery is not without risk, both acute risks and long-term risks. You're removing part of the brain, and, you know, every part of the brain is important. That's where I use prediction tools. But I think it's also important for the general neurologist, especially trying to triage which patients you are going to be aggressive with referring to a comprehensive epilepsy center for evaluation. Where you may use your limited time and capital with patients to counsel them on surgical treatments. Where a healthcare system with limited resources prioritizes patients. So, there's a significant need for having prediction tools that only take the input that a general neurologist seeing a patient in the clinic would have at hand. You know, the history, an MRI, an interictal EEG. Dr Monteith: I guess part of that prediction model includes adverse outcomes that you're communicating as well. Dr Friedman: Certainly, for me, when I'm discussing surgery for the patient in front of me, I will use prediction models for adverse outcomes as well that are informed by the kind of surgery we're proposing to do, especially when talking about things like language dysfunction and memory dysfunction after surgery. Dr Monteith: So, you mentioned a lot of great advances, and certainly since I was a resident, which wasn't that long ago. Why don't you tell me how some of these interventions have changed your clinical practice? Dr Friedman: Thinking about epilepsy surgery, like other surgical specialties, there's been a move to more minimally invasive approaches. For instance, when I started as an epilepsy fellow fifteen years ago, sixteen years ago, most of our surgeries involve removing a large portion of the skull, putting electrodes on the brain, doing resections through big craniotomies which were uncomfortable and risky, things like that. We now do our phase two or intracranial EEG monitoring through small burr holes in the brain using robotically placed electrodes. For many of our patients, we can actually treat their epileptic focus with a laser that is targeted through a small catheter and MRI guidance. And patients are usually home in two days with, you know, a lot less discomfort. Dr Monteith: Well, that's great. I didn't expect that one, but I do think that translates to many areas of neurology. Really just this idea of meeting their goals and personalizing their care. My last question is, what out of these advances and what you know about the future of epilepsy, what makes you the most excited and what gives you the most hope? Dr Friedman: I think there are a lot of exciting things in epilepsy. Last count I heard, there's something like over a hundred biotech companies developing epilepsy therapies. So that gives me hope that people are still interested in meeting the unmet needs of patients with epilepsy. And some of these therapies are really novel. For instance, there's a trial of stem cell treatments for drug-resistant temporal lobe epilepsy that's ongoing now, where inhibitory interneuron progenitor cells are implanted in the brain and kind of restore the brain circuit disruptions that we see in some of these epilepsies. There are combinations of drug and device therapies or gene therapy and device therapies that are in development, which have a lot of promise, and I think we'll have much more precise and targeted therapies within the next decade. Dr Monteith: Awesome. I really appreciate our conversation, and thank you so much for your wonderful article. I learned a lot reading it. Dr Friedman: Thank you. Dr Monteith: Today I've been interviewing Dr Daniel Friedman, whose article on surgical treatments, devices, tools, and non-medication management of epilepsy appears in the most recent issue of Continuum on epilepsy. Be sure to check out Continuum audio episodes from this and other issues. And thank you to our listeners for joining today. Dr Monteith: This is Dr Teshmae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

  --------  

  24:14
• First Seizures, Acute Repetitive Seizures, and Status Epilepticus With Dr. David Vossler

  Emergency treatment may be necessary after a person's first seizure or at the onset of abnormal acute repetitive (cluster) seizures; it is required for status epilepticus. Treatment for these emergencies is dictated by myriad clinical factors and informed by published guidance as well as emerging research.   In this episode, Lyell K. Jones, MD, FAAN, speaks with David G. Vossler, MD, FAAN, FACNS, FAES, author of the article “First Seizures, Acute Repetitive Seizures, and Status Epilepticus,” in the Continuum® February 2025 Epilepsy issue. Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota. Dr. Vossler a clinical professor of neurology at the University of Washington School of Medicine in Seattle, Washington. Additional Resources Read the article: First Seizures, Acute Repetitive Seizures, and Status Epilepticus Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @LyellJ  Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr Dave Vossler, who has recently authored an article on emergent seizure management, taking care of patients with the first seizure, acute repetitive seizures, and status epilepticus, which is an article in our latest issue of Continuum covering all topics related to epilepsy. Dr Vossler is a neurologist at the University of Washington, where he's a clinical professor of neurology and has an active clinical and research practice in epileptology. Dr Vossler, welcome. Thank you for joining us today. Why don't you introduce yourself to our listeners? Dr Vossler: Thank you very much for the