Continuum Audio

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Nathaniel M. Schuster, MD who served as the guest editor of the Continuum® October 2024 Pain Management in Neurology issue. They provide a preview of the issue, which publishes on October 2, 2024.  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. Schuster is an associate professor and associate clinic director in the Center for Pain Medicine and Department of Anesthesiology at the University of California, San Diego in La Jolla, California. Additional Resources Continuum website: ContinuumJournal.com 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: @NatSchuster 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, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal have access to exclusive audio content not featured on the podcast. If you're not already a subscriber, we encourage you to become one. For more information, please visit the link in the show notes.   Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr Nathaniel Schuster, who recently served as Continuum’s guest editor for our latest issue on pain management and neurology. Dr Schuster is a pain neurologist at the University of California, San Diego, where he is an Associate Professor of Anesthesia. Dr Schuster, welcome. Thank you for joining us today. Why don't you introduce yourself to our listeners?   Dr Schuster: Thank you so much, Dr Jones, for having me. My name is Nat Schuster. I am a pain and headache neurologist at UC San Diego, in the Department of Anesthesiology. I do research, clinical practice, and of course, education of med students through pain fellows, and it's been a pleasure to be the guest editor for this forthcoming issue of Continuum.   Dr Jones: Well, I want to thank you for editing the issue. I want to thank you for putting together, really, an incredible list of topics and, really, expert authors. It's been a long time since Continuum has dedicated significant space in an issue to pain management, which is obviously a hugely prevalent, major problem in society, and I think a big gap for many of us – I know it is for me in my practice, so I've enjoyed learning about it – so I want to congratulate you on the issue and thank you for doing it.   Dr Schuster: Yeah. I was just at AAN a few weeks ago. I was chatting with the person who edited one nearly 20 years ago, a prior pain Continuum issue - so, really glad that for another generation of neurologists that we're going to have this as a reference, and hopefully, it'll serve them in their care of so many patients, because this is just such a ubiquitous problem facing Americans and people around the world.   Dr Jones: Yeah, and a lot's changed in 20 years, so let's get into it. And I will say, you know, now that with our open podcast model, we're interviewing the guest editors, you have, really, an incredible view of the entire field at the moment. And with your reading of the issue and your experience as a pain expert, Dr Schuster, what do you think is the biggest controversy in pain medicine right now?   Dr Schuster: Yes, certainly. I think the most controversial thing facing our practicing neurologists is the opioid issue and how things have been changing with national guidelines since 2016, and, fortunately, we are going to have an article by Dr Friedhelm Sandbrink - who is not only a neurologist, but he is the national director for the VA system - on pain management, opioid safety, and prescription drug monitoring programs. So, it's really wonderful that we have him as an author, and I hope that all the neurologists take an opportunity to read his really important manuscript, because it's dizzying, and, you know, if you're not reading the latest things from people like Dr Sandbrink pretty much every couple of years, you're probably falling behind when it comes to what are current attitudes, what is necessary to be, you know, most responsibly continuing your patients who have been on opioids for so long (many of whom have really debilitating neurologic conditions, nothing else is helpful for them), how are you able to best treat them, best monitor them in the appropriate ways to be doing things in compliance with guidelines.   Dr Jones: And I think monitoring is one of the things that, for neurologists who are uncomfortable with pain management, uncomfortable with the modern role of opioids, I think part of it is, well, what are my accountabilities? What are my responsibilities for doing that? That article will have great insights for our readers. Cannabinoids - that's another one I hear a lot of questions about, and it's obviously evolving. The science is relatively less mature there. From your perspective, what's the role of cannabinoids in a modern pain practice?   Dr Schuster: Yeah. Once again, so much controversy there and so much variability across the US, of course, between institutions, between states - hugely different. And as we speak, it's looking like cannabis will very likely be recategorized as being schedule III, so things are changing, you know, even between right now, probably, and when people are going to be reading the forthcoming Continuum and listening to this podcast. At UC San Diego, we certainly have been on the forefront of doing clinical trials, looking at these clinical trials. They're academic studies using the NIDA drug supply. So, they're not the size and scope of so many of the things that we use that have had industry-funded, large, multicenter studies done, but the research that we've done has shown promise for quite a few different neurologic conditions, ranging from my most recent research was in the migraine space, looking at acute migraine (and I just had the pleasure of presenting that data at AAN a few weeks ago), looking at other things over the years, looking at spasticity pain and multiple sclerosis, spinal cord injury pain, diabetic peripheral neuropathy, other peripheral neuropathies. So, in the conditions that we as neurologists so often do treat, that does seem like there is a lot of promise. It's something that in our practice, some of our doctors are more comfortable with it, others are less comfortable. I know, myself, I'm very conservative when I discuss it with patients, because there is, you know, addiction concerns, misuse concerns, abuse concerns - I don't believe that it's to the degree of opioids, and I don't think that the risks are anywhere close to what they are with opioids - and while it's less in opioids, we have other things, fortunately, in this field that don't carry those concerns, and so, I certainly try to use those other options as much as possible before having the discussions about cannabinoids. That said, so many people are using them, and so I'm able to guide them towards, you know, telling that very often, doses that are lower than what they might need to get intoxicated might actually be the doses that are therapeutic, and recommending using high CBD and low THC is probably going to have less side effects, and there's some evidence towards, hopefully, having more therapeutic benefit, especially in our most recent study looking at acute migraine that you want to have that CBD component with the THC.   Dr Jones: That's outstanding. So, we know more than we used to. It still feels like a relatively understudied area (and that's partly been the regulatory barriers to doing science on cannabinoids), so we'll look forward to hearing the latest and greatest in the issue. When we think about in neurology - and I'm thinking here as a clinician - when we think about pain and neurology, we often think about neuropathic pain. And, personally, you know, I see a lot of patients who have peripheral generators for those symptoms of neuropathic pain, but central neuropathic pain is an issue, too - and we have articles on both of those, one on peripheral neuropathic pain, one on central neuropathic pain. For our listeners, what should they know about the differences between those two and the treatment approaches to those?   Dr Schuster: Yeah. So, we fortunately have two wonderful articles - one of them from Dr Charles Argoff looking at central neuropathic pain, another one looking at peripheral neuropathic pain from Drs Misha Bačkonja and Victor Wang. And one thing that I think is really interesting about central neuropathic pain is that for these same patients, we don't need to only be thinking about the central neuropathic pain alone, and not everything that they're experiencing is going to be central neuropathic pain, because they can have “frozen shoulder” - post-stroke shoulder pain is actually a really big deal. Of course, you need to be concerned about things like sacral decubitus ulcers in so many of these patients. And so, they can have nociceptive components in those same patients, and us as neurologists, taking care of these very complicated patients, need to have our eyes open for the central neuropathic components, but also in those same patients, the other pain generators that we can do a lot for.   Dr Jones: So, the musculoskeletal and other generators of pain are relevant. I think that's something that many of us have experienced. Certainly, when I trained, Dr Schuster, the general construct around pain was that it was a really biological phenomenon, and it's an adaptive phenom

Over the past 20 years, more than 50 antibodies have been identified and associated with autoimmune neurologic disorders. Although advances in diagnostic testing have allowed for more rapid diagnosis, the therapeutic approach to these disorders has largely continued to rely on expert opinion, case series, and case reports. In this episode, Allison Weathers, MD, FAAN, speaks with Tammy L. Smith, MD, PhD, an author of the article “Therapeutic Approach to Autoimmune Neurologic Disorders,” in the Continuum® August 2024 Autoimmune Neurology issue. Dr. Weathers is a Continuum® Audio interviewer and associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio. Dr. Smith is a GRECC investigator and staff neurologist at George E. Wahlen Veteran Affairs Medical Center and an assistant professor of neurology, at the University of Utah in Salt Lake City, Utah. Additional Resources Read the article: Therapeutic Approach to Autoimmune Neurologic Disorders 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 Transcript 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 Weathers: This is Dr Allison Weathers. Today, I'm interviewing Dr Tammy Smith about her article on therapeutic approach to autoimmune neurologic disorders, which she wrote with Dr Stacey Clardy. This article is a part of the August 2024 Continuum issue on autoimmune neurology. Although, one of the things I love most about being an interviewer for Continuum is getting the opportunity to meet new neurologists and learn all about their areas of expertise, there's something really special when I get the chance to interview and catch up with old colleagues - and today, I'm fortunate to do just that. I had the privilege of working with Dr Smith when she was a resident at Rush, and I'm so excited to be able to speak to her today about her fantastic and really comprehensive article on this very timely topic. Welcome to the podcast, Dr Smith, and please introduce yourself to our audience.   