Continuum Audio

Dr. Susan Mollan, a consultant neuro-ophthalmologist at University Hospitals Birmingham, shares her expertise on papilledema—optic disc swelling due to increased intracranial pressure. She dives into the critical importance of thorough ocular examinations and offers practical tips for accurate diagnosis. The discussion also explores managing incidental findings in neuroimaging and emphasizes compassionate communication when addressing weight management with patients. Insights from her published article provide valuable guidance for practitioners in the field.

The inflammatory and infectious optic neuropathies are a broad, heterogeneous, and common group of diseases producing visual loss. Although many now-distinct syndromes have been previously combined as “typical or atypical optic neuritis,” recent developments highlight the importance of precision terminology as well as an individualized evaluation and treatment approach. In this episode, Gordon Smith, MD, FAAN speaks with Eric Eggenberger, DO, MS, FAAN, author of the article “Optic Neuritis” in the Continuum® April 2025 Neuro-ophthalmology 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. Eggenberger is a professor of ophthalmology, neurology, and neurosurgery at the Mayo Clinic in Jacksonville, Florida. Additional Resources Read the article: Optic Neuritis 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: @gordonsmithMD Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Smith: This is Dr Gordon Smith. Today I'm interviewing someone who really needs no introduction, Dr Eric Eggenberger, about his article on optic neuritis, which appears in the April 2025 Continuum issue on neuro-ophthalmology. Eric, welcome to the podcast, and maybe you can introduce yourself to our audience. Dr Eggenberger: Thank you. Thanks for having me. So, my name is Eric Eggenberger. I work at Mayo Clinic Florida, and I am involved exclusively in neuro-ophthalmology. Dr Smith: I just had the pleasure, Eric, of talking yesterday with Lindsey De Lott about non-optic neuritis causes of optic neuropathy. And so, I'm going to kind of reference a little bit what I learned yesterday. She was great. I wonder if you might begin by talking a little bit about nomenclature. You talk about the need for use of precise terminology in your article. And yesterday she taught me a lot about the risk of misdiagnosis and other causes of optic neuropathy, and the two seem related. So, I wonder if you can maybe lay the foundation for our conversation by talking about terminology? Dr Eggenberger: I think that's a great point. So, we are in an era now where, instead of lumping all these different diagnoses together, we have learned to split apart some of these clinical entities. And so, I think it's really important that we focus on precise terminology and recognize that all optic neuritis is not the same. And we have very different, distinct clinical pathways for these imaging pathways, treatment pathways, for these different types of optic neuritis, whether that's MS related, whether it's MOG related or aquaporin-4 related. Dr Smith: So, I wonder maybe we can begin by just, you know, giving our listeners wisdom, pearls, and pitfalls about, how do you recognize when someone with a suspected optic neuropathy has optic neuritis versus a noninflammatory optic neuropathy? Dr Eggenberger: So, that's a really important issue because there's a lot of clinical overlap in terms of exam findings. So, for instance, in any optic neuropathy, let's say it's unilateral, you typically are going to see decreases in acuity and field and color, and you're going to see a relative afferent pupillary defect. And then it's really the context that that occurs in that helps us distinguish different disease entities. So, with optic neuritis, typically you're going to have pain. And that's oftentimes going to be in the younger populations compared to some of the other common optic neuropathies we see, like ischemic optic neuropathy, for instance. Dr Smith: Right. So maybe we can talk a little bit about, kind of, your overall diagnostic approach, right? A lot of this is, of course, based on age and context, but young people get ischemic lesions and older people can have inflammatory lesions. So, what's your overall approach to the patient you just described? Let's say it's a forty-eight-year-old woman who comes to the emergency department with subacute unilateral vision loss and there's dyschromatopsia, APD, reduced acuity. And, you know, let's just say a fairly, you know, benign-looking fundoscopic exam. What do you do to evaluate that patient? Dr Eggenberger: In that particular context, I think we're looking at other contextual clues. Is there other vascular risk factors or other things to point you in one direction or the other? One of the important parts you mentioned was the fundus exam. So, we know with ischemic optic neuropathy, 100% of the time with AIOM, you're going to see disc edema. And so, in the context of that story, we want to confirm on our exam an optic neuropathy, and then we can kind of focus on the retrobulbar courses or different types of optic neuropathies. From an exam perspective, in that particular patient we’d be looking to measure the acuity, quantify that. And in the ER, you're not