Continuum Audio

• 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.

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• 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.

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  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.

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  22:51
• Neuroimaging in Epilepsy With Dr. Christopher Skidmore

  Neuroimaging is a tool to classify and ascertain the etiology of epilepsy in people with first or recurrent unprovoked seizures. In addition, imaging may help predict the response to treatment. To maximize diagnostic power, it is essential to order the correct imaging sequences. In this episode, Aaron Berkowitz, MD, PhD, FAAN speaks with Christopher T. Skidmore, MD, author of the article “Neuroimaging in Epilepsy,” in the Continuum February 2025 Epilepsy issue. Dr. Berkowitz is a Continuum® Audio interviewer and professor of clinical neurology at the University of California, San Francisco Dr. Skidmore is  an associate professor of neurology and vice-chair for clinical affairs at Thomas Jefferson University, Department of Neurology in Philadelphia, Pennsylvania. Additional Resources Read the article: Neuroimaging 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: @AaronLBerkowitz Guest: @ctskidmore  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 Berkowitz: This is Dr Aaron Berkowitz, and today I'm interviewing Dr Christopher Skidmore about his article on neuroimaging in epilepsy, which appears in the February 2025 Continuum issue on epilepsy. Welcome to the podcast, Dr Skidmore. Would you please introduce yourself to our audience?  Dr Skidmore: Thank you for having me today. I'm happy to talk to you, Dr Berkowitz. My name is Christopher Skidmore. I'm an associate professor of neurology at Thomas Jefferson University in Philadelphia. I'm a member of the Jefferson Comprehensive Epilepsy Center and also serve as the vice chair of clinical affairs for the department.  Dr Berkowitz: Thank you very much for joining us and for this fantastic article. It's very comprehensive, detailed, a very helpful review of the various types of brain pathology that can lead to epilepsy with very helpful images and descriptions of some of the more common findings like mesial temporal sclerosis and some of the less common ones such as cortical malformations, heterotopia, ganglioglioma, DNET. So, I encourage all of our listeners to read your article and take a close look at those images. So, hopefully you can recognize some of these findings on patients’ neuroimaging studies, or if you're studying for the right or the boards, you can recognize some of these less common congenital malformations that can present in childhood or adulthood with epilepsy. In our interview today, what I'd like to do is focus on some practical tips to approaching, ordering, and reviewing different neuroimaging studies in patients with epilepsy. So to start, what's your approach when you're reviewing an MRI for a patient with a first seizure or epilepsy? What sequence do you begin with and why, how do you proceed through the different sequences and planes? What exactly are you looking for?  Dr Skidmore: It's an important question. And I think to even take a step back, I think it's really important, when we're ordering the MRI, we really need to be specific and make sure that we're mentioning the words seizures and epilepsy because many radiology centers and many medical centers have different imaging protocols for seizure and epilepsy patients as compared to, like, a stroke patient or a brain tumor patient. I think first off, we really need to make sure that's in the order, so that way the radiologist can properly protocol it. Once I get an image, though, I treat an MRI just like I would a CAT scan approach with any patient, which is to always approach it in the same fashion. So, top down, if I'm looking at an axial image. If I'm looking at a coronal image, I might start at the front of the head and go to the back of the head. And I think taking that very organized approach and looking at the whole brain in total first and looking across the flare image, a T2-weighted image and a T1-weighted image in those different planes, I think it's important to look for as many lesions as you can find. And then using your clinical history. I mean, that's the value of being a neurologist, is that we have the clinical history, we have the neurological exam, we have the history of the seizure semiology that can might tell us, hey, this might be a temporal lobe seizure or hey, I'm thinking about a frontal lobe abnormality. And then that's the advantage that we often have over the radiologist that we can then take that history, that exam, and apply it to the imaging study that we're looking at and then really focus in on those areas. But I think it's important, and as I've illustrated in a few of the cases in the chapter, is that don't just focus on that one spot. You really still