Dr Smith: Hi. Yeah, thank you for inviting me to participate in the podcast and to write this article. So, I'm Tammy Smith. I am a neurologist who practices in Salt Lake City. I primarily work at the Salt Lake City VA Medical Center where I get to treat veterans with all sorts of neurologic diseases. I'm also an assistant professor of neurology at the University of Utah in the division of Neuroimmunology and Autoimmune Neurology, and I serve as a Clinical Consultant for ARUP Laboratories to help improve diagnostic testing for immune-mediated neurologic diseases.   Dr Weathers: Wow. That is a lot of different roles and things that you have on your plate. I want to start, actually, by talking about the article. Again, you cover so much ground (you and Dr Clardy) in this really comprehensive article, but if you had to choose the one most important message - if you wanted our listeners to walk away remembering one key point, what would it be?   Dr Smith: I think the key point I want our listeners to think about is just to use the resources that are available to you. Nobody can have all of these drugs (as we're talking about treatment of autoimmune neurologic diseases in this article) - no one can have all of those drugs memorized, all of the mechanisms of action, all of the approved treatments and off-label treatments, and all of the symptomatic therapies. But that's why resources like the Continuum exist - so that we can provide those resources to clinicians who are busy at that touch of, er, hopefully - or when they open their issue - to get the information they need to make decisions to take good care of their patients.   Dr Weathers: I think that is so reassuring. As I was reading this article, that was, like, one of the things that really struck me is that, you know, thinking about even being a resident and studying for something like the rate exam, you know, how much easier it used to be when there was such a limited number of drugs thinking about the autoimmune diseases or epilepsy, where just the number of drugs has just, kind of, multiplied so manyfold since I was in training, that it's really overwhelming. And I think you make a great (and as I said, a very reassuring) point that we don't have to memorize these, that there are these incredible resources (like Continuum) where it's not any longer about kind of memorization and keeping it in our heads, that it's more about knowing where to look and thinking about what's the right thing for the patient - knowing how to go and get the information is the more important knowledge there. And, actually, thinking about that and moving on, given your expertise, how do you personally approach the management of a patient with an autoimmune neurologic disorder? Again, in the article, you speak about all the different things to keep in mind, both from a therapeutic (really, treatment) standpoint, as well as a symptomatic standpoint - but what is your personal approach?   Dr Smith: My personal approach really involves considering whether the diagnosis of an autoimmune neurologic disorder is correct, first and foremost, and gathering the information to help support that diagnosis - and I think that's something that often gets overlooked in the excitement of a patient coming in with a rare-looking syndrome. Someone sends off diagnostic testing, rules out a few things, decides it's autoimmune, and starts down a pathway and keeps pushing forward. And I understand that inclination on a busy neurology service or in a busy clinic to just decide on one path and move forward, but I'm always questioning the diagnosis, even in the presence of positive antibody results sometimes. If my patient doesn't respond to the treatment that I'm giving them based on their presentation and the antibody results, I reassess and wonder if there's something else going on, are there two syndromes going on, or was that antibody result really not the right answer for some reason. So, I think my approach, really, is to always have a healthy amount of skepticism around the diagnosis, and even when I'm fairly confident in the diagnosis, to continually reassess that patient and their unique response to treatment. And then, also, their unique circumstances - so, everyone will need different symptomatic management, as well as different rehabilitation resources and other resources mobilized to help them maximize their recovery. And so, there's just not a “one size fits all” approach, but always keep talking to the patient, keep re-evaluating, stay curious, and don't be afraid to change paths when things aren't making sense.   Dr Weathers: I think that is incredibly sound, really thoughtful advice. So, I can imagine how incredibly challenging those cases must be when you think you have the right answer, it looks like it's lining up, the antibodies are pointing you in the right direction, and then, they're not responding. What else do you feel is the most challenging aspect of the management of these conditions? Is there some other kind of aspect that you also feel is really challenging in the treatment of these patients?   Dr Smith: Yeah, I think other challenges are really access to state-of-the-art therapies due to financial barriers - I think that's a pretty significant challenge for a lot of these patients, and I think we need to continue to work on advocacy efforts to make sure all patients have access to the medications they need to treat the disorders they are diagnosed with. And it's a real challenge, even when there's FDA-approved therapeutics - a lot of them are quite expensive, and then we end up playing the insurance game, and we learned that AI is automatically denying people's insurance claims, and so, we're battling computers as well as insurance companies. And I think that's a really significant challenge for a lot of these patients. And then, really, just the fact that a lot of immune-mediated neurologic disorders have a long tale. So, we don't treat a patient the same way we do for an infection and expect a dramatic and rapid recovery - a lot of the recovery for these patients happens over months to years. It's a process, and I think it's really important to be counseling patients and caregivers and other providers and educating them about this that we continue to mobilize resources to help our patients long past their inpatient hospitalization and the most dramatic part of their recovery.   Dr Weathers: Again, you raised some really insightful points there. No, I think they're really key. And I think, to your point, that even for some of these patients, that even if we can get over the economic barriers of the medications themselves and get them authorized, get them covered, you're left with, for a lot of patients, all of the other limitations of some of their social determinants of health challenges, right? So, the transportation challenges to even kind of get them to the appointments, and some of the other challenges they face, which makes some of these treatments very, very hard for them to be abl

Basic knowledge of the common CNS manifestations of rheumatologic diseases and sarcoidosis is important. In the context of many systemic inflammatory diseases, CNS disease may be a presenting feature or occur without systemic manifestations of the disease, making familiarity with these diseases even more important. In this episode, Kait Nevel, MD speaks with Jennifer A. McCombe, MD, author of the article “Neurologic Manifestations of Rheumatologic Disorders,” in the Continuum® August 2024 Autoimmune Neurology issue. Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana. Dr. McCombe is an associate professor in the Division of Neurology, Department of Medicine at the University of Alberta, Edmonton in Alberta, Canada. Additional Resources Read the article: Neurologic Manifestations of Rheumatologic Disorders 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: @Div_Dubey Transcript 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 Jennifer McCombe about her article on neurosarcoidosis and neurologic involvement of rheumatological disorders, which appears in the August 2024 Continuum issue on autoimmune neurology. Welcome to the podcast, and I would love to have you introduce yourself to the audience.   Dr McCombe: Well, thank you, and thank you for having me. As you said, my name is Jen McCombe. I'm a neurologist in Edmonton, Alberta, Canada, where I spend kind of a third of my time in teaching roles (I coordinate the undergraduate block for our medical school there), I spend about a third of my time in a neuroinflammatory clinic in Edmonton, Alberta, and then about a third of my time doing clinical research.   Dr Nevel: Wonderful. Well, thank you so much for being here today and for chatting with me about your article on this topic.   Dr McCombe: Thank you for having me.   Dr Nevel: To start off, can you share with the listeners a little bit about your career path?   Dr McCombe: Absolutely. Yeah. So, I've had, uh, a bit of a circuitous career path. I did my medical school in Queens (which is in Eastern Canada, in Kingston, Ontario) and then went back to Edmonton, Alberta, for my residency (in Canada, we have a five-year residency program, so a little bit different than the US), but finished my residency and then did a master's degree in Public Health at Johns Hopkins while completing clinical research in HIV, actually, and did this thing we call the Clinical Scholar Training Program – so, kind of like a fellowship, but a little bit more, you know, research and academic-based. So, when I first started, I was focused more on neuroinfectious diseases, and that's kind of what my career path looked like at the time - but, actually, shortly after I finished my residency program, I also had my first child, and he, unfortunately, developed opsoclonus-myoclonus syndrome, and at the time (this was in 2010), it was a rather rare condition, so, I ended up finding myself having to become a bit of a neuroinflammatory disease specialist at the same time. So, at that point, I transitioned into working in the neuroinflammatory clinic with some mentorship but was getting all of the kind of weird and wonderful referrals and diagnostic dilemmas from my colleagues who recognized I kind of developed some expertise, and so decided (actually, mid-career) to take a sabbatical, and in 2021, completed a fellowship in autoimmune neurology at the Mayo Clinic. So, I finished that quite recently and then went back, and now I'm feeling much more, I guess, confident, too. Sometimes, you wonder about, you know, the choices you're making. I recognize most of the conditions I'm dealing with don't have, in fact, any evidence for their treatment, and that was confirmed when I went to the Mayo Clinic and found that, really, it was just trying to gain an understanding of the disease process to make a rational choice to medications and treatments. So, now, I'm back and kind of trying to focus a little bit more on some clinical research in that area since I've kind of solidified that expertise.   Dr Nevel: Wow. Well, thank you for sharing with us your career path and how, you know, unexpected life events kind of changed your interests or molded your interests (changed kind of the things that you became expert in, you know), and being fluid in your career path and willing to kind of take a break and reassess and get additional training. That's really inspiring to, I think, to me, and probably to a lot of listeners, that you can always, you know, develop more expertise in the more niche area or additional area no matter where you are in your stage of life or career path.   