going to be able to do a perfect field, but you'll get some sense of the field and how much field loss there is. And then as you mentioned, the afferent pupillary defect is critical. And we're going to get a little bit of the historical features in terms of pain. With typical retrobulbar optic neuritis, most of those patients are going to experience some pain, and usually it's pain on eye movements. And those would be the clinical things to focus on. Other exposures the patient may or may not have had, any other concomitant conditions, would all help point you in different directions, perhaps, and then we're probably on towards imaging. Dr Smith: Yeah, maybe you can talk a little bit about that? What's the appropriate use of imaging? I mean, presumably the patients, like the one I just threw out there, are pretty much all going to get neuroimaging. What's your approach to that? How do you protocol the study? What should we be looking for? Dr Eggenberger: In our clinic, we would typically be ordering an MRI orbit and brain, and each of those has a specific purpose. The orbit is going to show us the extent of the optic neuropathy. So, we're particularly looking for a longitudinally extensive optic nerve lesion or more than half of the optic nerve involved. And most patients acutely, if it isn't an “itis" situation, we'll see enhancement. And then the MR brain is going to be useful for looking for other evidence of demyelination within the central nervous system. We may at some point get down to doing an MR cord, but I think acutely it's going to be brain and orbit that most of our patients are getting. Dr Smith: Let's say that we did the scan and, sure enough, there's sort of a shorter segment, so less than half the length of the nerve region of enhancement. What's the rest of your diagnostic evaluation look like for that patient? Dr Eggenberger: So, in that particular case, we would look at the remainder of the brain. So, we're looking for other evidence of demyelination and any other contextual clues, systemically that would point you one direction or another. But with a shorter segment involved, one of the more common things we might encounter would be multiple sclerosis-related optic neuritis. Dr Smith: Would you look for aquaporin-4 and MOG in a patient with what appears to be an isolated, uncomplicated short segment optic neuritis? Dr Eggenberger: So, I think it really depends a bit on the context. I would never fault anybody for looking at MOG or an aquaporin-4 in that context because those are really treatment-altering diagnoses, but the yield in this particular case with a short segment involved and depending on the acuity and other features is probably going to be pretty low. Dr Smith: I really liked as an aside- I wasn't going to go there next, but you kind of got me thinking about it, you have a really nice section in your article. Which, all of it's great, but talking about how to manage low titer MOG antibodies. I wonder if you could talk about that because I think that's a lesson, maybe, that is transferable to a lot of other testing that we do. in terms of pre-prior probability and titer and so forth. Dr Eggenberger: Yeah, that's really an important point. So, we've seen this come up a number of times where the MOG antibody is a very good test, but in low titer it has a relatively low positive predictive value, perhaps 50%. In those cases, particularly without a classic clinical context, you have to be extremely alert for some other diagnosis that could mimic what you think is inflammatory demyelinating optic neuritis, but in fact is infectious or some other cause. Dr Smith: Yeah, super, super important and helpful. In terms of aquaporin-4, how does that compare in terms of predictive values, lower titer positive results? Dr Eggenberger: So aquaporin-4, the test has a very high specificity. So, it's quite useful if positive. You have to keep in mind there can be some false negatives, but the test otherwise is quite specific. And that is a diagnosis, you know, we never want to miss. It's a vicious disease. It tends to be a blinding disease, particularly without treatment. Bad things happen when we miss that, and we want to get on that diagnosis early and do pretty aggressive early and prophylactic treatment. Dr Smith: Your article covers not only the common causes of optic neuritis and, you know, MS, isolated optic neuritis, MOGAD NMO, you talk about a bunch of other things. I wonder, in this patient that we've been discussing, in the absence of any other historical information that seems relevant---or maybe you can define what would seem relevant---would you do other evaluation in that individual, other serologic evaluation and so forth, just in terms of diagnosis? Dr Eggenberger: In that particular case, without other red flags, I don't think I would initially. And follow-up is going to give you a lot of this context. So, you'd be on the lookout for other systemic conditions. So, if the patient had some arthropathy, if the patient had any pulmonary disease hints, if there was anything else that could lead you on a broader expedition. But I think in the context of this case, acutely in the ER, I probably wouldn't do a big lab plug for this. I probably would kind of go down the most likely road and start