need to look at the whole brain to see if there's any other abnormalities as well. Dr Berkowitz: Great, that's a very helpful approach. Lots of pearls there for how to look at the imaging in different planes with different sequences, comparing different structures to each other. Correspondent reminder, listeners, to look at your paper. That's certainly a case where a picture is worth a thousand words, isn't it, where we can describe these. But looking at some of the examples in your paper, I think, will be very helpful as well. So, you mentioned mentioning to the neuroradiologist that we're looking for a cause of seizures or epilepsy and epilepsy protocols or MRI. What is sort of the nature of those protocols if there's not a quote unquote “ready-made” one at someone 's center in their practice or in their local MRI center? What types of things can be communicated to the radiologist as far as particular sequences or types of images that are helpful in this scenario? Dr Skidmore: I spent a fair amount of time in the article going over the specific MRI protocol that was designed by the International League Against Epilepsy. But what I look for in an epilepsy protocol is a high-resolution T2 coronal, a T2 flare weighted image that really traverses the entire temporal lobe from the temporal tip all the way back to the most posterior aspects of the temporal lobe, kind of extending into the occipital lobe a little bit. I also want to see a high resolution. In our center, it's usually a T1 coronal image that images the entire brain with a very, very thin slice, and usually around two millimeters with no gaps. As many of our neurology colleagues are aware, when you get a standard MRI of the brain for a stroke or a brain tumor, you're going to have a relatively thick slice, anywhere from five to eight millimeters, and you're actually typically going to have a gap that's about comparable, five to eight millimeters. That works well for large lesions, strokes, and big brain tumors, but for some of the tiny lesions that we're talking about that can cause intractable epilepsy, you can have a focal cortical dysplasia that's literally eight- under eight millimeters in size. And so, making sure you have that nice T1-weighted image, very thin slices with no gaps, I think is critical to make sure we don't miss these more subtle abnormalities. Dr Berkowitz: Some of the entities you describe in your paper may be subtle and more familiar to pediatric neurologists or specialized pediatric neuroradiologists. It may be more challenging for adult neurologists and adult neuradiologists to recognize, such as some of the various congenital brain malformations that you mentioned. What's your approach to looking for these? Which sequences do you focus on, which planes? How do you use the patient 's clinical history and EEG findings to guide your review of the imaging? Dr Skidmore: It's very important, and the reason we're always looking for a lesion---especially in patients that we're thinking about epilepsy surgery---is because we know if there is a lesion, it increases the likelihood that epilepsy surgery is going to be successful. The approach is basically, as I mentioned a little bit before, is take all the information you have available to you. Is the seizure semiology, is it a hyper motor semiology or hyperkinetic semiology suggestive of frontal lobe epilepsy? Or is it a classic abdominal rising aura with automatisms, whether they be manual or oral automatisms, suggesting mesial temporal lobe epilepsy? And so, take that clinical history that you have to help start to hone your eye into those individual locations. But then, once you're kind of looking in these nonlesional cases, you're also then looking at the EEG and where their temporal lobe spikes, where their frontal lobe spikes, you know, using that and pulling that information in. If they saw a neuropsychologist pulling in the information in from the neuropsychological evaluation; if they have severe reductions in verbal memory, you know, focusing on the dominant temporal lobe. So, in a right-handed individual, typically the left temporal lobe. And kind of then really spending a lot of time going slice at a time, very slowly, because in some of these vocal-cortical dysplasias it can be just the blurring of the gray-white margin. What I find easiest is to identify that gray-white margin and almost track it. Like, you use the mouse to kind of track it around and say, can I outline the exact border of the gray white margin in the frontal lobe that I'm interested in or the temporal lobe that I'm interested in, kind of looking for those subtle abnormalities. Often as neurologists, we don't have the luxury of being able to immediately reformat. As I mentioned, our T1 volume acquisition study is done in the coronal plane, but sometimes you might want it in the axial plane. And so, I might reach out to the radiologist and say, hey, can you reformat this in the axial plane because I'm interested in the frontal lobe