Dr McCombe: Yeah.   Dr Nevel: So, can you tell us a little bit more about - you know, you shared with us kind of autoimmune inflammatory disorders and how you became interested in that, neurosarcoidosis, specifically (you know the article focuses on that), and what's your background in neurosarcoidosis, how you became interested in that specifically and in neurologic manifestations of rheumatologic disorders?   Dr McCombe: I started in our neuroinflammatory clinic over a decade ago, and, you know, at the time, a lot of the expertise in any of these neuroinflammatory disorders was quite spread out over the country, and so, as I kind to alluded to before, often some of the more complicated patients where there wasn't necessarily clear-cut evidence or even, you know, a fellowship path to get there, I would end up getting referrals for - and so, I developed quite a cohort of patients with central nervous system primarily, but other types of neuroinflammatory and autoimmune neurologic diseases, and part of that cohort was a rather large (and still growing) group of patients with neurosarcoidosis. And so, I kind of developed some practical expertise, although, as you can see in the article (and as I'm sure you all know), the approach to the treatment is extremely variable. One of the most telling things is when we were at the Mayo Clinic, one of my co-fellows actually pulled all of the neurologists in neuroinflammation at all of the Mayo Clinic sites and asked them, you know, what is your treatment approach to a patient with neurosarcoidosis, and I think got twelve completely different responses as to the medications chosen and the length of time for the tapers and things like that. So, you know, it is very much a part of neurologic disease treatment that we still really don't have great evidence for, and although we do have some kind of rational choices that we can make based on other types of evidence, so -   Dr Nevel: Yeah.   Dr McCombe: And I enjoy working with patients with these types of diseases where we can kind of work together to come up with a treatment plan that makes sense for them and also makes sense based on whatever evidence we do have at this time.   Dr Nevel: Yeah. So, moving on to the article a little bit, knowing that this is a area of neurology where there's a lot of, you know, maybe personal expertise and experience but not a ton of data or evidence to necessarily guide our standardization to our treatments and approach, what do you think is the most important clinical takeaway from your article for our listeners?   Dr McCombe: Well, I mentioned before I coordinate the neuro block for our undergraduate program here, so I've developed over the years (I've been doing that for a number of years) a curriculum that's all based on, kind of, that approach to - and I like to do it that way because it's very practical. I like the students to be able to basically take their class notes and then go to the emergency department on their first shift as a clerk and, you know, use their approach to headache that I've developed for them to kind of take a clinical history and examine a patient with that sort of problem. And so, similar to that, I tried to do an approach to, you know, a couple of the more common presentations that would make you think of a rheumatologic condition or neurosarcoidosis in looking at the approach to CNS vasculitis and the approach to, uh, pachymeningitis - and these are difficult differentials for lots of neurologists, because it really relies on a lot of medicine knowledge, and we graduate from our residencies slightly more confident in our medicine knowledge, because we get a lot of that in our residencies. But as neurologists, as we go through our careers, we get much more confident in our areas of specialty, and at least for myself and many of my colleagues, much less confident in other things like general medicine. And so, it's difficult, because you have to face your areas of potentially less confident knowledge and really think about that in the differential - and so, I think, you know, I put those two big “approach to” sections in there, because they're the most relevant for the conditions that I was covering. But, I think a

Many autoimmune neuromuscular disorders are reversible with prompt diagnosis and early treatment. Understanding the potential utility and limitations of antibody testing in each clinical setting is critical for practicing neurologists. In this episode, Teshamae Monteith, MD, FAAN speaks with Divyanshu Dubey, MD, FAAN, author of the article “Autoimmune Neuromuscular Disorders Associated With Neural Antibodies,” in the Continuum® August 2024 Autoimmune Neurology issue. Dr. Monteith is the 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. Dubey is an associate professor in the departments of neurology and laboratory medicine and pathology at the Mayo Clinic in Rochester, Minnesota. Additional Resources Read the article: Autoimmune Neuromuscular Disorders Associated With Neural Antibodies 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: @Div_Dubey Transcript 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, Associate Editor of Continuum Audio. Today, I'm interviewing Dr Divyanshu Dubey about his article on autoimmune neuromuscular disorders associated with neural autoantibodies, which is part of the August 2024 Continuum issue on autoimmune neurology. Welcome to the podcast. How are you?   Dr Dubey: Hi, Dr Monteith. Thank you for inviting me to be a part of this podcast. I'm doing well.   Dr Monteith: Well, why don't you introduce yourself to the audience? And, call me Tesha.   Dr Dubey: I'm Divyanshu Dubey (please, call me Div). I'm one of the autoimmune neurology consultants here at Mayo Clinic Rochester. I'm an Associate Professor of neurology, as well as lab medicine and pathology. My responsibilities here are split - partly seeing patients (primarily patients with autoimmune disorders, including neuromuscular disorders), and then 50% of my time (or, actually, more than 50%), I spend in the lab, either doing research on these autoimmune disorders or reporting antibodies in a clinical setting for various antibody panels which Mayo’s neuroimmunology lab offers.   Dr Monteith: That's a nice overlap of subspecialty area. How did you get into this work?   Dr Dubey: I think a lot of it was, sort of, by chance. Meeting the right people at the right time was the main, sort of, motivation for me. Initially, I trained in India for my medical school and didn't really got much exposed to autoimmune neurology in India. I think our primary concern in my training was sort of treating TB meningitis and cerebral malaria - that was my exposure to neurology, including stroke and some epilepsy cases. As a part of application for USMLEs and coming here to residency, I did some externships, and one of the externships was at Memorial Sloan Kettering Cancer Center, and that's when I worked a few weeks with Dr Posner and got introduced to the idea of paraneoplastic neurological syndrome working with him. And that sort of started - I wouldn't call it vicious cycle - but my interest in the area of autoimmune neurology and paraneoplastic neurological disorders, which subsequently was refined further through residency and fellowships.   Dr Monteith: That's interesting. I actually rotated through - I did a externship also at Sloan Kettering, and I had a clinic with Dr Posner. And I thought, at the time, he was such a rock star, and, like, I took a picture with him, and I think he thought it was insane. And I didn't go into autoimmune neurology. So, you know, interesting pathways, right?   Dr Dubey: Yes. And I think he's inspired many, many people, and sort of trained a lot of them as well.   Dr Monteith: So, why don't you tell us what you set out to do when writing this article?   Dr Dubey: So, I think, given my background and training in various subspecialties in neurology, I was, sort of, formally did fellowships in autoimmune neurology, as well as neuromuscular medicine. One of the areas in these areas that I focus on is in my clinical practice, as well as in my sort of lab work, is autoimmune muscular disorders - and that to, specifically, autoantibodies and their clinical utility for autoimmune muscular disorders. So, that's what I wanted to focus on in an article. When I was invited to write an article on autoimmune muscular conditions in general, I thought it was very difficult to pack it all in one chapter or one article, so I narrowed my focus (or tilted my focus) towards antibody-positive disorders and trying to understand how we as neurologists can firstly sort of identify these conditions (which may end up being antibody-positive) – and then, on the other hand, once we get these antibody results, how we can find the utility in them or find them useful in taking care of our patients. At the same time, I also wanted to kind of highlight that these antibodies are not perfect, they do have certain limitations – so, that's another thing I sort of highlighted in the article.   Dr Monteith: So, why don't we just start with a very broad question - what do you believe the role of autoantibodies is in the workup of neuropathies and then neuromuscular disorders? Obviously, when we think of myasthenia gravis, but there are some presentations that you may not necessarily think to first order autoantibody tests. So, what is the role, and where does it fit in the paradigm?   Dr Dubey: I think it's extremely crucial, and it's evolving as time goes on, and it's becoming more and more clinically relevant. Let's say three, four decades ago, the number of biomarkers which were available were very limited and only a handful - and there has been a significant increase in these biomarkers with growing utilization of newer techniques for discovery of antibodies, and more and more people jumping into this field trying to not only discover, but try and understand and validate these biomarkers (what they truly, clinically mean). These antibodies, like you pointed out, ones for myasthenia (such as acetylcholine receptor-binding antibodies, or MuSK antibodies), they can be extremely helpful in clinical diagnosis of these patients. We all know the importance of EMG in managing our patients with neuromuscular disorders. But, oftentimes, EMG nerve conduction studies are often not available at every center. In those scenarios, if you have antibodies with very high clinical specificity, and you're seeing a patient on examination whom you're seeing ptosis (fatigable ptosis), double vision, you're suspecting myasthenia, you send antibodies, and they come back positive. It brings you closer to the answer that may, in turn, require you to refer to a patient to a place where you can get high-quality EMGs or high-quality care. In addition to getting to the diagnosis, it also, sometimes, leads you in directions to search for what is the trigger. A good example is all these paraneoplastic neurological syndromes (which we started our conversation with), where once you find a biomarker (such as anti-Hu antibodies or CRMP5 antibodies) in a patient with paraneoplastic neuropathies, it can direct the search for cancer. These are the patients where, specifically, these two antibodies, small-cell lung cancer is an important cancer to rule out - they require CT scans, and if those are negative, consider doing PET scan – so, we can remove the inciting factor in these cases. And then, lastly, it can guide treatment. Depending upon subtypes of antibodies or particular antibodies, it can give us some idea what is going to be the most effective treatment for these patients.   