introduction, Lyell. It's a pleasure to speak with you on this podcast, and I hope to go over a lot of important new information in the management of seizure emergencies. As you said, I'm a clinical professor in neurology at University of Washington, been in medicine for many decades now and have published and done research in this area. So, I'm anxious to give you not only my academic experience, but also talk about my own management of patients with status epilepticus over the last four decades. Dr Jones: Yeah, that's fantastic. And I always appreciate hearing from experienced clinicians, and I think our readers and our listeners do appreciate that voice of clinical expertise. And I'll tell you this is a topic, you know, as a neurologist who doesn't see many patients with acute seizure emergencies in my own practice, I think this is a topic that gives many clinicians, including neurologists, some anxiety. Your article, Dr Vossler, is really chock-full of helpful and clinically relevant considerations in the acute management of seizures. So, you now have the full attention of a huge audience of mostly neurologists. What's the one most important practice change that you would like to see in the care of patients with either first or acute prolonged seizures? Dr Vossler: Without a doubt, the most important clinical takeaway with regard to the status epilepticus---and for status epilepticus, many, many clinical trials, research trials have been done over the last couple decades and they all consistently show the same thing, that by and large most patients who have status epilepticus are underdosed and undertreated and treated too slowly in the initial stages of the status epilepticus. And it's important to use full bolus dosages of benzodiazepines to prevent mortality, morbidity, and later disability of these patients. To prevent the respiratory depression, many physicians are afraid to use higher doses of benzodiazepines, even guideline-recommended doses of benzodiazepines for fear of respiratory depression. But it's actually counterintuitive. It turns out that most cases of respiratory depression are due to inadequate doses and due to the status epilepticus itself. We know there's greater mortality, we know there's greater morbidity and we know that there's greater need for higher dose, subsequent, anti-seizure medications, prolonged status, if we don't use the proper doses. So, we'll kind of go over that a little bit, but that is the one clinical takeaway that I really would like our listeners to have. Dr Jones: Let's follow that thread a little bit. Dave, I know obviously we will speak in hypotheticals here. We're not going to talk about actual patients, but I think we've all been in the clinical situation where you have a patient who comes into the emergency room usually who's actively seizing, unknown history, don't know much about the patient, don't know much about the circumstances of the onset of the seizure. But we now have a patient with prolonged convulsive seizures. How do we walk through that? What are the first steps in the management of that patient? Dr Vossler: Yeah, well, I'll try to be brief for the purposes of the podcast. We do, of course, go through all of that in detail in the Continuum article, which hopefully everybody will look at very carefully. Really in the first table, the very first table of the article, I go through the recommended guideline for the American Epilepsy Society on the management of what we call established status epilepticus. The scenario you're talking about is just exactly that: established status epilepticus. It's not sort of evolving or developing status. We're okay they're having a few seizures and we're kind of getting there. No, this patient is now having evidence of convulsive seizure activity and it's continuing or it's repeated seizures without recovery. And so, the first phase is definitely a benzodiazepine and then the second phase is then a longer-acting bolus of a drug like phosphenotoine, valproic acid or levetiracetam. I could get into the details about dosing of the benzodiazepines, but maybe I'll let you guide me on whether we wanted to get into that kind of detail right at the outset. It's going to be a little bit different. For children, its weight-based dosing, but for adults, whether you use lorazepam or you use diazepam or you use midazolam, the doses are a little bit different. But they are standardized, and gets back to this point that I made earlier, we're acting too slow. We're not getting these patients quick enough, for various reasons, and the doses that are most commonly used are below what the guidelines call for. Dr Jones: That's great to know, and I think it's fine for the details to refer our listeners to the article because there are great details in there about a step-by-step approach to the established status epilepticus. The nomenclature and the definitions have evolved, haven't they, Dr Vossler, over time? Refractory status epilepticus, new-onset refractory status epilepticus, super refractory status epilepticus. Tell us about those entities, how they're distinguished and how you approach those. Dr Vossler: That's an important thing to kind of go over. They- in 2015, the International League Against Epilepsy, ILAE, which is, again, our international organization that guides our understanding of all kinds of things epileptic in nature around the world. In 2015 they put out a definition of status epilepticus, but it used to be that patients had thirty minutes of continuous seizure activity or repetitive obvious motor seizures with impairment of awareness and they