epilepsy and it's a little bit better at looking at it in that plane? And I'll have them reformat and put it back on the pack so I can look at it in that manner. And so that's a, kind of another strategy is to take what you have, but also then go back to the radiologist and say, I need to look at it this a different way. Can you reformat it for me? Looking for that gray-white matter junction is the nice way to pick up for kind of subtle cortical dysplasias. And then when you see an abnormality, to be able to put the T1, the T2, and the flare image all up next to each other and use the technology built into most of our browsers to put on what's called the localizer mode, where I can highlight a specific spot that I'm seeing on the T1 and then very easily quickly see, what does it look like on the T2? What does it look like on the flare? To kind of quickly decide, is it a true abnormality or am I only seeing it on one slice because of an artifact on that one imaging sequence? And I think that's the biggest kind of key is to make sure, is it an artifact or is it not an artifact? That's kind of the most common thing that we, I think, get confused with.  Dr Berkowitz: So, some very helpful pearls there in terms of reviewing the imaging, being in dialogue with our neuroradiology colleagues to think about potentially reacquiring certain images on certain planes or looking at the images with our neuroradiology colleagues to let them know more about the clinical history and where we're sort of zooming in about possible abnormalities.  Dr Skidmore: I would just add in there that when looking at especially the mesial temporal structures, because of a lot of artifacts that can be present in an individual MRI machine, it's not uncommon that the mesial temporal structure will appear brighter because of an MRI magnet artifact. And so, it's a good key to look at the hippocampus compared to the insula. And so, the hippocampus and the insula should have similar signal characteristics. You're seeing the hippocampus is bright, but the insula  ipsilateral to it’s normal intensity. That would suggest that that's probably a true hyperintensity on the flare-weighted image as opposed to if both are bright, unless you're suspecting a hemispheric abnormality, it's more likely to be a kind of artifact in the MRI machine. Dr Berkowitz: Okay. Those are really helpful tips, not just to analyze the hippocampus and medial temporal lobe itself---let's remember our anatomy and the circuit of Papez---and to look at associated structures for supporting evidence of a possible abnormality in the hippocampus itself. It looks like there may be something subtle. We can use some additional information from the image to try to decide if that is real or artifactual, and of course correlating with the clinical picture and EEG. I'd like to talk briefly now about some other imaging modalities that you discuss in your paper, the use of functional imaging such as PET, SPECT and fMRI. Let's talk a bit about each of these. When would you order a PET scan for a patient with epilepsy? What would you be looking for and how would you be using that to make clinical decisions?  Dr Skidmore: Yeah, so these functional imaging modalities are really utilized when we're evaluating somebody that's not responding to medications. So, they're medically intractable, and we're wondering, could they be a candidate for epilepsy surgery? And so, most of these imaging modalities are really relegated to the world of epileptologists at surgical epilepsy centers. I wanted to include them, though, in the article because I do think it's important for general neurologists to understand kind of what they are, because invariably a patient sees me and then they go back to their general neurology and be like, hey, Doctor Skidmore said I had this PET scan abnormality. What do you think? So, I think it's a good idea for general neurologists to kind of understand them. So, probably the oldest that we've utilized is the FDG PET scan, basically looking at fluorodeoxyglucose and the brain's utilization of glucose. As we all remember, again, glucose is the primary molecule for energy and ATP production in the brain. And so basically, by injecting radioactive glucose in the interictal state--- so not during a seizure but in between seizures---areas of the brain that are not taking up the radiotracer will show as being hypometabolic. So, low metabolism. And hypometabolic regions in the interictal state have been associated with onset regions for epileptic seizures. Let's say you have a patient clinical history, you think they have temporal of epilepsy, EEG suggests temporal of epilepsy, but the MRI is nonlesional, meaning there's no abnormality that anybody could appreciate even at a 3 Tesla scanner. We'll get an FDG PET scan and see, is there hypo metabolism in that temporal lobe of interest? And if there is, well, that's been shown through several published papers, that's just as valuable as having an abnormality on the MRI. And