Dr Monteith: I think paraneoplastic syndromes are a very good example of how autoantibodies can help guide treatment. But, what other examples can you provide for us?   Dr Dubey: Yeah, so I think one of the relatively recent antibody tests which our lab started offering is biomarkers of autoimmune neuropathies - these are neurofascin and contactin, and those are great examples which can target or guide your treatment. I personally, in the past, have had many CIDP patients before we were offering these testings, where we used to kind of start these patients on IVIG. They had the typical electrodiagnostic features, which would qualify them for CIDP. They did not show any response. In many of these cases, we tried to do sort of clinical testing or sort of research-based testing for neurofascin and contactin back in the day, but we didn't have this resource where we can sort of send the blood, hopefully, and within a week, get an answer, whether these patients have autoimmune neuropathy or not. Having this resource now, in some of these cases, even before starting them on IVIG, knowing that test result can guide treatments, such as considering plasma exchange up front as a first-line therapy, followed by rituximab or B-cell depleting therapies, which have been shown to be extremely beneficial in these conditions. And it is not just limited to neurofascin or contactin (which are predominantly Ig

Stiff Person Syndrome (SPS) is treatable if managed correctly from the outset. It is essential to distinguish SPS spectrum disorders from disease mimics to avoid both overdiagnoses and misdiagnoses. In this episode, Allison Weathers, MD, FAAN, speaks with Marinos C. Dalakas, MD, FAAN, author of the article “Stiff Person Syndrome and GAD Antibody–Spectrum Disorders,” in the Continuum® August 2024 Autoimmune Neurology issue. Dr. Weathers is a Continuum® Audio interviewer and associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio. Dr. Dalakas is a professor of neurology and director of the neuromuscular division at Thomas Jefferson University in Philadelphia, Pennsylvania; a professor of neurology and chief of the neuroimmunology unit and the National and Kapodistrian at the University of Athens in Athens, Greece. Additional Resources Read the article: Stiff Person Syndrome and GAD Antibody–Spectrum Disorders 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 @ContinuumAAN facebook.com/continuumcme 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 Weathers: This is Dr Allison Weathers. Today, I'm interviewing Dr Marinos Dalakas about his article on stiff-person syndrome and GAD antibody-spectrum disorders, which is part of the August 2024 Continuum issue on autoimmune neurology. Dr Dalakas is a world- renowned expert in neuromuscular diseases and, really, the first name any neurologist thinks of when they hear the diagnosis of stiff-person syndrome. Dr Dalakas, this is such an honor to be able to speak to you today. Welcome to the podcast, and would you please introduce yourself to our audience?   Dr Dalakas: Yes, thank you very much. I'm so happy to participate in this interview. I'm the Chief of the Neuromuscular Division at Thomas Jefferson University in Philadelphia, and I am interested in autoimmune neuromuscular diseases for many years and also on disease mechanisms and immunotherapy.   Dr Weathers: Thank you again for talking with me today. So, given how very rare stiff-person syndrome and the GAD antibody-spectrum disorders are, prior to December 2022, I would have started our time together by asking you to explain this collection of diagnoses to our listeners and by also talking about how often they occur. It feels like that's a bit unnecessary ever since Celine Dion went public with her diagnosis - that moment really changed the public awareness of what was previously outside of neurology and almost unheard-of disease. So, instead, I'll start with, what is the key message of your article? If our listeners are going to walk away remembering one thing from our discussion, what would you like it to be?   Dr Dalakas: Well, I think the publicity has been very good for the disease, this disease spectrum. On the other hand, there have been some misleading messages, like, it's extremely rare, it's untreatable, it's disabling – which, they are partially correct, so, my message is, first, to make sure the neurologists make the correct diagnosis, because there are a lot of diseases similar to stiff-person, but they are not stiff-person. So, to make sure the diagnosis is correct and to make the patients aware of what to expect when they have this disease and what therapies we have and what we may have in the future. So, the number one message is the correct diagnosis and then to avoid overdiagnosis or misdiagnosis, because now we see both - we see overdiagnosis and misdiagnosis.   Dr Weathers: I think that's such a critically important point, and one you really delve into really beautifully in the article, so I encourage our listeners who do have access to it to really read through it. As I said, you do a great job really explaining that - and, actually, to go into that further, could you explain how you approach the diagnosis of a patient with possible stiff-person syndrome or one of the other GAD antibody-spectrum disorders? And I know you probably get asked that on a daily basis. As I was telling you before we actually formally started recording, I remember back when I was a resident and saw my first case of a suspected patient with stiff-person syndrome, my mentor advised me to look up your case series, your articles at the time, and really use that to guide my diagnosis. What do you feel is the most challenging aspect of diagnosing a patient with one of these conditions?   Dr Dalakas: Well, the first is the clinical symptomatology. We say the patients present with spasms and stiffness, but also, there are phobias. They are very hyperexcitable to sudden stimulations, to sudden noises, to unexpected touches, and all of them can cause spasms, and then when you examine the patients, they have stiffness. Now, the stiffness (if there is a true stiffness) results in gait abnormalities (the patients are falling because they're so stiff), and also, the hyperexcitability causes a lot of anxiety and a lot of phobias (they're afraid to cross the street, they're afraid to make a destination promptly) – so, all these things are sort of suggestive of stiff-person. So, these are the symptoms that you hear, you listen, and you ask the patients, and then, when you examine the patient, you look for certain signs that there are, specifically, like stiffness of what we call agonist muscles and antagonist muscles, which means there is stiffness of the abdominal muscles and at the same time, stiffness of the back muscles - so, this concurrent stiffness of these opposing muscles is very specific, very characteristic of the stiff person, so if you see that, and then you listen to the history, you're very close to the diagnosis, and then you do the antibodies. And the antibodies (the specific antibodies, the GAD antibody), but it is specific as we say in the article, and we tried to make this very clear to the neurologists, that it's the high titers that matter, because low titers are not necessarily specific. So high titers of antibodies in the serum, above 10,000 by ELISA (or whatever method they use; but it has to be this many times above normal), and then if you have high serum titers and all the symptoms they mentioned, it is stiff-person. On the other hand, if the titers are low, then you may want to do a spinal tap to see if there is synthesis of antibodies in the spinal fluid. That helps you. Now if the GAD antibodies are negative, then you start wondering, is this seronegative SPS? And how do you confirm the seronegative SPS? You do electrophysiology, and the electrophysiology is, again, to see if there is activity (muscle activity) concurrently from the agonist and antagonist muscles - in other words, from the, let's say the tibialis anterior and the gastrocnemius (so, it's two opposing muscles, eg, biceps and triceps) - and if you see activity in both of these opposing muscle groups, and you see also hyperexcitability (you touch the patient, you stimulate just a little, and you see activity in other muscle groups). So, the electrophysiology is very important if the patient's antibody negative, but they have the other symptoms that I mentioned before.   Dr Weathers: I can imagine how challenging those must be (those seronegative cases) to try to really make sure you're identifying and carefully determining that you have the right disease as you alluded to at the beginning. I know how hard it must be for patients to want to at least have some answers to have a diagnosis.   Dr Dalakas: And this is the main thing today, because the publicity, as I mentioned, the beginning, increased the receipt of some information, so they overdiagnose it, like, “Oh, you have this and this and this, so it may be stiff-person”. And so, in fact, recently, we had a series of patients together with the Mayo Clinic Group of out of 173 patients referred to the Mayo Clinic for stiff-person – that’s referred to them - only 28% had stiff-person. It's a low percentage, but it is an indication that the neurologists now refer patients to us for stiff-person, but we need to be very careful to correctly make a diagnosis.   Dr Weathers: On one hand, it's good that people are aware and considering the diagnosis, but it does highlight that risk of overdiagnosing.   Dr Dalakas: Yeah. It's the opposite of when I started this stiff-person syndrome (was close to 30 years ago at NIH) - at that time was underdiagnosed. This was the most rare disease, and I collected patients because at the NIH, I was also the Chief of the neuromuscular division there, and I was doing a study, so it was easy to collect patients (I collected more than 100 patients), but at that time, it was misdiagnosed. So, we had patients that I was seeing and they're really disabled, because they have been having the disease for many years, but they had been diagnosed either for Parkinson disease, for anxiety disorder, for psychiatric diseases, or for MS, or for myelopathies, or for myelitis - so many different things, and of course, they didn't have the correct diagnosis and they were disabled.   Dr Weathers: The side effect of having one of the most famous celebritie

This bonus episode of Continuum Audio features Continuum Aloud, a program of verbatim audiobook-style recordings of Continuum articles. In this episode, Dr. Michael Grasso reads the NMOSD and MOGAD article from the August 2024 issue on Autoimmune Neurology.  This article is open access until December 2, 2024. Read it here. Continuum Aloud is available to Continuum subscribers at the article level on ContinuumJournal.com or on the AAN’s Online Learning Center at continpub.com/Aloud. For more information on subscribing to the journal visit shop.lww.com/continuum.