our treatments, and then follow that patient up. Dr Smith: Yeah, I know your article does a really great job, I think, of outlining when do you need to think about some of these less common causes. Well, can we talk about treatment, Eric? Because I want to move on to some other things. But- so, we've got a patient with isolated optic neuritis, nothing else, you know, in terms of the other antibodies we've talked about. What state-of-the-care- or, state-of-the-art treatment for that patient? Dr Eggenberger: So, the acute treatment for these inflammatory, optic neuritis-type cases is very similar Initially. High dose steroids remains kind of the standard. And then, in MS-related optic neuritis, we may or may not see a taper. So many times it's just an acute treatment of three to five days high dose. Whether that's oral or PO, we could institute either depending on the particular case. And then the taper would depend on the potential cause. So, for instance, with these antibody-driven diseases---so with MOG- or particularly with aquaporin-4---if it's a longitudinally extensive region of optic nerve involved, we tend to use a longitudinally extensive taper. And so, we use prednisone in those cases for several months while we're getting everything else set and deciding what the overall course is going to bring. Dr Smith: What about IV versus oral? There must be something about my practice. I was telling this to Lindsey. Every time on our hospital service, we seem to have at least two patients with optic neuropathies, which I always enjoy, but I find it's a little weird to admit someone who's doing just fine otherwise to the hospital with three days of IV SOLU-MEDROL. So, I'm always trying to figure out, like, how can I get this patient home? And your article had the best term I've heard in a long time, which is “SOLU smoothies.” I mean, are there other strategies that you sometimes use, other than just high-dose IV methylprednisolone? Dr Eggenberger: So, I agree with you. It's sometimes hard to admit somebody for just an IV therapy. And we'll do this as an outpatient, high-dose IV, but we'll also use high-dose orals. And in times in the past when there's been methylprednisolone shortage, we've used high-dose oral or IV dexamethasone as well. I think the IV form, although it's the gold standard, the high-dose oral forms have pretty equivalent bioavailability and are pretty tolerable in my experience. And certainly more convenient. Dr Smith: I wonder if we should switch and maybe talk a little bit about aquaporin-4, I mean, you emphasized that this is a vicious disease---I love the way you describe that---and often blinding. What updates do you have in terms of our therapeutic approach to NMO? That's been rapidly evolving of late. Dr Eggenberger: Right, so these are cases we're always going to share with neuroimmunology. And it requires kind of a multidisciplinary approach, in my opinion, for ideal or for best outcomes. And so, all of these patients are going to get put on prophylactic medications. So, this is a disease you just can't leave untreated. Bad stuff will happen for sure. And we now, fortunately, have some approved, FDA-approved medications that can positively impact the course of this disease. So, that's been a welcome addition. Dr Smith: What are the FDA-approved medications at this point for NMO? Dr Eggenberger: So, there are several at this point, and this is an area that's in growth, fortunately. And again, these are cases we're going to be sharing with our neuroimmunology colleagues. So, these are IV medications typically aimed at complement or CD19. And they all are relatively effective at quieting the course of the disease. Dr Smith: Maybe we can talk a little bit about MOG? I think that most of our listeners are probably pretty familiar with aquaporin-4 and NMO, what- maybe you could describe MOG a little bit and the therapeutic approach for patients with MOG-associated disease? Dr Eggenberger: So, MOG has been a real interesting kind of condition to learn more about. We certainly see a lot of MOG, and I'm sure we saw MOG before it was formally described, but I think we just thought it was kind of a benign, maybe monophasic MS type of presentation. But MOG tends to come in with a loss of acuity that kind of rivals aquaporin-4. So, the acuity tends to be pretty, pretty depressed, but it's very steroid-responsive. So, a lot of times these are the patients, you'll see that their vision will start to improve even when they're on the initial few days of the high-dose steroids. And many times we can get their vision back to 20/20 or very close to that. Dr Smith: And do these patients need chronic management? Dr Eggenberger: So, that's an area of controversy to some degree. About 50% of the optic neuritis MOG-related cases are going to have a relapsing course. And because the disease is steroid-responsive, many times we'll follow these patients after a first attack to see if this is the condition that’s going to declare itself to be relapsing or if this is just going to be a monophasic kind of presentation of optic neuritis. We don't have great biomarkers to separate patients who are going to be in that 50% monophasic course versus the other half. It'll be relapsing. And so, it depends on the patient. If