so, we often again use these PET scans, especially in nonlesional cases, to try to find that subtle cortical dysplasia. Now you have your nice epilepsy protocol MRI, it says it's nonlesional. You get your PET scan, it shows hypometabolism in a region of the frontal lobe, let's say, in a in a frontal lobe epilepsy case. And then often we go back, we kind of talked about strategy of how you find those subtle lesions. Then you go back and say, well, look, this gyrus specifically on the PET scan said it's abnormal. You end up looking for really subtle, very tiny abnormalities that, even with somebody that's skilled, often at first review gets missed. So, that's how we use the PET scan. The SPECT scan is done typically in the ictal state. So, now somebody’s in an epilepsy monitoring unit often, where you're injecting radio tracer at the exact moment that somebody starts having a seizure. And we know when there's increased seizure activity, the increased seizure activity---let's say it's from my right temporal lobe---is going to increase cerebral blood flow transiently to the right temporal lobe. And then if that seizure discharge spreads from the right temporal lobe maybe to the entire right hemisphere and eventually becomes a focal to bilateral tonic chronic seizure by spreading to the other side, the entire brain is going to be hypoperfused at that point. So, if you want to, as soon as the seizure starts, inject that radio tracer to see, where is the blood flow earliest in the seizure? And then we might do an interictal SPECT when you're not having a seizure. Look at, all right, what's the normal blood flow when somebody's not seizing? What's it like when they're having a seizure? And then the area that has increased activity would- might suggest that's where the seizure started from. But we have to be very careful because again, some seizures can spread very rapidly. So, if you delay injecting an injection ten, fifteen, twenty seconds, the seizure could have already propagated to another region of the brain, giving you a false positive in another location. So, you have to be very careful about that modality. I think what's most exciting is the functional MRI because the functional MRI, for many, many centers, is replacing a very old technique called the WADA test. So, in the WADA test, typically you place a catheter angiogram into the internal carotid artery and transiently introduce a sedative medication to put, let's say, the left hemisphere to sleep because you wanted to see what functions were still active in the right hemisphere. And then the surgeon would move the catheter or the right internal carotid artery, and you inject a sedative on that side after the left hemisphere is recovered and see what the left hemisphere can do. And we used that for language dominance, we used that for memory dominance. And while most individuals did fine with angiograms, unfortunately complications do occur and there's injury to the artery, there could be strokes that can- that have happened, which can be quite devastating for the patient. And so, functional MRI is a nice, noninvasive way for us to map out language function, motor function, sensory function, visual function, and is starting to show some usefulness also for mapping out kind of memory function, dominant memory function, meaning verbal memory compared to visual memory. To be able to do those things noninvasively becomes really important because, if we're talking about epilepsy surgery, we want to make you seizure-free but neurologically intact. And so, we need to understand the relationship between where we think the seizures are coming from and where eloquent cortex is so we can properly counsel you and avoid those regions during any planned surgery. Those are the three most common functional imaging modalities that we're using now to supplement the rest of the presurgical work.  Dr Berkowitz: Very helpful. So, these are studies, PET, SPECT, and fMRI, that would really be obtained predominantly in patients in whom epilepsy surgery was being considered to have more precise lesion localization, as well as with the fMRI to get a better sense of how to provide the safest maximal resection of epileptogenic tissue while preserving functions. Dr Skidmore: That's a perfect summary.  Dr Berkowitz: Fantastic. This has been a really helpful interview with Dr Skidmore and a really fantastic article. As I said, a picture is worth a thousand words, so I definitely encourage you to read the article and look at the images of some of the conditions we've been talking about and some of these findings that can be seen on interictal PET or ictal SPECT to get a sense of the visual aspects of what we've been discussing. So again, today I've been interviewing Dr Christopher Skidmore about his article on neuroimaging and 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 so much to our listeners for joining us today.  Dr Skidmore: Thank you for having me. 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.