Autoimmune cerebellar ataxia and other autoimmune movement disorders encompass a broad spectrum of different clinical syndromes, antibodies, and immunopathophysiologic mechanisms. Given the overlap between phenotypes and antibodies, panel testing in serum and CSF is recommended. In this episode, Gordon Smith, MD, FAAN, speaks with Bettina Balint, MD, author of the article “Autoimmune Movement Disorders,” in the Continuum August 2024 Autoimmune Neurology issue. Dr. Smith is a Continuum® Audio interviewer and 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. Balint is an assistant professor for clinical research on complex movement disorders and Parkinson’s diseases, a consultant neurologist, the head of the Department of Movement Disorders, and co-lead for the Centre for Movement Disorders and Functional Neurosurgery in the Department of Neurology at the University Hospital Zurich in Zurich, Switzerland. Additional Resources Read the article: Autoimmune Movement Disorders 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: This is Dr Gordon Smith. Today, I'm interviewing Dr Bettina Balint about her article on ataxia and other autoimmune movement disorders, which appears in the August 2024 Continuum issue on autoimmune neurology, which is a highly anticipated and exciting issue. Dr Balint, welcome to the podcast, and, perhaps, you can just introduce yourself to our audience and tell us a little bit about your practice and how you became interested in this topic.   Dr Balint: Thank you, Gordon, for having me. I am an assistant professor for clinical research in complex movement disorders and Parkinson's disease at the University of Zurich and the Head of the Movement Disorders Department at the University Hospital in Zurich. So while I'm originally German (from Heidelberg), I have now been to Switzerland since end of 2021.   Dr Smith: So, you know, how many movement disorder chiefs have a focus on autoimmune movement disorders? I found that really interesting. Most of the movement disorder folks I interact with, their primary interest is in neurodegeneration.   Dr Balint: Very good question. Even so, I never asked myself that question, really, but I think I'm the only one with this designated focus as such. Many people come from the neurology angle - most of them. Even so, movement-disorder people really welcome this field and are interested, but I think somebody who has dedicated their interest and time to it? I think I can't actually think of many other people.   Dr Smith: Yeah, I think it's really cool, and, of course, autoimmune neurology is the flavor of the day these days, right? I mean, I remember when I was at the University of Utah, we were recruiting Stacy Clardy (who I think many of our listeners will know). I remember thinking, you know, she's never going to be busy. How many of these autoimmune problems are there, really? And she was, like, deluged when she came. These are really common problems. I guess that was one question I had for you. You know, we think of these as rare disorders, and when we look at the article, you have these tables of these antibodies, and a lot of them are pretty uncommon – but, cumulatively, how common are autoimmune movement disorders?   Dr Balint: It's a very difficult question, because we don't have good epidemiological data. And if you look at series, I mean, most papers addressing this issue come actually from the ataxia field. And then, depending on where you look at, you might find varying numbers, and they might be also influenced by the fact that they come from ataxia centers with own certain biases. Even so, it's very close to my heart, but, I also still think it's overall very rare. So, in my practice, I see all sorts of movement disorders, and overall, they're still quite rare, but the point is that they are treatable and have important management implications, so you want to be sure not to miss any of them.   Dr Smith: Well, maybe we can go to that next. Part of the challenge here, of course, is there's just so many of these different syndromes and antibodies. Are there pearls that you can provide our listeners that would help them guide when they should be thinking about these disorders when they confront a patient with a particular phenotype? Like ataxia, for instance - you know, there are certain aspects of the clinical scenario that should trigger, “Wow, this might be an autoimmune problem”.   Dr Balint: So, in general, I would say there are certain scenarios where you would want to think of an autoimmune etiology in your differential. One is a very characteristic phenotype. So, speaking broadly in terms of movement disorders, stiff-person spectrum disorders have a very characteristic phenotype which you need to recognize, and then you will be able to see it when a patient enters. Important phenotypes to know which are very characteristic are faciobrachial dystonic seizures, for example, with anti-GA1 antibodies, or pseudofinalistic movements in non-REM sleep is IgLON5 antibodies, leg myoclonus is CASPR2 antibodies. I don't want to necessarily enumerate all the scenarios. The point here is there are some characteristic phenotypes where you would think of autoimmune neurology. Another scenario where you would think of autoimmune, for example, the context of late-onset paroxysmal movement disorders. So, classically, when we think of paroxysmal dyskinesia, we think of a group of genetic disorders, but if somebody develops a paroxysmal movement disorder later in life in adulthood, then you would think of autoimmune neurology, and this applies also in the context of episodic ataxias. Another red flag might be a propensity to autoimmunity. For example, somebody with type one diabetes and vitiligo coming in for cerebellar ataxia, of course, you would think of anti-GAD ataxia. And, similarly, if somebody has recently been diagnosed with a cancer and develops a rapidly disabling syndrome, of course, then you would think of a paraneoplastic autoimmune disorder. And with autoimmune syndrome, there are some symptoms which are also like tell-tale signs. So, for example, somebody with a stiff-person spectrum disorder, an ataxia with long-lasting diarrhea over months, losing weight - investigations haven't found anything, then you would think of DPPX antibodies or celiac disease. Or, if you have, like, a neuropathic pain which is otherwise not explained, then you might think of CASPR2 antibodies in somebody with a cerebellar ataxia. So, there are some features of some antibodies. (Again, I will not now list all of them which might point you to a diagnosis.) Then, of course, another scenario which is important, I think, is if you have a hemisyndrome without a structural lesion on imaging. Classically, neurologists are trained to think of a hemisyndrome - we look for a lesion on the contralateral side. But if you have, like, for example, a hemichorea without a lesion or a hemiataxia without a lesion, one should also think of an autoimmune disorder with antibodies. And then, more generally, of course, if you have changes on brain MRI or information on CSF, of course, if the clinical cause is more rapidly progressive - and last, but not least, if somebody does not really fit into our categories of the degenerative symptoms or metabolic syndromes or functionality disorders, then, of course, one should just take a step back and think, could it be something autoimmune? Having said that, if I may, I just want to say that, I mentioned that rapid disease course, and on the other hand, it's important to stress that a slowly progressive disease cause does not exclude an autoimmune etiology.   Dr Smith: So, that was a great summary. Thank you. I don't know if you're familiar with the term “Aunt Minnie” (something I learned in medical school and radiology). There are certain findings that are “Aunt Minnie”, you know what “Aunt Minnie” looks like, and if you see these particular findings, you should really think about a specific disease - and I think you gave a lot of pearls in that answer, so I appreciate that. This may seem like a bit of a random question, but it's interesting that there are some of these phenotypes that do replicate genetic phenotypes, and you used episodic ataxia, which, in a younger individual, we think of a spectrum of various genetic disorders. Is that random, or are there instances where the underlying mutation in a genetic disorder actually serves as a target for autoimmunity in a later-onset autoimmune problem? Not that the mutation causes autoimmunity, but are there shared targets - in one disease it's the mutation, and another, there's an antibody that binds to the protein, for instance?   Dr Balint: That's an excellent topic, and even though it's not addressed in the Continuum article, I actually covered this in an articl

Awareness of the specific clinical and MRI features associated with AQP4-NMOSD and MOGAD and the limitations of currently available antibody testing assays is crucial for a correct diagnosis and differentiation from MS. Growing availability of effective treatment options will lead to personalized therapies and improved outcomes. In this episode, Gordon Smith, MD, FAAN speaks with Elia Sechi, MD, author of the article “NMOSD and MOGAD,” in the Continuum August 2024 Autoimmune Neurology issue. Dr. Smith is a Continuum® Audio interviewer and 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. Sechi is a neurology consultant in the neurology unit of the Department of Medical, Surgical and Experimental Sciences at the University Hospital of Sassari in Sassari, Italy. Additional Resources Read the article: NMOSD and MOGAD 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 Guest: @EliaSechi 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 Elia Sechi about his article on aquaporin-4 antibody-positive NMOSD and MOGAD, which appears in the August 2024 Continuum issue on autoimmune neurology. Dr Sechi, before we dig into this really exciting topic about NMOSD and MOGAD, perhaps you can tell our listeners a little bit about yourself, where you practice, how you got interested in this topic.   Dr Sechi: Hi, Dr Smith, and thank you for having me. So, my story begins here in Italy, actually - I did my med school and residency in neurology at the University Hospital of Sassari here in Sardinia. And after residency, I was lucky enough to be accepted at the Mayo Clinic in Rochester, Minnesota for a research fellowship - and that's where I spent the next three-and-a-half years, approximately. My fellowship was focused on autoimmune neurology, specifically demyelinating diseases of the CNS associated with antibodies – so, of course, NMOSD and MOGAD mostly, but also myelitis, MS, and autoimmune encephalitis – so, there's where I built most of my expertise in the field. And then, it was at the beginning of the pandemic (of the COVID pandemic) that I came back here to Italy to practice. And now, I work mostly as a neurohospitalist, and I also have my subspecialty outpatient service for patients with autoimmune neurological diseases.   Dr Smith: I wonder if you might just give us a minute or two about what it was like training in Mayo? I went to medical school there, and, you know, at the time, I thought that was just normal healthcare and normal training, and, you know, it was only later that I realized how amazing that was. I mean, this is where aquaporin-4 was discovered - I mean, what was that like? It must have been really cool training there with that team.   Dr Sechi: Yeah. You know, it's the temple of autoimmune neurology. It's fantastic. It's a great environment, very stimulating. You know, I think the great strength is that they see many patients with rare diseases, so, you get really confident with MRI features and clinical features with the history of the diseases, and this is important to recognize the typical features and differentiate from MS to do a good differential. And, of course, you know, the team is fantastic - superstars in the field. It's very, very stimulating. So, it's something that I definitely recommend. It was a fantastic experience.   Dr Smith: Well, you know what's great is, I don't know if you follow sports, but, you know, like, in the United States and college football, people refer to Gator Nation – right, these are all people who are fans of the Florida Gators. Or, maybe it's AC Milan nation in Italy. I don't want to get there (Roma, whatever), but there are all these people who've trained at Mayo, and, uh, what's great is it's a small world, right? So, I'm super excited to meet you and talk about this, because - I'm going to add you to my Rolodex, because when I see these patients (I'm a neuromuscular guy, but I do a fair bit of inpatient time), I'm always calling a small number of people, so I'm really pleased to meet you so I can put you on speed dial and ask you questions about these patients. I wonder if, maybe, we can begin? You know, in our preparatory discussions, I shared that I just came off our hospital service, and we had several of these patients, you know, where we were thinking about NMO or MOGAD as a cause for their problem - and I wonder if you just have any pearls or pitfalls in when we should suspect this, right? Most of us recognize bilateral optic neuritis, longitudinally extensive myelitis - we need to be thinking about these. Any pearls or pitfalls for when we should or should not be looking for these disorders?   