don't recover impairment between these seizures. And that goes on for thirty minutes. That was the old definition of status epilepticus. Now, the operational definition is five minutes. And I think that's key to understand that, after five minutes of this kind of overt seizure activity, you need to intervene. And that's what's called T1 in the 2015 guideline, the international guideline. There are a bunch of different axes in the classification of status that talk about semiology, etiology, EEG patterns, and what age group you're talking about. We won't really get into those in the Continuum article because that's really more detailed than a clinician really should be. Needing to think about the stages, what we call the stages of status epilepticus that you mentioned and I alluded to earlier are important. And that is sort of new nomenclature, and I think probably general neurologists and most emergency room physicians aren't familiar with those. So, it just briefly goes through those. Developing status epilepticus is where you're starting- the patient’s starting to have more frequent seizures, and it's heading essentially in the wrong direction, if you will. Established status epilepticus, as I mentioned, is, you know, this seizure act, convulsive or major, major outward overt seizure activity lasting five minutes or more, at which time therapy needs to begin. Again, getting back to my point, what doesn't happen often enough is we're not- we're intervening too late. Third is refractory status epilepticus, which refers to status epilepticus which continues despite adequate doses of an initial benzodiazepine given parenterally followed by a full loading dose of a single non-sedating anti-seizure medicine, which today includes phosphenotoine IV valproic acid or IV levetiracetam. In the United States, and increasingly around the world, people really are using levetiracetam. First, it has some advantages. There's now proof from a class one NIH-funded trial. We know that these three drugs are equivalent at the full doses that I go over in the article. You have your kind of dealer's choice on those. Phenobarbital, which we used to use and I used as a resident as long as forty years ago, is really a second choice drug because of its sedating and other side effects. But around the world in resource-poor countries phenobarbital can be used and, in a pinch, certainly is an appropriate drug. And then finally, you mentioned super refractory status epilepticus and that's status that's persisting for more than twenty four hours. Now, despite initial benzo and non-sedating anti-seizure medicine, but also lasting more than twenty four hours while receiving an intravenous infusional sedating, anesthetizing anti-seizure medicine like ketamine, propofol, pentobarbital or midazolam drips. Dr Jones: So, it sounds like the definitions have evolved in a way that improves the outcomes, right? To do earlier identification of status epilepticus and more aggressive management, I think that's a great takeaway. If we move all the way to the other end of the spectrum, let's move to the ambulatory setting and we have a patient who comes in and they've had one seizure, they're an adult; one seizure, the first seizure. The key question is, how do we anticipate the risk of future seizures? But walk us through how you talk to that patient, how you evaluate that patient to decide if and when to start anti-seizure medicines. Dr Vossler: Well, it depends a little bit if it's an adult or a child, but the decision making process and the data behind it is pretty robust now. And the decision making process is pretty similar for adults and children, with some differences which I can talk about. First of all, first seizures. I think it's really important to stress that there's been so much research in this area. I'd like to get a cross point that they're not as innocuous as I think many general neurologists might suspect. We know that there is a two- to threefold increased risk of death in children and adults following a first seizure. Moreover, the risk of a second seizure, both in kids and adults, is about 36% two years after that first seizure. It's about 46% five years after that first seizure. It's really pretty substantial. The risk of a second seizure is increased twofold. It doubled in the presence of any kind of a history of prior brain insults that could result in seizures. Could be infections, it could be a prior stroke, it could be prior significant brain trauma. It's also doubled in the presence of an EEG, which shows epileptiform discharges like spikes and sharp waves---and not just a sort of borderline things like sharply contoured rhythmic Theta activity. That's really not what we're talking about. We're talking about overt epileptiform discharges. It's doubled in the presence of lesion that can be seen on imaging studies, and it's doubled in the presence of seizures if that first seizure occurs during sleep. So, we have a number of things that double the risks, above the risk of a second seizure, above that 36% at two years and 46% at five years that I spoke about. And so those things need to be considered when you're counseling a patient about that. Should you be on an anti-seizure medicine after that first seizure? Specifically, to the point of anti-seizure medications, the guideline that was done, the 2015 guideline that was done by the American Academy of Neurology for adults, and the 2003 guideline was actually a practice parameter that was done by the Academy and the American Epilepsy Society for children, are really kind of out of date. They talk about