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• EEG in Epilepsy With Dr. Daniel Weber

  EEG is the single most useful ancillary test to support the clinical diagnosis of epilepsy, but if used incorrectly it can lead to misdiagnosis and long-term mental and physical health sequelae. Its application requires proper understanding of its limitations and variability of testing results. In this episode, Katie Grouse, MD, FAAN, speaks with Daniel Weber, DO, author of the article “EEG in Epilepsy,” in the Continuum® February 2025 Epilepsy issue. Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California San Francisco in San Francisco, California. Dr. Weber is the director of adult epilepsy and vice chair of clinical affairs at the St. Louis University in St. Louis, Missouri. Additional Resources Read the article: EEG 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 Guest: @drdanielweber 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 Grouse: This is Dr Katie Grouse. Today, I'm interviewing Dr Daniel Weber about his article on EEG and epilepsy, which appears in the February 2025 Continuum issue on epilepsy. Welcome to the podcast and please introduce yourself to our audience. Dr Weber: Hi, thanks for having me. My name is Dan Weber and I'm an epileptologist at Saint Louis University. I direct the adult epilepsy program here and also serve as the vice chair for Clinical Affairs. Been my pleasure to work on this article. Dr Grouse: I'm so happy to have you today. I read your article. I found it to be incredibly useful as someone who often orders EEG in the general neurology clinic. So, I wanted to start with asking, what is the most clinically relevant message or takeaway from your article that you'd really like neurologists to know?  Dr Weber: Yes, when I was asked to write this article, I looked back at the previous Continuum on epilepsy and just the general literature. And there's a lot of good articles and books out there on EEG and epilepsy and sort of giving you a primer on what you might see and how to interpret it. So, we wanted to try to go a slightly different direction. This article gives you some of that gives you the background of EEG and some of the basic things that you may see, but the real thrust of it is more about the limitations of EEG in the clinical picture of epilepsy and common things you might avoid. There are some things that we get hammered into our brains in training that aren't always true and there's plenty of examples in the literature to review, and this article sort of tries to encapsulate as many of those as possible in a digestible format. The main takeaway would be that EEG is an extremely helpful tool in the diagnosis of epilepsy, is the best tool we have to help supplement your clinical acumen. But it does not make the diagnosis of epilepsy. And there are certain circumstances when it may not be as helpful as you may have been led to believe in residency. Dr Grouse: Maybe not the most comforting of messages, but certainly an important one, very important to learn more about this. So, we appreciate that. Can you tell us your decision-making process when deciding whether to order a routine EEG, an extended EEG, prolonged ambulatory EEG, or inpatient video EEG? Dr Weber: Sure. So, it's a multi-part question because each one, I think, has a different clinical scenario. In the current state, our best data for estimating risk of recurrence after an initial seizure comes with routine EEG abnormalities. So, often I will order routine EEGs in those scenarios. So new patient presentation, new patients coming in with an initial seizure who want to know what's their risk of recurrence. So, risk stratification, I use a lot of routine EEG for, often sleep deprived if possible to increase the sensitivity. If you'd like, the extended EEG does offer higher sensitivity, or you can repeat the routine EEG if the first routine EEG is nonconclusive. For generally extended EEGs, I tend to order them in my practice if patients have come to see me with a suspected diagnosis of epilepsy but haven't yet had any electrographic confirmation. Maybe they've already had routine EEGs done in the past, so we'll try to obtain just a little more data. The longer-term EEGs I tend to use in different clinical scenarios, in patients usually who already have established diagnosis or people who have become refractory and we haven't yet confirmed their diagnosis. I tend to do inpatient EEGs in those situations. Ambulatory EEGs I do more when there are certain characteristics of the patient or the patient 's presentation that may not fit well on the inpatient side. Patients who are reliant on substances who can't use while they're inpatient and may have withdrawal effects complicating the stay. Or people who have a strong activation component to their epilepsy where activity really draws it out, certain activities that they do at home that they might not do during the inpatient stay. Those are the sorts of people I'll do ambulatory EEGs on. There are a couple other scenarios as well that come up less commonly, but everything has its own little niche. Dr Grouse: That's a really helpful review as we sort of think about which way we want to go as we're working up our patients in the inventory setting. Can you tell me a little more about the difference between sensitivity of, for instance, doing maybe two routine EEGS versus prolonged ambulatory EEG? Dr Weber: Generally speaking, the longer you're recording someone's brain waves, the higher the sensitivity is going to be. So routine EEG is twenty to forty minutes at most places. One of those gives you