Dr Sechi: Yeah, I think this is a great question. I think the first thing to pay attention is the phenotype. So, the clinical MRI phenotype that are typically associated with NMOSD and MOGAD, they are quite characteristic - and it's important to be aware of those phenotypes and how they differ from MS, because in my experience, one of the common misinterpretation (misconception) in clinical practice is just to test for AQP-4 and MOG antibodies in any patient with new-onset demyelinating disease of the CNS, even if it's typical MS. And, this is quite wrong, because MS is way more common in clinical practice - it’s sixty, eighty times more common than NMO and MOGAD - and so, if you test all those patients without filter (indiscriminately) for antibodies, you increase the risk of false positivity exponentially, even if you have a highly specific test. So, first of all, I think it's good to select the right patients to test. As you said, patients with LTM, extensive involvement of the optic nerves on MRI, ADEM - there’s also patients with cortical encephalitis phenotype (which is a rare phenotype of MOGAD), but not definitely good to test the typical MS patients. This is the first thing.   Dr Smith: Yeah, I mean, that's an issue in all of neurology, isn't it, right? I mean, it's an issue in sort of just sending, you know, the Mayo panel, the autoimmune encephalitis panels - you need to select patients carefully, but I think this attention to prior probability is something that we need to really focus on in multiple areas. So, I wonder if you might expand a little bit on assays. I do a lot of work in myasthenia and I know which labs do a really good job with, you know, acetylcholine receptor antibody testing and those that maybe do not, and there are different methodologies for testing - do you have any wisdom in terms of how to select a lab, what to look for, and how to interpret the results you see based on the particular assay that's being used?    Dr Sechi: Yeah, that's a critical point. I agree. And especially if you work in myasthenia, you're very well aware of the differences between different assays, and nowadays, most of the high-quality assays are cell-based assays (either fixed or live) - it's the same in myasthenia, and people need to pay attention to some of the less-specific assays. Let's say ELISA, for instance - testing AQP-4 and MOG antibodies with ELISA is quite dangerous, because the risk of false positivity is quite high. So, it's good to know what assays to trust most and also good to know what's the right specimen to send for antibody test. For instance, with AQP-4, we know that serum testing is recommended only, and the CSF doesn't add much, but with MOG, we know that approximately 10% of patients have an isolated positivity in the CSF, which is interesting, because it means that when you have a patient with a strong diagnostic suspicion as a phenotype that is highly suggestive for MOGAD and the serum testing is negative, you may consider testing the CSF to increase your sensitivity. So, this is very important.   Dr Smith: So, I have a question for you that may seem a little naïve, but I bet other people are thinking it - can you tell us why it is that these disorders affect optic nerve and spinal cord preferentially? And I think, for NMO, the whole area postrema thing seems awfully specific to me. What's the deal? Why are these areas preferentially affected by these antibody-mediated disorders?   Dr Sechi: This is a tough question. For NMO, we know, probably, there is higher expression of some of the isoforms. Let's say there is a higher density of AQP-4 molecules that target the most affected regions - so, of course, AQP-4 is preferentially expressed in the subependymal regions around the ventricles and in the spinal cord and optic nerves, but you may have, also, solutions along the cortical spinal tracts in case of the brain involvement. The area postrema is kind of a different explanation, because there is a sort of permeability - increased permeability - of the blood-brain barrier there. So, there are several factors in MOGAD - this is not very clear, so, this is

Paraneoplastic neurologic syndromes can present with manifestations at any level of the neuraxis. In patients with high clinical suspicion of a paraneoplastic neurologic syndrome, cancer screening and treatment should be undertaken, regardless of the presence of a neural antibody. In this episode, Katie Grouse, MD, FAAN, speaks with Anastasia Zekeridou, MD, PhD, author of the article “Paraneoplastic Neurologic Disorders,” in the Continuum August 2024 Autoimmune Neurology issue. Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California San Francisco in San Francisco, California. Dr. Zekeridou a senior associate consultant in the departments of neurology, laboratory medicine, and pathology, and for the Center for Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic in Rochester, Minnesota. Additional Resources Read the article: Paraneoplastic Neurologic Disorders Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Guest: @ANASTASIA_ZEK Transcript Full transcript available here   Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum’s guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.   Dr Grouse: This is Dr Katie Grouse. Today, I'm interviewing Dr Anastasia Zekeridou about her article on classical paraneoplastic neurologic disorders, which is part of the August 2024 Continuum issue on autoimmune neurology. Welcome to the podcast, and please introduce yourself to our audience.   Dr Zekeridou: Hi. Thank you, Dr Grouse. I'm always excited to talk about paraneoplastic neurological diseases. So, I'm an autoimmune neurologist at Mayo Clinic in Rochester, and I spend my time between the lab and seeing patients in the autoimmune neurology clinic.   Dr Grouse: Thank you so much for joining us, and we're really excited to talk about this really important topic. So, to start, I'd like to ask what, in your opinion, is the key message from this article.   Dr Zekeridou: That's a good question - there are a lot of messages, but maybe if I can distill it down. For me, one of the first things is that paraneoplastic neurological diseases can actually affect any level of the neuraxis. It can manifest with different types of presentations. If we do suspect a paraneoplastic neurological syndrome, then we need to look for the cancer, and then if we're not certain, even do an immunotherapy trial. A negative antibody does not make for an absence of a paraneoplastic neurological disease (because, often, we depend a lot on them), but you can see patients with paraneoplastic disease that do not have neural antibodies. And then, we always need to be thinking that if we have a paraneoplastic neurological disease, we actually need to be thinking of both the cancer and the immune response together - so, we need to be treating the cancer, we need to be treating the immune response – because, essentially, paraneoplastic neurological syndrome is evidence of this antitumor immune response. So, the main (if I can distill this down in one) is probably that we need to be discussing all of these patients with the treating oncologist, because they have complicated care.   Dr Grouse: Great. Thank you so much for that summary. It's very helpful. While many of our listeners are likely familiar with paraneoplastic disorders in their workup (which you've mentioned just now), the concept of neurologic autoimmunity in the context of immune checkpoint inhibitor therapy has more recently become widely recognized. Can you summarize this briefly for our listeners who may be less familiar with this?   Dr Zekeridou: I think that we learn more and more about this and we see more and more patients with immune checkpoint inhibitor-related neurological immunity, so, I always think about it in a very straightforward way. So, I think the way we think about immune responses is a balance between tolerance and regulation and immune activations. And then, immune checkpoints are the molecules that help us maintain self-tolerance. So, our immune system - it's probably the best tool that we have to fight against cancer. So, essentially, when we inhibit the immune checkpoints, we actually use our own immune system to fight cancer, but taking the breaks of the immune system essentially can lead to a lot of complications that are immune-mediated. Some of them are neurological - the neurological complications are rare, especially the ones that we need to do something about (so, it's 1% to 4%, in some cases up to 14%), and they do increase when you use multiple immune checkpoint inhibitors together. The main thing for me with the neurological complications is that, sometimes, they are difficult to recognize, they can (again) affect every level of the neuraxis - like, it can be the neuromuscular or the central nervous system (even though neuromuscular complications are much more common than central nervous system complications) - and then a lot of them (the vast majority) will happen within the first three months, but they can also happen even after you stop the immune checkpoint inhibitor. But this three-month interval, it's sometimes useful when you're in a diagnostic silence - it kind of helps you make the decision more towards an immune-related adverse event affecting the nervous system. And then, I think that, practically, once we have diagnosed this patients, we still are not very certain how to treat. All of them will get steroids upfront, but some of them will be difficult to treat, so then, we have to decide on the next treatment depending on evolution. And then, I will just say that (I mentioned it previously, but) these are the patients that the coordination with other subspecialties is one of the main things that we need to do (eg, oncologists) - they often have immune-related adverse events from other systems, so, there is a lot of coordination of care. And, always, the question at the end comes up, Should we be putting these patients back to their immune checkpoint inhibitor cancer immunotherapy that might help them with the cancer? And I think that this is difficult sometimes, and it needs to be decided - most cases - in a case-by-case basis, even though there are some recommendations that I've been discussing in the Continuum article.   Dr Grose: That’s great, and I encourage everyone to read more about this, because it is a very complex and fascinating topic. On the note of the immune checkpoint inhibitor neurologic dysfunction - I would imagine these are pretty rare - how common are these? And I would suspect they're getting missed a lot - is that correct?   Dr Zekeridou: I think it's a very good question. Essentially, what we say for the neurological immune-related adverse events (the ones that we need intervention) - so, they are at least of grade two. (I think that there are less than 4%, mostly, probably close to 1.5%.) There was a study where they used double immune checkpoint inhibitors (so CTLA-4 and PD-1, PD-L1) - they were up to 14%, but this was any grade (so, a little bit of tingling, a little bit of headache), while the ones that we actually need to act upon and we need to actually do something about, they are probably closer to 1.5%. So, are they being missed? I am certain that some of them never make it to the neurologist. So, the ones that we know that we are underestimating is definitely the meningitis - because I think it’s more common – but, often, when the patients present, they have something else as well. So, the oncologists will put them on steroids and then they will get better - so, we don't really see them in the neurology clinic (the ones with the very mild side effects). And then, also, these patients are often very sick, and they have a lot of things going for them, so they sometimes do not make it to the diagnosis.   Dr Grouse: So then, I want to just take a step back and ask you, what's the most challenging aspect of paraneoplastic neurologic disorders in your opinion?   Dr Zekeridou: I think, for me, one of the main things, the classic paraneoplastic disorders - and when I say “classic paraneoplastic disorders”, they are the ones that we think more of with antibodies that are mostly biomarkers of the immune response, and they suggest a cytotoxic T-cell mediated disorder (so, like PCA1 [or anti-Yo] or ANNA-1 [or anti-Hu]) - these patients are very sick often, and we don't have a lot of good treatments for them. And then, even if we treat them, we actually sometimes do not manage to reverse their course - the best that we can do is stabilize. So, I think that this is part of the discussion that we have upfront with these patients - but it is quite challenging, because most of them, we will be giving them a cancer diagnosis ourselves, because we recognize the paraneoplastic neurological syndrome, and we look for the cancer, and then we'll be giving them a cancer diagnosis. And even if we treat their cancer and we treat the immune system, sometimes, then, we don't make a real improvement – like, we stabilize their disease and we sometimes get improvement, but there are cases that we do not and they continue to progress – so, that has been the