the adverse effects of anti-seizure medications, but when you look back at the studies that were included in developing that practice parameter for kids and guidelines for adults, they are the old drugs: carbamazepine, phenytoin, phenobarbital and valproate. Well, I don't think I need to tell this audience, this well-educated audience, that we don't use those drugs anymore. We are using more modern anti-seizure medicines that have been developed since 1995; things like lamotrigine, levetiracetam, and lecosamide. Those three in particular have very low adverse events. So, the guideline that the Academy, American Academy Neurology and American Epilepsy Society put together for kids and for adults talks about this high adverse event profile. And so, you need to take a look at the risks that I talked about of a seizure recurrence and balance that against adverse effects. But I'm here to tell you that the newer anti-seizure medicines---and by newer I'm talking in the last thirty years since lamotrigine was approved in 1995---these drugs have much better side effect profiles. And I think all epileptologists would agree with that. They're not necessarily more effective, but they are better tolerated. That makes the discussion of the risk of a second seizure, the risk of mortality versus side effects of drugs, it really pushes the risk category higher on the first side and not on the side of drugs. We know that if you take an anti-seizure medicine, you reduce your risk of a second seizure by half. Now, that's not sustained over five years, but over the first two years, you've reduced it by half. In a person who's driving, needs to get to work, has to take the kids to school, whatever, most of my patients are like, yeah, okay, sign me up. These drugs are really pretty well tolerated. There's a substantial risk of a second seizure. So, I'll do that. In a kid,  a child that's, you know, not driving yet, that might be a different discussion. And the parents might say, well, I'd rather not have my son exposed, my daughter exposed to this. They're trying to go to school. They're trying to learn. We don't want to hinder that. We'll wait for a second seizure and then if they have a second seizure, which by the way is, you know, one of the definitions of epilepsy, well then they have epilepsy, then they probably will need to go on the seizure medication. Dr Jones: Great summary, Dr Vossler, and it is worth our audience being aware that the evidence has evolved alongside the improvement in the adverse effect profile. And sounds like your threshold is a little lower to treat then maybe it would have been some time ago, right? Dr Vossler: I would say that's exactly correct in my opinion. Particularly for adults, absolutely. Dr Jones: That's fantastic, Dr Vossler. I imagine there are a lot of aspects of caring for these patients that are challenging, and I imagine many scenarios are actually pretty rewarding. What do you find the most rewarding aspect of caring for patients with acute seizure management? Dr Vossler: Yes, I mean, that is really true. I would say that the most challenging things are treating refractory status epilepticus, but worse yet, new onset refractory status epilepticus and the super refractory status epilepticus, which I talk extensively about or write extensively about in the article and provide a lot of guidance on. Really, those conditions are so challenging because they can go on for such a long time. Patients are hospitalized for a long time. A lot of really good clinical guidance doesn't exist yet. There is a tremendous amount of research in that area which I find exciting, and really there's an amazing amount of international research on that, I think most of our audience probably is unaware of. And certainly, with those conditions, there is a high risk of later disability and mortality. We go through all of that in the article. The rewards really come from helping these people. When someone was super refractory status and it were non- sorry, new onset refractory status epilepticus, has been in the hospital for thirty days, it gets really hard for everybody; the family, the patient. And for us, it wears on us. Yet when they walk out the door, and I've had these people come back to the epilepsy clinic and see me later. We're managing their anti-seizure medications. They've survived. The NORSE patients often have substantial disability. They have cognitive and memory and even some psychiatric disability. But yet we can help them. It's not just management in the hospital, but it's getting to know these people, and I take them from the hospital and see them in my clinic and manage them long-term. I get a lot of great satisfaction out of that. We're hoping to do even better, stop patients’ status early and get them to recover with no sequelae. Dr Jones: What a great visual, seeing those patients who have a devastating problem and they come back to clinic and you get the full circle. And what a great place to end. Dr Vossler, thank you so much for joining us, and thank you for such a thorough and fascinating discussion on the importance of understanding and managing patients with the first seizure, acute repetitive seizures, and status epilepticus. Dr Vossler: Thank you very much, Lyell. Dr Jones: Again, we've been speaking with Dr Dave Vossler, author of an article on emergent seizure management, first seizures, acute repetitive seizures and status epilepticus in Continuum's most recent issue on epilepsy. Please check it out, and thank you to our listeners for joining today. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