a certain sensitivity. More of them will give you more sensitivity. And there was a recent study highlighted in the article that compared routine EEGs to initial multi-day ambulatory EEG, and the ambulatory EEG obviously, as would be expected, has a higher sensitivity than either of the routines. So, there may be some cases with that initial evaluation where an ambulatory EEG may be held and we get into that in more detail in the article. But with the caveat, a lot of this article is about limitations, and the data that we have to talk about increased risk of recurrence was based off seeing epileptic form discharges on routine EEG. So you could hypothesize that if you only have one epileptic form discharge in three days on an ambulatory EEG, that may not carry the same recurrent significance as catching one on a twenty minute EEG. But we don't have that knowledge. Dr Grouse: Getting a little bit more into what you mentioned about the limitations, when is the scalp EEG less useful or limited in the evaluation of epilepsy? Dr Weber: So, one thing I see a lot in my residence at here and other places where I've worked is, I get them very excited about EEG and they may order it a bit too much. So, if patients have a known, established diagnosis of epilepsy, electrographically confirmed, and they come in with a breakthrough seizure and they're back to their baseline, there's really not a strong reason to get an EEG. We often seem to in the emergency department as part of our evaluation, but we already know what happened to the patient. The patient's not doing poorly right now, so the EEG is not going to give you any additional information. Just like really any test, you should think, what are the possible outcomes of this test and how would those outcomes alter the care of this patient? And if no outcome is going to affect the care of the patient or give you any additional diagnostic information, then probably don't need to be doing that test. Dr Grouse: This is probably a good segue into asking, what is an area of confusion or common pitfalls that you've seen in the clinical application of EEG and epilepsy? Dr Weber: So, a lot of times on the inpatient service, we'll get longer-term EEGs for patients who are having spells that are occurrent while they're in the ICU or other places or altered in some way, encephalopathic. And these patients will have their spell, and in my report, I'll say that there is not any electrographic correlate. So, there's no EEG finding that goes along with the movement that they're doing that's concerning for a seizure. And that doesn't always mean that it's not an epileptic seizure. An EEG is not a one-hundred-percent tool. Epilepsy and seizures are a clinical diagnosis. The EEG is a helpful tool to guide that diagnosis, but it is not foolproof, so you need to take the whole clinical picture into account. Particularly focal seizures without impaired awareness often can be electrographically silent on surface EEG. If you see something that looks clinically like a seizure but doesn't show up on the EEG, there are circumstances that they get to in the paper a little bit where that can still be an epileptic seizure. And you just have to be aware of the limitations of the tests that you're ordering and always fall back on the clinical skills that you've learned. Dr Grouse: Are there any tips or tricks you can suggest to improve the clinical utility of EEG for diagnosis of epilepsy? And also thinking about the example you just gave, but maybe other cases as well? Dr Weber: Again, definitely need to incorporate EEG as part of a larger picture. The video component of EEG is incredibly helpful. You can't interpret EEG in isolation. Regardless of what the EEG shows, you can't make a diagnosis of epilepsy, but you certainly can be very suspicious of one. So, in those cases where you have a high suspicion for an epileptic seizure and the EEG has not given you any confirmatory evidence, it's really helpful to rely on any clinical expertise that you have access to. So, people who have seen lots of seizures may be helpful in that situation. Getting good recordings, good data to prove yourself one way or the other is helpful and continuing to evaluate. So usually, as I said, focal seizures that don't show up well on the EEG. People who have focal seizures will often have larger seizures if left untreated. So, you can try to admit them to an epilepsy monitoring unit where we try to provoke seizures and try to provoke a larger seizure to help confirm that diagnosis. Dr Grouse: This kind of gets into what we've already reviewed to some degree, but what is the easiest mistake to make (and hopefully avoid) when using EEG to diagnose epilepsy or make other treatment decisions? Dr Weber: I think the easiest, most common mistake I see is overreliance on the test. There's a lot of subjectivity to the interpretation of this test. There are a lot of studies out there on interrater reliability for epilepsy and intrarater reliability for epilepsy. We continue to try to make the findings more objective and get more quantified. The articles talk about our six criteria for epileptiform discharges and have reference to where that came from and the sorts of specificity that each of those criteria lead to. Just because an EEG report has said something, that does not diagnose or negate a clinical diagnosis of epilepsy. It is common for folks with non-epileptic seizures to have a history of reported epileptic form discharges on their EEG. Again, because there is some subjectivity to the test, some abnormal-looking normal variants will pop up and get interpreted as epileptiform