there's somebody that's, as many of these patients are, been very steroid responsive, they get back to 20/20, we can teach them about the disease so that if they do have a relapse, we can get them high-dose steroids in a relatively rapid fashion and they're otherwise healthy, we're probably going to watch that patient. And if it's somebody that doesn't recover 100%, there's other issues with treating them with high-dose steroids potentially in the future, then we may learn more towards an earlier prophylactic approach in that patient. Dr Smith: And what would that approach look like? Is it different from NMO or using more IVIG or B cell depletion as opposed to complement inhibition, for instance? Dr Eggenberger: In MOG, we know that the B cell depletion strategies don't work as well. And so most times we're turning to IVIG, and we found that pretty effective. That's kind of our go-to at this point. Dr Smith: Eric, it's a joy talking to you and I'd love to keep going about content, but I'll refer our listeners to your outstanding article. I mean, you're such a highly regarded neuro-ophthalmologist and educator. I wonder if you could talk to us about why you've done neuro-ophthalmology, and maybe this is an opportunity for you to convince all of our great residents that are listening or students what's great about being a neuro-ophthalmologist. Dr Eggenberger: I think neuro-ophthalmology is by far the most interesting part of neurology. So, it's an area that I think a lot of general neurologists, in my view, don't get enough of in their residency. But it's kind of the essence of neurology, where in neurology you're localizing down to the millimeter and in neuro-ophthalmology,  we're localizing down to the micron level. We have several new emerging diseases like these varieties of optic neuritis we're focused on. We're learning lots about those. You get to be involved in lots of different areas of neurology. So, we'll see not just demyelinating conditions, we'll see trauma as it relates to the visual system. And we'll see tumor, and we see all different flavors, stroke, and in any piece of neurology, commonly we'll have some vision aspect that we that we get involved in. So, we see a wide variety of conditions. So, I think it's been a really exciting place to be within neurology. And it's rapidly changing at this point. We're getting new therapeutics. So, it's, I think it's a great time to be a neuro-ophthalmologist. Dr Smith: Yeah, listening to you talk and just reflecting on it, it's really true. Neuro-ophthalmology does cover the entire span of neurology, right? I'm a neuromuscular guy and we see a lot of ocular myasthenia, which is another super exciting area. But we've been talking about optic neuritis, and your article talks about infectious causes and the paraneoplastic and a whole host of things. So, you're a great advocate and salesperson for your field. You convinced me. Dr Eggenberger: Efferent neuro-ophthalmology we love, we could talk about ocular myasthenia and other aspects for another hour. And we get involved in all kinds of cases: third nerve palsies, ocular myasthenia, trauma that involves the efferent system, all different aspects. It's really a great subspecialty, and you get to see a bit of all of neurology. Dr Smith: I'm trying to remember who it was, Eric. It was an attending of mine at medical school. I went to medical school at the Mayo Clinic in Rochester, and I want to say it was Manny Gomez, who was a very famous tuberous sclerosis person, who told me that neuro-ophthalmology was the most elegant specialty within neurology. That stuck with me. Thank you so much for joining me today. I really appreciate it. Dr Eggenberger: Thank you. I appreciate it as well. Dr Smith: So again, today I've been interviewing Dr Eric Eggenberger about his really wonderful article on optic neuritis, which appears in the most recent issue of Continuum on neuro-ophthalmology. Be sure to check out Continuum audio episodes from the neuro-ophthalmology and other issues. And listeners, thank you very much 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 the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Dr. Lindsey De Lott, a neurologist and neuro-ophthalmologist at the University of Michigan, delves into the complexities of optic neuropathies. She explains how misdiagnoses can lead to poor patient outcomes and highlights the importance of precise clinical assessments. The discussion covers the critical role of neuroimaging, particularly MRI, in differentiating between conditions like ischemic optic neuropathy and optic neuritis. De Lott also shares insights on treatment strategies, including the effective use of steroids and tocilizumab.

Dr. Nancy Newman, a renowned professor of ophthalmology and neurology at Emory University, discusses the intricate world of vision loss diagnosis. She highlights the importance of patient history and examination in navigating monocular and binocular vision loss. The conversation delves into the complexities of optic neuropathies, emphasizing that not all optic nerve issues are optic neuritis. Dr. Newman also advocates for using advanced imaging technologies to enhance diagnostic accuracy and underscores the collaboration needed between neurologists and ophthalmic specialists.