  --------  

  19:57
• Epilepsy Genetics With Dr. Sudha Kessler

  Genetic testing plays a key role in the evaluation of epilepsy patients. With the expanding number of choices for genetic tests and the complexity of interpretation of results, genetic literacy and knowledge of the most common genetic epilepsies are important for high-quality clinical practice. In this episode, Gordon Smith, MD, FAAN speaks Sudha Kilaru Kessler, MD, MSCE, author of the article “Epilepsy Genetics,” in the Continuum February 2025 Epilepsy issue. Dr. Smith is a Continuum® Audio interviewer and a professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia. Dr. Kessler is an associate professor of neurology and pediatrics at Perelman School of Medicine at the University of Pennsylvania and Children’s Hospital of Philadelphia in Philadelphia, Pennsylvania. ADDITIONAL RESOURCES Read the article: Epilepsy Genetics Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the Academy of Neurology: aan.com SOCIAL MEDIA facebook.com/continuumcme @ContinuumAAN  Host: @gordonsmithMD Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. Dr Smith: Hello, this is Dr Gordon Smith. Today I've got the great pleasure of interviewing Dr Sudha Kessler about her article on epilepsy genetics, which appears in the February 2025 Continuum issue on epilepsy. Sudha, welcome to the podcast and please introduce yourself to our audience. Dr Kessler: Oh, thank you so much. I'm Sudha Kessler. I am a pediatric epileptologist here at the Children's Hospital of Philadelphia and the University of Pennsylvania. Dr Smith: Tell us a little bit about yourself. Are you a geneticist too, or how did you get into this particular topic? Dr Kessler: Yes, I want to emphatically say that I am not a geneticist. I'm not an expert in epilepsy genetics at all. I take care of all sorts of patients with epilepsy. I actually do mostly epilepsy surgery-related care. But this part of epilepsy is, every year, increasingly important to our everyday practice. And I think it's fascinating, often a little daunting. I think I was asked to get involved with this article as a non-expert to help translate from the experts to the rest of us. Dr Smith: We're going to get there, because one of the things you do a really good job of in the article is talking about genetic concepts that are germane to everything we do. And I think you're an expert. You do it in a way that I understood. So, I'd like to get there, but- and this is a really hot area. For instance, I really loved your figure that shows the arc of discovery of genetic causes for epilepsy. It's really breathtaking, something we wouldn't have thought possible that long ago. And it's also a lot to digest. And so, I wonder if maybe we can begin by thinking about a framework and, for instance, you talk about these different groups of disorders. And one that seems to be particularly impacted by this unbelievable A-rated discovery. Our developmental and epileptic encephalopathies, or DEEs. What can you tell our listeners about that group of disorders? Dr Kessler: Sure. I think that, you know, most of what we think about in epilepsy genetics now has to do with disorders that are attributable to changes in a single gene. Genetics is obviously much more complicated than that, but that's still where we are in the stage of discovery. And the graph in the article is definitely one to take a look at because it represents the explosion that we've had in our understanding of single gene disorders leading to epilepsy and related manifestations. The DEEs are a group of disorders where any individual disorder is fairly rare, but as a group they are not that rare, and very impactful because they often cause epilepsy at a very young age. And either as a consequence of seizures or as a consequence of the underlying pathophysiology of that gene change, they are typically associated with really significant developmental impairments for a child 's entire life. Dr Smith: My understanding is that there's therapeutic development going on in this space. So, the early recognition of these genetic testing offers the promise of very impactful treatment---like we now do for SMA, for instance---early in the disease course. Dr Kessler: I think that's right. That's one of the most exciting parts of this field is that so much, just around the corner, for drug development, therapy development in this area. And as you can imagine, with a lot of these disorders, earlier intervention is likely to be much more impactful than later intervention when a lot of the developmental consequences are sort of… you know, when the cat 's already out of the bag, so to speak. Dr Smith: Yeah. So, this is really transformational and something that everyone who takes care of kids with epilepsy needs to know about, it seems. So on the other extreme, I guess, there are the self-limited epilepsies. I didn't really know about this in terms of genetic discovery, but can you talk about those disorders? Dr Kessler: Yeah, sure. I mean, I think some of these are the classic childhood epilepsy syndromes that we think about like childhood absence epilepsy or what we used to call benign romantic epilepsy and now call self-limited epilepsy of childhood with centrotemporal spikes. It's a mouthful, shortened to SeLECTS. Those are the epilepsies that occur typically in previously healthy children, that affects them for a few years and often remits so that epilepsy is just age-limited and doesn't continue for life. They clearly have genetic influences because they tend to run in families, but the genetics of them is not generally single gene