discharges. It's important to review the whole patient, as much of the data as you can, and make the best clinical judgment you can of the overall case. Dr Grouse: What is quantitative EEG and how can it be clinically useful? Dr Weber: Now that most EEG is obtained digitally through the use of computer software, we have been able to employ computers to do a lot of the work for us. There are many different ways of looking at the EEG data, but it's all frequency bands over time. The quantitative EEG goal is really to simplify and condense what you're seeing on your normal EEG page into a more digestible format. Lets you look at a larger amount of data faster, which becomes more and more important as we're doing more of these long-term recordings, particularly in the intensive care unit. Quantitative EEG can help you assess a lot of data at a snapshot and get a general sense of what's going on with the patient over the past several hours. It does require some extra training to become familiar with it, but it's training that can be done at all levels. Again, it can help you see more, faster. Obviously, like everything, it has its own limitations. Sometimes the sensitivity and specificity may be a little off from the raw data review, and you should always go back to the raw data anytime there are questions. But it can be helpful to make things faster. Dr Grouse: Do you think you could give me a hypothetical example of a case where this would be something really nice to have?  Dr Weber: The most common example is folks with repetitive seizures in the ICU. If you're just looking at the raw data, you will get a sense of how often the seizures are happening. But if you look at the quantitative data, it sort of compresses that all down to a much smaller snapshot. So you can see much more readily, yes, these are how many seizures were happening. And here's where we gave our intervention; and look, there are fewer seizures after that intervention. So, it can help you assess response to treatment, help you assess just overall volume of seizures in a much more condensed fashion, and you can get through it much faster with the appropriate training. Dr Grouse: Can you tell us about any new developments in EEG that are on the horizon we should be aware of?  Dr Weber: Yeah. So, I think my two favorites, which I highlight in the article, are longer-term recordings---so, there's some companies that are working on subcutaneous EEG. So, implanted EEG electrodes that can stay in your body for the short, long term on the order of year or years and constantly send some EEG data. Obviously, it's not a full montage in most of those cases, but some EEG data that can help you assess long-term trends in epilepsy and long-term response to therapies. I think that's going to be really cool. I think it's very exciting and I think it'll change how we do clinical trials in the future. I think we'll be able to rely less on seizure diaries from folks and more on objective seizure data for patients who have these implanted. But with that will come an ever-increasing amount of data to be reviewed, which leads into the other exciting future trend is AI in the use of interpretations. AI is becoming more and more advanced and there are very exciting articles out on how good AI is getting at interpreting our EEGs. I think soon, in the very near future, the AI platforms will be able to dramatically reduce the amount of time it takes the experts to review an EEG. They'll be able to do a lot of the screening for us and then we can go back, just like I was talking about the quantitative EEG, go back and review segments of the raw data rather than having to review every page of every file, which is quite time consuming. Dr Grouse: Wow, that's really exciting. It certainly does seem like AI is making breakthroughs in just about every area of how we touch the practice of medicine. Exciting to hear that EEG is no exception. Dr Weber: Yeah, I'm fully excited. I think it's going to revolutionize what we're doing and also just greatly expand people's ability to access that level of expertise that the AI will offer. Dr Grouse: I wanted to transition to talking a little bit more about you and your career in neurology. How did you become interested in this area of neurology to begin with? Dr Weber: Yeah, it's sort of a roundabout fashion. So, I started out planning to be a neurointerventionalist, and then I realized that I didn't want that sort of call. For a hot minute in my PGI 3 year. I was planning to be a neuro-ICU doctor. I think that's largely because medicine is all I had been exposed to at that point and the ICU seemed like a very comfortable place. Then as I transitioned into PGI 3 we started doing more electives and outpatient rotations in my residency. And then I was planning on being a movement disorder specialist or an epileptologist, couldn't make up my mind for the longest time. And then I started to like EEG more than I liked watching videos. So, tilted myself towards epilepsy and haven’t looked back.  Dr Grouse: Well, I really appreciated you coming to talk with us today about your article. I can't recommend it enough to anyone out there, whoever treats patients with epilepsy or orders the EEGs, I just think it was just incredibly useful. And it was such a pleasure to have you. Dr Weber: Thank you very much for having me, Katie.  Dr Grouse: Again, today I've been interviewing Dr Daniel Weber about his article on EEG and 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.  

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  18:24

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