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Valérie Biousse, MD, who served as the guest editor of the Continuum® April 2025 Epilepsy issue. They provide a preview of the issue, which publishes on April 3, 2025.   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. Biousse is a professor in the departments of neurology and ophthalmology, as well as the Reunette Harris Chair of Ophthalmic Research, at Emory University in Atlanta, Georgia.  Additional Resources Read the issue: Neuro-ophthalmology Subscribe to Continuum®: shop.lww.com/Continuum More about the American Academy of Neurology: aan.com  Social Media  facebook.com/continuumcme  @ContinuumAAN  Host: @LyellJ  Guest: @vbiouss  Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about subscribing to the journal, listening to verbatim recordings of the articles, and exclusive access to interviews not featured on the podcast. Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr Valerie Biousse, who recently served as Continuum's guest editor for our latest issue on neuro-ophthalmology. Dr Biousse is a professor in the departments of neurology and ophthalmology at Emory University in Atlanta, Georgia where she's also the Renette Harris Chair of Ophthalmic Research. Dr Biousse, welcome and thank you for joining us today. Why don't you introduce yourself to our listeners? Dr Biousse: In addition to what you just mentioned, I would like to highlight that I have a French accent because I was born and raised and went to medical school in France in Saint Pete Pierre, where I trained as a neurologist. And I even practiced as a stroke neurologist and a headache specialist in the big university in Paris before I decided to move to the US to pursue my passion, which was really neuro-ophthalmology. And at the time, it was impossible to get a license in the US, so I had to repeat a residency and became an ophthalmologist. And this is what led me where I am today. Dr Jones: We're fortunate that you did that. I'm glad you did all that extra work because your contributions to the field have obviously been magnificent, especially this issue, which I think is an incredibly important topic for neurologists. This is why we include it in the rotation of Continuum topics. We all know the saying that the eyes are the windows to the soul, but for neurologists they are also the windows to the brain. The only part of the CNS that's visible to us is the optic disc. I think in spite of that, I think neurologists, our readers and our listeners would acknowledge the importance of the ophthalmic exam and respect the importance of that aspect of the neurologic exam. It's an area that feels challenging to us, and many of us, even with lots of years of experience, don't always feel very comfortable with this. So, it's a really important topic and I'm glad you have edited this. And let's start off with, you know, as you've reviewed all these articles from, really, the pinnacle experts in their specific topics in neuro-ophthalmology, as you were editing this issue, Dr Biousse, what would you say is the one biggest, most important practice-changing message about neuro-ophthalmology you would want to convey to our listeners? Dr Biousse: I think its technology, advances in technology. Without any doubt. The ophthalmology world cannot evaluate a patient anymore without access to fundus photography, optical coherence tomography (OCT) of the back of the eye, not just the optic nerve, but the retina. These advantages in technology have completely changed the way we practice ophthalmology. The same applies to neuro-ophthalmology. And these techniques can really help neurologists do a basic eye exam. Dr Jones: So, let's get right into that. And I'm glad you started with that because I still feel, even though I've done it thousands of times, I still feel a little fumbly and awkward when I'm trying to examine and fundus through an undilated pupil, right? And so, this is I think where technology has helped us quantitate with, as you mentioned, OCT, but I think from an accessibility perspective, I think nonmydriatic fundus photography is a very interesting tool for neurologists and non-neurologists.  Tell us how, how does that work and how could neurologists implement that in their practice? Dr Biousse: It's a very important tool that of course neurology should be able to use every day. You can take fundus photographs of the back of the eye without dilating the pupil. The quality of the photographs is usually very good. You only have access to what we call the posterior pole of the eye, so the optic nerves and the macula and the vascular arcade. You don't see the periphery of the retina, but in neuro-ophthalmology or neurology you don't need access to the periphery of the retina, so it doesn't matter. What is remarkable nowadays is that we have access to very highly performing fundus cameras which can take pictures through very, very small pupils or in patients of all ages. You can use it on a two-year-old in a pediatric clinic. You can use it on a much older person who may have a cataract or other eye problems. And what's really new and what this issue highlights is that it's not just that we can take pictures of the back of the eye, we can also perform OCT at the same time using the same camera. So, that's really a complete game changer for neurologists. Dr Jones: And that's extremely helpful. If I'm in a neurology clinic and I would like to use this technology, how would I access that? Do I need special equipment? Can I use my smartphone and an app? How would that work in terms of getting the image but also getting an interpretation of it? Dr Biousse: It all depends on what your ultimate