associated. And so, we haven't actually explained why most of those kids actually get epilepsy. I think that'll be sort of another interesting area of discovery that will help us even understand some really fundamental things about epilepsy, like, why does this syndrome start at this age and tend to resolve by adolescence? Dr Smith: And the other thing I found interesting is disorders that I might have thought going into it would have a defined genetic cause or some of the disorders that there are not. So JME, for instance, or childhood absence, which is a little counterintuitive. Dr Kessler: It's completely counterintuitive. We call them genetic generalized epilepsies, and we know that they run in families, but we still know so little. I would say of all of the disorders that are mentioned in this article, that is the group where I think we have explained the genetic underpinnings the least well. Dr Smith: Yeah. Isn't that interesting? It's… wasn't it Yogi Berra who said, it's hard to predict things, particularly the future? So… Dr Kessler: Yes. Dr Smith: Who would have thought? So, we’ve talked a lot about kids. What about adults? You know, what role does genetic testing play in adults who have unexplained epilepsy? Dr Kessler: Yeah, I think that that is also a really important emerging area of knowledge. I think many epileptologists may think of genetic epilepsy as being solely pediatric. There are definitely not how many of these disorders can manifest for the first time in adulthood. Not only that, many of our children with childhood onset epilepsy that is due to a genetic problem grow up to become adults and will then need adult epilepsy care. In order to take care of both of those groups, it's really important for all epileptologists, including those that take care of adults, to have some knowledge of the potential impact of genetic testing. And how do you even approach thinking about it? Dr Smith: The message I guess I'm getting is if our listeners take care of patients with epilepsy, no matter how old those patients are, they need to be familiar with this. And the other message I'm getting is, it sounds like there are a lot of patients who really need genetic testing. And this came through in one aspect of your article that I found really interesting, right? So, what are the recommendations on genetic testing? So, the National Society of Genetic Counselors, as I understand it, said everyone needs genetic testing, right? Which I mean, they're genetic counselors, so. Which is great. In the International League Against Epilepsy, they recommended a more targeted approach. So, what's your recommendation? Should we be testing anyone with unexplained epilepsy, or should we be focusing on particular populations? Dr Kessler: Well, I guess I think about it as a gradation. There are certain populations that really deserve genetic testing, where it is going to be absolutely critical. You know, it's very likely that it will be critical knowledge to their care. If you diagnose somebody with epilepsy and you do imaging and that imaging does not reveal an answer, meaning you don't see a tumor or you don't see an old stroke or some other sort of acquired lesion, the next pillar of testing for understanding underlying etiology is genetic testing. That is the point at which I typically send my patients, and that's whether they're refractory or not. I think in the past some people felt that only patients with refractory epilepsy deserve or require testing. I think the reason why not to limit it to that population is that what's on a person's mind with epilepsy, or a family's mind with epilepsy, is what's going to happen to my child or to me in the future? And if genetic testing can shed some light on that, that will have a huge impact on that person's life. Dr Smith: You've got great cases in your article, which, I just want to give you a compliment. The information and entertainment, frankly, for per page: off the charts. It's not a long article, packed with useful information. And, I mean, some of your cases are great examples of patients who are heading down the surgical epilepsy path and you discovered, nope, there's a genetic cause that really impacted their care. What's the yield, right? The number of patients that you send genetic testing on for epilepsy, what percentage come back positive for a relevant sequence variant that you think is either causing or contributing to their epilepsy? Dr Kessler: That's a great question. I think that is actually still in flux because it depends on the population of patients that are being sent for testing, obviously, and then also on what testing is being done. So, I know in at least one large recent meta-analysis, the overall yield was 17%. And somebody hearing that number might think, oh, that's not very high, but it's actually very comparable to the yield for imaging. And we all do MRIs and patients that have new-onset epilepsy where the yield of MRI testing is about 20%  or so. So, quite comparable. And then with children with DEEs, the yield is much, much higher than that. Dr Smith: So, 17% is actually a really great diagnostic yield. When I think of my yield and doing genetic testing on patients who have an axonal CMT phenotype, right? I mean that's better than what I get. So, good for you. That's exciting. Dr Kessler: It's interesting. I think that maybe an assumption might be that you're working somebody up. You do a genetic test, it reveals a difference, and thus surgery is off the table. It's actually quite different than the head, which is that some results may make surgery be even more “on