Autoimmune neurology is a rapidly evolving subspecialty that focuses on neurologic disorders with atypical immune responses. In this episode, Aaron Berkowitz, MD, PhD FAAN, speaks with Sean J. Pittock, MD, an author of the article “Overview and Diagnostic Approach in Autoimmune Neurology,” in the Continuum August 2024 Autoimmune Neurology issue. Dr. Berkowitz is a Continuum® Audio interviewer and professor of neurology at the University of California San Francisco, Department of Neurology and a neurohospitalist, general neurologist, and a clinician educator at the San Francisco VA Medical Center and San Francisco General Hospital in San Francisco, California. Dr. Pittock is the director for the Center for Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic in Rochester, Minnesota. Additional Resources Read the article: Overview and Diagnostic Approach in Autoimmune Neurology Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Transcript Full transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum’s guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.    Dr Berkowitz: This is Dr Aaron Berkowitz, and today, I'm interviewing Dr Sean Pittock about his article, “Introduction to Autoimmune Neurology and Diagnostic Approach”, which he wrote with his colleague, Dr Andrew McKeon. This article is a part of the August 2024 Continuum issue on autoimmune neurology. Welcome to the podcast, Dr Pittock. Could you introduce yourself to our audience?    Dr Pittock: Well, thank you very much, Dr Berkowitz. So, yeah, I'm a neurologist at the Mayo Clinic. I direct the neuroimmunology laboratory with Dr McKeon and Dr Mills here, and I have also been very much involved in the autoimmune neurology section at the American Academy of Neurology.    Dr Berkowitz: So, many of you probably know Dr Pittock - or if you don't know, you've certainly diagnosed diseases that he has described and written about, and so it's a real honor to get to talk to you today and pick your brain a little bit about some of these complex diseases. So, autoimmune neurology is certainly one of the most exciting subspecialties of our field. I feel like when I talk to students and they ask me to make a case for why they should consider neurology as a career, I tell them, “Of course, I have many reasons I love neurology”, but one thing I mention is that, although many other fields of medicine may have made incredible advances as far as treatments, I can't think of too many other fields outside neurology where entirely new diseases have been described since I've been in training and come out of training - and many of those have been in your field of autoimmune neurology. I can think of cases where I've heard you or one of your colleagues on a neurology podcast describing a new antibody, new disease, and a few weeks later, we see that disease and give a patient a diagnosis that had been elusive from other physicians and hospitals. It's a very exciting, gratifying area. It's also daunting, like, every time I go to the AAN and hear one of your colleagues, there's a new disease, and we realize, “Oops! Was I missing that?” or, “Am I going to see this?” And so, hoping to pick your brain a bit today about some of the key concepts and how to keep them in mind so our listeners can recognize, diagnose, and treat these conditions, even if they can't remember every single antibody in your article and all the new ones you and your colleagues will probably discover between now and when this, um, podcast is released. So, before we get into some of the important clinical aspects of these conditions, could you just lay out sort of the broad breaststrokes, the lay of the land of cell-mediated versus antibody-mediated paraneoplastic versus nonparaneoplastic cell surface versus intracellular - how can we sort of organize this area in our minds?    Dr Pittock: Yeah. It's complex, and it's really an evolving story. But the importance, really, from the perspective of the reader and the perspective of the clinician is that we're talking about disorders where we can actually do something - we can actually impact patients.  And we think about the concept of stopping and restoring in neurology now. We're talking about disorders where we have the potential to stop these inflammatory immune-mediated disorders and, potentially, by stopping early, we may be able to restore function - so, a really important new and evolving field in neurology, because you don't want to miss these conditions. Trying to get your head around the complexity of these entities is difficult, but what we've done in this chapter is, really, to try and lay the groundwork for the following chapters, but provide somewhat of a simplistic approach, but a practical approach that really, I think, can help clinicians. So, the way I think of it, a lot of autoimmune neurology really has stemmed from the discovery of antibodies that cause neurological disease, and the examples of those would be going back to myasthenia gravis (with antibodies to the acetylcholine receptor), going back to Lambert-Eaton syndrome. And then, you know, even if you go back to the older traditional paraneoplastic disorders (the Hu, the Ri, the Yo), at the end of the day, you really have two essential entities, if you want to be very simple. The first is disorders that are caused by an antibody, and the second are disorders where the antibodies you detect are not causing the disorder, but they're telling you that there's predominantly a cellular or T-cell mediated attack of the nervous system. And I think thinking about the diseases in those kind of simple terms helps us when we think about what would be the best treatment to use in these types of cases.   Dr Berkowitz: Fantastic. I think that's very helpful. And just to make sure it's clear in the minds of our listeners when we're dividing into these sort of causative antibodies versus antibodies that might be, uh (I don’t know if I'm using the word properly), but, sort of epiphenomena (or they're present, but they're not causative) as you said, can you just give some examples of the ones on either side and how making this distinction helps us in practice?    Dr Pittock: Yes. So, antibodies that are causative of disease - I think, you know, the one that I've done a lot of work on is in neuromyelitis optica, where you have antibodies that are targeting a water channel that sits on an astrocyte, and so it causes NMOSD, or what we consider an autoimmune astrocytopathy. And we know that when the antibody binds to the target, many things can happen. So, when aquaporin-4 antibodies bind to aquaporin-4, they can do a lot of things. They can cause internalization, they can activate complement that results in the killing of the cell - but there can be other situations. For example, when NMDA-receptor antibodies bind to the NMDA receptor, then a variety of different things can occur different to water channel autoimmunity - where, for example, the receptor (the NMDA receptor) is downregulated off the cell surface, and that results, to some extent, in the neuropsychiatric phenomenon that we see in NMDA-receptor autoimmunity. And, obviously, when you have a situation where the antibodies are causing the disease, removal of those antibodies, or the reduction in the production of those antibodies, is going to help patients. Now, on the other side, we have antibodies that we detect in the blood or in the spinal fluid, and those antibodies are targeting proteins that are inside the cell - so those antibodies we don't consider as being pathogenic. Now, remember, there are sometimes situations where proteins that are inside the cell occasionally can be available for antibodies to bind at certain situations. So, for example, in the synapse, amphiphysin or the septins, may at times become available. And so, sometimes, there are targets or antibodies that are somewhat in between those two simplistic concepts. But when we're talking about antibodies that are targeting proteins on the inside of the cell, remember that antibodies don't just suddenly occur. There's a whole process of presentation of target antigen at the lymph node, and then both a T- and a B-cell response. The B-cell response potentially produces the antibodies but also triggers and stimulates T-cells, and those T-cells then go on to cause the disease. And those T-cells are very problematic, because those classical paraneoplastic and the newer ones we've described (and many have described) - these are associated with quite severe neurological disability, and they're very, very difficult to treat. And if you ask me, “Where is the holy grail of autoimmune neurology therapeutic research?” It's in trying to actually figure out ways of treating the predominantly T-cell mediated paraneoplastic and autoimmune neurological disorders. We're making great headway in terms of the treatments of the antibody-mediated neurological disorders.   Dr Berkowitz: That's a helpful overview. So, sticking with this framework, you mentioned as sort of the “causative antibody” category and the antibodies that

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Eoin P. Flanagan, MBBCh, FAAN who served as the guest editor of the Continuum® August 2024 Autoimmune Neurology issue. They provide a preview of the issue, which publishes on August 1, 2024. 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. Flanagan is a professor of neurology at Mayo Clinic in Rochester, Minnesota. Additional Resources Continuum website: ContinuumJournal.com 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: @EoinFlanagan14 Transcript 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, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal have access to exclusive audio content not featured on the podcast. If you're not already a subscriber, we encourage you to become one. For more information, please visit the link in the show notes.    Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr Eoin Flanagan, who recently served as Continuum’s guest editor for our latest issue on autoimmune neurology. Dr Flanagan is a neurologist at Mayo Clinic in Rochester, Minnesota, where he's a professor of neurology. Eoin, why don't you introduce yourself to our listeners?   Dr Flanagan: Yeah, it's a great pleasure to be here today. I'm a neurologist. I'm originally from Ireland – I did my medical school training over there, and then came over to the Mayo Clinic to train in neurology and in neuroimmunology. And delighted to be able to edit this exciting issue of autoimmune neurology of Continuum. I think, um, it's a really fascinating area that's moving very quickly, and I'm hoping that we can educate listeners to be able to feel comfortable when they come to see these patients and to realize how much of a growing specialty it is and how we're getting treatments, and we can really help these patients.     Dr Jones: Yeah, it's a pretty exciting area. And, so, not only are you the Guest Editor for our latest issue of Continuum, this is the first-ever Continuum issue dedicated to autoimmune neurology, so I want to thank you for taking it on. This is something that our readers have been asking for for many years. I hope the topic wasn't too daunting.   Dr Flanagan: No, absolutely, it's a pleasure to be able to do it, and it's just great when you read all the articles to kind of feel where the field is going and how much of  a benefit we can now make for our patients. So, that's been a real joy to do.   