goal is. The fundus cameras, they are like regular cameras or like any technology that would allow you to get brain imaging. The more sophisticated, the better the quality of the image, the more expensive they are. You know, that's the difference between a three-tesla MRI and a head CT. You buy a camera that's more expensive, you're going to have access to much easier cameras and to much higher resolution of images, and therefore you're going to be much happier with the results. So, I always tell people be very careful not to get a tool that is not going to give you the quality of images you need or you may make mistakes. You basically have two big sorts of cameras. You have what we call the tabletop cameras, which is a little more bulky camera, a little more expensive camera that's sitting on the table. The table can be on wheels, so you can move the table to the patient or you can move the patient to the table. That's very convenient in a neurology clinic where most patients are outpatient. It works in the emergency department. It's more difficult at bedside in the hospital. Or you can have a handheld camera, which can be sophisticated, a device that just uses a handheld camera or, as you mentioned, a small camera that you place on your smartphone, or even better, a camera that you can attach to some of the marketed direct ophthalmoscopes. In all situations, you need to be able to transfer those images to your electronic medical records so that you can use them. You can do that with all tabletop cameras, most handheld cameras; you cannot do it with your smartphone. So that gives you an idea of what you can use. So yes, you can have a direct ophthalmoscope with a little camera mounted. This is very inexpensive. It is very useful at bedside for the neurologists who do- who see patients every day, or the resident on call. But if you really want to have a reliable tool in clinic, I always recommend that people buy a tabletop camera that's connected to the electronic medical record. Dr Jones: You know, the photos always make it so much more approachable and accessible than the keyhole view that I get with my direct ophthalmoscope in clinic. And obviously the technology and the tools are part of the story, but also, it's access to the expertise. Right? There are not many neuro-ophthalmologists in the world, and getting access to the experts is a challenge, I think, everywhere, everywhere in the world really. When you think about how technology can expand that---and here I'm getting at AI, which I hesitate to bring up because it feels like we talk about AI a lot---are there tools that you think are here now or will be coming soon that will help clinicians, including neurologists, interpret fundus photography or other neuro-ophthalmologic findings, maybe eye movements, to make that interpretation piece a little more accessible? Dr Biousse: Absolutely. It's going to happen. It's not there yet. OK? I always tell people, AI is very important and it's a big part of our future without any doubt. But to use AI you need pictures. To get pictures, you need a camera. And so I tell people, first you start with the camera, you implement the camera, you incorporate the camera in your electronic medical record. Because if you do that, then the pictures become accessible to everyone, including the ophthalmologist who’s maybe offsite and can review the pictures and provide an official interpretation of the pictures to help you. You can also transfer those pictures using secure mode of transfers and not your smartphone text application, which you really don't want to use to transfer medical information. And that's why I insist on the fact that those pictures should definitely appear in the patient's medical record. Otherwise you're going to break HIPAA laws, and that's an issue that comes up quite often. Once you have the pictures in the electronic medical record and once you have the pictures in the camera, you can do three things. You can look at them yourself. And many of my neurology colleagues are very competent at declaring that an optic nerve is normal or an optic nerve is swollen or an optic nerve is pale. And very often that's all we need. You can say, oh, I don't know about that one, and page the ophthalmologist on call, give the patient 's medical record number, have them look at the pictures, provide an interpretation, and that's where you have your answer. And this can be done in real time, live, when you're at bedside, no problem. Or you can use AI as what I call “Diagnostic A.” I always compare it as, imagine if you had a little robot neuro-ophthalmologist in your pocket that you could use at any time by just taking a picture, clicking submit on the AI app. The app will tell you never, it's normal or it's papilledema or it's pale. The app will tell you, the probability of this optic disk of being normal is 99% or the probability that this is papilledema. And when I say papilledema, I mean papilledema from rest intracranial pressure that's incredible as opposed to optic disc edema from an optic neuritis or from an ischemic optic neuropathy. And the app will tell you, the probability that this is papilledema is eighty six percent. The probability that it's normal is zero. The probability that it's another cause of disc edema is whatever. And so, depending on your probability and your brain and your own eyes, because you know how to interpret most fundus photographs, you really can make an immediate diagnosis. So that is not available for clinical use yet because the difficulty with the eye, as you know, is to have it have a deep learning algorithm cleared by the FDA. And that's a real challenge. But many research