the table” because you might find a gene that is known to be associated with a propensity to vocal cortical dysplasia, for example. And you may take a good second look at that person's MRI imaging or do other imaging to reveal the MRI invisible vocal cortical dysplasia. Dr Smith: Outstanding point. Let's talk a little more about the genetic testing itself. So, we've got all these genes. We understand when to test. What do you do? For instance, last night I just looked at the company that we use for most of our neuromuscular testing and they have a genetic epilepsy next gen panel with, I don't know, three hundred and twenty genes, right? Do you use that kind of panel? Do you go directly to a whole EXO? What's the right approach? Dr Kessler: Yeah, I think that that is quite dynamic right now, meaning that recommendations seem to change often enough that I rely on help. I have the enormous good luck of working here at CHOP where there is a fantastic epilepsy genetics group that I can easily refer to, and I know not everyone has that resource. The current recommendation is to start with an exome if that is available and is covered by that patient's insurance. When exome is not available, then the next best thing is a gene panel. You know, in recent years there have been a lot of sponsored gene panels, meaning free to the patient, administered by a company that then, you know, has other uses for compiled or grouped genetic data. And I think that as long as all of that can be clearly explained to a patient, and- along with all of the other things so you have to explain to a patient before doing genetic testing, about the pluses and minuses of doing it, I think that you sort of go for the best test you can that's available to that patient. Dr Smith: The sponsored programs can be very, very helpful, particularly from a payer or a patient payment perspective. And so, I guess the lesson there is it's great if you got the resources and CHOP to help you decide, but better to get whatever panel you can get than to do nothing; or, of course, refer to a center if you're not comfortable. Dr Kessler: And also, just know that these things change often enough that if it's been a couple of years and you might want to recheck whether the EXO is available to that patient or whether a gene panel can be sent that includes more than they had eight years ago. Dr Smith: So, are there situations to go to the other extreme where you just do targeted sanger sequencing? Like, just sequence the specific gene of interest?  Dr Kessler: Yeah, absolutely. I'm still a big proponent of thinking clinically about a patient. If there are clues in that patient's history, exam, imaging, anything that gives you some sense of the disorder that this patient might have. And I think a classic example would be tuberous sclerosis. If you see an infant who has new onset spasms, you see hypopigmented macules on their skin and their MRI shows a tuber, you know, also known as a focal cortical dysplasia, then sure, send the targeted sequencing for the TSC1 and TSC2 genes. Dr Smith: And Rett syndrome?  Dr Kessler: And Rett syndrome would be another example. And there are many examples where, if you feel like you have a good sense of what the disorder is, I think it's completely acceptable to send the targeted testing.  Dr Smith: So, I'm going to get further down the rabbit hole and get to from easier to harder. I always get confused about things like chromosomal microarrays or, like, karyotypes and rings and stuff like that. What role do these tests play and what do our listeners need to know about them? Dr Kessler: Yeah, I think that it is really important to have at least some knowledge of what each test can't tell you. I tell my medical students at my residence that all the time. With anything in medicine, you should know what you're asking of a test and what answers a test can tell you and can't tell you. It is baseline knowledge before requesting anything. And if you don't know, then it's best to ask. So, chromosomal microarray is used when you think that there is a large-scale derangement in a bunch of genes, meaning there is a whole section of a chromosome missing---that would be deletion, or that that information is duplicated or is turned around in a, you know, in a translocation. That is what- the kinds of things that that test can tell you. I think of doing a microarray when a child has not just epilepsy and intellectual disability, but also has, for example, other organ systems involved, because sections of chromosome can include many, many, many different genes and it can affect the body in larger ways. That's often when I think about that. So, a child with multiple congenital anomalies. Karyotype, which we think of as the most old-fashioned way of looking at our genes, still has some utility because it is useful for looking at a specific situation where the ends of arm of a chromosome get cut off and get sticky and then stick to each other and make a ring. For example, ring chromosome 20 is a disorder which can cause epilepsy, particularly hard-to-treat frontal lobe epilepsy, and that sometimes doesn't show up until adolescence or even early adulthood. That's just one example of something that karyotype can tell you.  Dr Smith: And it goes without saying, but just to emphasize, these are things that you would miss completely on a next generation panel or a next genome? Dr Kessler: That's correct. Because this isn't about sequencing. This is about large structures. You know, with my patients, it's sometimes, I think, very hard to explain. It's hard enough to explain it to other physicians who aren't in genetics, but it's a whole other undertaking to explain it to families who may not have a lot of literacy about cell biology or genetics or, you know, anything related to that. So, I often rely on analogies. And one analogy I use is that if you're- all of your genetic information is like a book, that book is split into chapters and those are the chromosomes. And you can be missing entire paragraphs or have paragraphs duplicated. And that would be the kind of thing that we would be looking for with the chromosomal microarray with sequencing or, you know, with sequencing, we're looking for spelling of words, and we can look at one word at a time. That would be targeted sequencing. Or we can look at many, many words at a time. And that would be next gen sequencing.  Dr Smith: I just want to say that you are the genetic whisperer. You know, translator. I love it.  Dr Kessler: You can continue using it down to the level of explaining the possibility of a variant of unknown significance, which I think is sometimes difficult to explain. So, I often will say, I know how the word color is spelled: C O L O R. But sometimes in other places it will be spelled C O L O U R and that's still the same word, that's still color. That's just what we would call a population variant. If it is spelled C O M O R, that changes meaning; that is not a word, and that is probably a pathogenic variant. But if it gets misspelled and it’s K O L O R, then I'm not sure. Could that be a variant that means something different or not. And so that I would call that a variant of unknown significance, meaning its impact is to be determined. Dr Smith: So, I was going to ask you about variant calling, but you'd beat me to the punch. And that's a great metaphor that I will definitely remember. All right, here's another concept that I think people often find challenging, which is read depth. Can you tell us about reading depth or sequence depth?  Dr Kessler: Yes, hopefully I can. Again, not an expert here, but as I understand it, the way next gen sequencing works is that pieces of DNA are getting read. And the number of times any given nucleotide is read in this process is the read depth. It basically just translates to the number of times the processor, the machinery of doing this, pays attention to anyone site. The reason it's important is that the process by which this reading is done can sometimes result in errors. The greater your depth, the more times something is read, the less likely you are to have a mistake.  Dr Smith: In either direction. So, you're presumably less likely to have a false positive or false negative. Yep, again, very well explained. You know, I've got a lot of other questions I want to ask you, but I do want to be respectful of our listeners’ time. I wonder if we could pivot a little bit and just let's go back to where we began. Really exciting time, right? Amazing. And you've been doing this long enough. I'm sure you didn't think when you started that it was going to look like this. What does the future look like? I mean, we talked a little bit about therapeutics, but the world's changing fast. Five, ten years from now, what's your hope for that?  Dr Kessler: Oh, that's such a great question. You know, we are at the point with genetic epilepsies that gene-based therapies, either antisense oligonucleotide-based therapies or viral vector-based gene therapies, are actually now being developed and administered in trial situations to actual patients. And so, it always feels like we're on the cusp, but I think actually now we really are on the cusp of having gene-based therapies for genetic epilepsies. I think that there is still so much to sort out, both from basic scientific point and from a practical administering these things to patients and what are the potential long term consequences.For example, unlike medications, which are therapies that you can stop if there are adverse effects, often administering a gene therapy is a one-and-done thing that can't be retracted. Thinking even about the ethical framework of that and the framework of explaining to patients that we don't know the ten, twenty-year consequences of that, is part of the informed consent process, for example. So, there's still so much work that is going to be transformational, not just from the, you know, the big picture, but from developing all, you know, from going through all of these steps to really make these kinds of therapies a reality. Dr Smith: Well, it's really amazing. And, you know, we're seeing this in multiple different areas in neurology. So, well done. You run the child neurology residency program there, I understand. I try to snoop on people before I talk to them because we haven't met before this. And you're obviously a very a very good educator. Thank you so much for talking with me today. I don't spend a lot of time in epilepsy, but every time I do one of these, I kind of want to go back and do something different because it's such a neat field. Thank you.  Dr Kessler: You're welcome. It was my pleasure.  Dr Smith: Again, today I've been interviewing Dr Sudha Kessler about her article on epilepsy genetics, which is truly outstanding. This article appears in the most recent issue of Continuum on epilepsy. Be sure to check out Continuum audio episodes from this and other issues. And thank you, listeners, for joining us today. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

  --------  

  22:51

Más podcasts de Salud y forma física

Podcasts a la moda de Salud y forma física

Acerca de Continuum Audio

Continuum Audio: Podcasts del grupo