projects have shown that it can be done. It is very reliable, it works. And we know that such tools can either be either incorporated inside the camera that you use---in which case it's the camera that gives you the answer, which I don't think is the ideal situation because you have one algorithm per camera---or you have the algorithm on the Cloud and your camera immediately transfers in a secure fashion the images to the Cloud and you get your answer that way directly in your electronic medical record. We know it can be done because it happens every day for diabetic retinopathy. Dr Jones: Got it. And so, it'll expand, and obviously there has to be a period of developing trust in it, right? Once it's been validated and it becomes something that people use. And I get the sense that this isn't going to replace the expertise of the people that use these tools or people in neuro-ophthalmology clinics. It really will just augment. Is that a fair statement? Dr Biousse: Absolutely. Similar to what you get when you do an EKG. The EKG machine gives you a tentative interpretation, correct? And when the report is “it's normal,” you really can trust it, it's normal. But when it says it's not normal, this is when you look at it and you ask for a cardiology consultation. That's usually what happens. And so, I really envision such AI tools as, “it's normal,” in which case you don't need a consultation. You don't need to get an ophthalmology consultation to be sure that there is no papilledema in a patient with headache, in a patient with possible cerebrospinal fluid shunt malfunction. You don't need it because if the AI tool tells you it's normal, it's normal. When it's not normal, you still need the expertise of the ophthalmologist or the neuro-ophthalmology. The same applies to the diagnosis of eye movement. So that's a little more difficult to implement because, as you know, to have an AI algorithm, you need to have trained the algorithm with many examples. We have many examples of pathology of the back of the eyes, because that's what we do. We take pictures every day and there are databases of pictures, there are banks of pictures. But how many examples do we have of abnormal line movement in myasthenia, of videos or downbeat nystagmus? You know, even if we pulled all our collections together, we would come up with what, two hundred examples of downbeat nystagmus around the world? That's not enough to train an AI system, and that's why most of the research on eye movement right now is devoted to creating algorithm that mimic abnormal eye movements so that we can make them and then train algorithm which job will be to diagnose the abnormal eye movement. There's an extra difficult step, it's actually quite interesting. But it's going to happen. You would be able to have the patient look at the camera on the computer and get a report about “it’s normal” or “the saccades, whatever, are not normal. It's most likely an internucleosomal neuralgia” or “it is downbeat nystagmus.” And that's not, again, science fiction. There are very good groups right now working on this. Dr Jones: That's really fascinating, and that- you anticipated my next question, which is, I think neurologists understand the importance of the ocular motor exam from a localizing perspective, but it's also complex and challenging. And I think that's certainly an area of potential growth. And you make a good point that we need some data to train the models. And until we have these tools, Dr Biousse, that will sort of democratize and provide access through technology to diagnosis and, you know, ultimately management of neuro-ophthalmology disorders, we know that there are gaps in the care of these patients right now in the modern day. In your own practice, in your own work at Emory, what do you see as the biggest gap in practice in caring for these patients?  Dr Biousse: I think there is a lack of confidence amongst many neurologists regarding their ability to perform a basic eye exam and provide a reliable report of their finding. And the same applies to most ophthalmologists. And that's very interesting because we have, often, a large cohort of patients who are in between the two specialties and are getting a little bit lost. The ophthalmologist doesn't know what to do. The neurologist usually knows what to do, but he's not completely sure that it's the right thing to do. And that's where the neuro-ophthalmologist comes in. And when you have a neuro-ophthalmologist right there, it's fantastic, okay? We bridge the two specialties, and we often just translate what the ophthalmologist said to the neurologist or what the neurologist said to the ophthalmologist and suddenly everything becomes clear. But unfortunately, there are not enough neuro-ophthalmologists. There is a definite patient access issue even when there is a neuro-ophthalmologist because not only is there a coverage heterogeneity in the country and in the world, but then everybody is too busy to be able to see a patient right away. And so, this gap impairs the quality of patient care. And this is why despite all this technology, despite the future, despite AI, we teach ophthalmologists and neurologists how to do a neuro-op examination, how to use it for localization, how to use it to increase the value and the power of a good neurologic examination so that nothing is missed. And I'm taking a very simple example. Neurologists see patients with headaches all the time. The vast majority of those headaches are benign headaches. 90% of headache patients are either migraine or tension headache or analgesic abuse headaches, but they are not secondary headache that are life threatening or neurologically threatening. If the patient has papilledema, it's a huge retina that really should prompt immediate workup, immediate prevention of vision loss with the help of the ophthalmologist. And unfortunately, that's often delayed because the patients with headaches do not see eye doctors. They see their primary care providers who does not examine the back of the eye, and then they reach neurology sometimes too late. And when the neurologist is comfortable with the ophthalmoscope, then the papilledema is identified. But when the neurologist is not comfortable with the ophthalmoscope, then the patient is either misdiagnosed or sent to an eye care provider who makes the diagnosis. But there is always a delay in care. You know, most patients end up with a correct diagnosis because people know what to do. But the problem is the delay in appropriate care in those patients. And that's where technology is a complete life-changing experience. And, you know, I want to highlight that I am not blaming neurologists for not looking at the back of the eye with a direct ophthalmoscope without pharmacologic dilation of the pupil. It is not possible to do that reliably. The first thing I learned when I transitioned from a neurologist to an ophthalmologist is that no eye care provider ever attempts to look at the back of the eyes without dilating the pupils because it's too hard. Why do we ask neurologists to do it? It's really unfair, correct? And then the ophthalmoscope is such an archaic tool that gives only a very small portion of the back of the eye and is extraordinarily difficult to use. It's really not fair. And so, until we give the appropriate tools to neurologists, I don't think we should complain about neurologists not being reliable when they look at the back of the eye. It's a major issue.  Dr Jones: I appreciate you giving us some absolution there. I don't think we would ask neurologists to check reflexes but then not give them a reflex hammer, right? So maybe that's the analogy to not dilating the pupil. So, for you and your practice, in our closing minutes here, Dr Biousse, what's the most rewarding thing for you in neuro-ophthalmology? What do you find most rewarding in the care of these patients?  Dr Biousse: Well, I think the most rewarding is the specialty itself. I'm a neurologist at heart. This is where my heart belongs. What's great about those neuro-ophthalmology patients is that it is completely unpredictable. They are unpredictable. They can have anything. I am super specialized because I'm a neuro-ophthalmologist, but I am a general neurologist and I see everything in neurology. So my clinic days are fascinating. I never know what's going to happen. So that's, I think, the most rewarding part of my job as an neuro-ophthalmologist. I'm having fun every day because it's never the same, I never know what's going to happen. But at the same time, we are so useful to those patients. When you use the neuro-ophthalmologic examination, you really can provide exquisite localization of the disease. You're better than the best of the MRIs. And when you know the localization, your differential diagnosis is always right, always correct, and you can really help patients. And then I want to highlight one point that we made sure was covered in this issue of Continuum, which is the symptomatic treatment of patients who have visual disturbances from neurologic disorders. You know, a patient with chronic diplopia is really disabled. A patient with decreased vision cannot function. And being able to treat the diplopia and provide the low vision resources to those patients who do not see well is extremely important for the quality of life of our patients with neurologic disorders. When you don't walk well, if you don't see well, you fall. When you're cognitively impaired, if you don't see well, you are very cognitively impaired. It makes everything worse. When you see double, you cannot function. When you have a homonymous anopia, you should not drive. And so, there is a lot of work in the field of rehabilitation that can greatly enhance the quality of life of those patients. And that really covers the entire field of neurology and is very, very important. Dr Jones: Clearly important work, and very exciting. And your enthusiasm is contagious, Dr Biousse. I can see how much you enjoy this work. And it comes through, I think, in this interview, but I think it also comes through in the articles and the experts that you have. And I'd like to thank you again for joining us today for a great discussion of neuro-ophthalmology. I learned a lot, and hopefully our listeners did too.  Dr Biousse: Thank you very much. I really hope you enjoyed this issue. Dr Jones: Again, we've been speaking with Dr Valerie Biousse, guest editor of Continuum's most recent issue on neuro-ophthalmology. 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.

In this enlightening discussion, Dr. Dave Clarke, the Kozmetsky Family Foundation Endowed Chair of Pediatric Epilepsy at Dell Medical School, shares his expertise in addressing disparities in epilepsy care. He highlights barriers faced by underserved populations, including geographic and socioeconomic challenges. The conversation delves into how innovative technologies like telemedicine are improving access to care. Dr. Clarke also emphasizes the importance of cultural sensitivity in treatment and advocates for increased diversity in epilepsy research to enhance outcomes for all patients.

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

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.

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.

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.