Dr Jones: Well, congratulations, and it's a magnificent issue. You have a lot to be proud of putting this group of authors together. So, for a few of our issues now, we've had the opportunity on the Continuum Audio podcast to interview the Guest Editor, which is really fun for me. I have to confess it's really a joy to talk to someone who is up to the minute not only in their narrow area of expertise at the article level, but, really, across the entire breadth of the subspecialty. And so, you've had an opportunity to delve into all relevant topics in autoimmune neurology. When you look at the issue as a whole, or the field as a whole, what do you think the biggest debate or controversy in the world of autoimmune neurology is right now?     Dr Flanagan: Yeah, I think there's some changes happening. You know, initially, people used to recognize a disease called Hashimoto’s encephalitis, where patients would have a presentation of encephalitis in the setting of thyroid antibodies. And what we're now realizing is that many of these patients actually have antibodies to neural-specific targets, because we know that the antibodies that target the thyroid don't really impact the brain. And what we're now realizing is that there's many antibodies out there that bind to different receptors in the brain (the NMDA receptor, for example, AMPA receptor), so we're really trying to refine the field towards these different antibody-associated disorders - and each different disorder may behave very differently. A patient with NMDA receptor encephalitis, for example, may be in the ICU, in hospital, may take them six, nine months to recover. On the other hand, a patient with LGI1-antibody encephalitis may get five days of steroids and be almost back to normal within a few weeks. So, it's a really broad spectrum. And, I think, what we’re now learning is that each antibody has a role in helping define the disease, guide your treatment, guide your search for cancer - but, also, they behave differently - so these neural-specific antibodies are really important, while the older antibodies (like the thyroid antibodies) may just be a bystander and something that's happening in the background in a patient who's more prone to autoimmune disease.   Dr Jones: Very helpful, and I think that resonates with our listeners who have taken care of patients with autoimmune neurologic disorders, and it really is, I think, a great prototype in our specialty, maybe (for lack of a better word) of how observations start at the bedside, and then discoveries are made at the bench, and those benefits are brought back to patients. You know, there's been a recognition of autoimmunity in neurology for a long time, right - responsiveness to immunosuppression, even before the biomarkers were discovered - tell us a little story about how that works for our listeners.    Dr Flanagan: Yeah, so, I think one of the first steps is defining a clinical syndrome. So what you'll find is that some of these syndromes (for example, neuromyelitis optica spectrum disorder, where they have longitudinally extensive lesions within a spinal cord) provoked people to be interested that these looked different to MS, and then that went to the lab, and the aquaporin-4 antibodies were discovered - or, more recently, MOG antibodies were discovered. The aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder is a good prototype, because that went to the laboratory. Initially, they saw complement deposition on the pathology of these patients, they saw antibody deposition - the antibody was then discovered to aquaporin-4. And then, many labs around the world went to their own labs and they tried to delve in to determine what the pathogenesis was, and they found that complement was important in cell killing, that interleukin-6 elevation was important, and that complement appeared to be important. So, then, what they did was they tried to find treatments that would target those pathways. So, and now, we have treatments that are successful for this disease that can target complement, target interleukin-6, and target B cells (be it CD19 or CD20). So, we now have many different treatments, and this disease used to be very severe (so, had a 33% mortality at five years), and now these patients can live a long life with these treatments. So, I think that gives you an example of how you can follow the immunology of the disease and use targeted treatments to help our patients, and I think we can use that as a good prototype for many of   the other antibodies, because every year we discover two to three new antibodies, and each disease is a bit different in its mechanism. So, there are now clinical trials in NMDA receptor encephalitis starting up. There’s clinical trials in MOG antibody-associated disease. And I think we’re going to see that as we move forward, that these treatment trials will come and we’ll be able to help our patients better with proven treatments that we know work, rather than a history of we would just use five days of steroids and then we didn’t know exactly what to do in the long term - and we could manage some of the relapse as well, but we couldn’t really take care of the disease in the background - so, I think the NMO is a good model for moving forward, and the pharmaceutical companies are supporting moving forward with different trials for the disease.   Dr Jones: So, a key message there is understanding the biology so we can be a little more targeted and less indiscriminate in the immunomodulation we’re going to use. And we have parallels to that in the neuromuscular world, right, like using B-cell depletion for MuSK-associated neuromuscular junction disorders, as opposed to the trial-and-error approach, right? That's got to be a little more patient-centric and you get to a therapeutic response faster, right?   Dr Flanagan: I think so. Yeah, and I think, in the future, that might be something where, you know, a different patient, if they had elevated cytokines that pointed more to an IL-6 elevation, then maybe, in that patient, you would target IL-6, while the next patient with the same disease has more prominent complement activation, maybe you would target complement, or another patient has more prominent B-cell markers elevated, that you would target B cells. So, I think, we’re really moving towards a more individualized treatment in some of these disorders. So, it's a very exciting time, but we've only really made that breakthrough in one of the antibodies, and we have probably sixty, seventy antibody-mediated disorders now. So, it's going to get complicated, but it's also going to be, really, an exciting time for our patients, and I think an exciting time for neurology trainees and people who see patients in practice that we can now make diagnoses and guide their treatment that, previously, you know, these patients

Patients with severe acute brain injury often lack the capacity to make their own medical decisions, leaving surrogate decision makers responsible for life-or-death choices. Patient-centered approaches and scientific methodologies can guide clinicians’ prognostications. In this episode, Teshamae Monteith, MD, FAAN, speaks with Susanne Muehlschlegel, MD, MPH, FNCS, FCCM, FAAN, author of the article “Prognostication in Neurocritical Care,” in the Continuum® June 2024 Neurocritical Care issue. Dr. Monteith is the 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. Muehlschlegel is a professor (PAR) in the departments of neurology, anesthesiology/critical care medicine and neurosurgery, division of neurosciences critical care at Johns Hopkins University School of Medicine in Baltimore, Maryland. Additional Resources Read the article: Prognostication in Neurocritical Care 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: @SMuehlschMD Transcript Full 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, a companion podcast to the Journal. Continuum Audio features conversations with the guest editors and authors of Continuum, 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 by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you’re not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening. Dr Monteith: This is Dr Tesha Monteith, Associate Editor of Continuum Audio. Today, I'm interviewing doctor Susanne Muehlschlegel about her article on prognostication in neurocritical care, which is part of the June 2024 Continuum issue on neurocritical care. Well, Susanne, thank you so much for coming on the podcast, and thank you for writing that beautiful article. Dr Muehlschlegel: Thank you so much for having me. Excited to be here. Dr Monteith: Why don't we start with you just introducing yourself? Dr Muehlschlegel: Yeah, sure. My name is Susanne Muehlschlegel. I'm a neurointensivist at Johns Hopkins in Baltimore, Maryland. I have been a neurointensivist for about eighteen years or so. I worked previously at the University of Massachusetts and recently arrived here at Hopkins. Dr Monteith: Cool. So, what were you thinking about - What information did you want to convey - when you set out to write your article? Dr Muehlschlegel: Yeah. So, the article about neuroprognostication is really near and dear to my heart and my research focus, and I'm very passionate about that part. And as neurologist and neurointensivist, prognostication, you know, might be considered the bread and butter of what we're asked to do by families and other services, but as the article states, is that we don't usually do a great job (or physicians sometimes believe they do). But when you actually do research and look at data, it’s probably not as good as we think, and there’s a lot of room for improvement. And, so, the reason for this article really was to shine the light at the fact that I think we need to really make neuroprognostication a science, just like we make prediction models a science - and, so, that is the main topic of my research, as well as the article. Dr Monteith: So, we know about your interest in research in this area, but what got you into critical care to begin with? Dr Muehlschlegel: Yeah. It's, pretty much, a story of always being drawn to what's exciting and what others may want to avoid. So, in medical school, people were afraid of neurology and learning all the anatomy, and I just loved that and loved interacting with these patients. And then, in neurology residency, I was drawn to not just treating the brain and the spinal cord, but also the entire patient (so the lung and the heart and the interaction of all the organs). And then, naturally, I'm a little bit of an impatient person, and so I like the environment of the ICU of rapid change and always having to be on my toes. And so that's what drew me into neurocritical care. It was a very new field when I was training, and so, I was probably, you know, one of the, maybe, first- or second-generation neurointensivists. Dr Monteith: And it sounds like you're maybe okay with uncertainty and a lot of variability? Dr Muehlschlegel: Well, you know, neuroprognostication - I think everyone has to acknowledge that we cannot take away uncertainty, right? So, folks who pretend that they know for sure what's going to happen - I think the only time we can say that is in a patient who's braindead. But everyone else, we really don't know for sure, and all we can do is do the best to our ability to give a rough outlook - but we need to acknowledge uncertainty, that's for sure. Dr Monteith: So, can you just give us a few of the biggest causes of variability when it comes to withdrawing life-sustaining therapies in patients with severe acute brain injuries? Dr Muehlschlegel: So, that's the focus of quite some research. And, of course, there are many epidemiological factors, patient severity of disease, and, you know, how fast someone might arrive to the hospital, ethnic, racial, social demographic factors (and there's research on that), but when you adjust and control for all of those factors, variability remains. And so, what I've observed in my practice and what I also describe in the article is that maybe it's the way physicians describe prognostication or communicate with families, meaning there is potentially the chance for physician bias - that may also drive prognostication. And I can tell you from my own experience, what really drove me into this area is anecdotal experience that probably we've all had of other physicians kind of nihilistically prognosticating, thinking, you know, "This is going to be bad no matter what”, and not even wanting to try to provide aggressive care to patients. So, I think these what we call “self-fulfilling prophecies” we need to be very aware of. So, I think some of the variability may be driven by other factors other than family, patient, or health system factors. Dr Monteith: And you outline that really nicely in the article, so thank you for that. Why don't you just give us an example of a challenging case that maybe you're still thinking about today, that maybe happened years ago, that helps us understand what you go through? Dr Muehlschlegel: Yeah, I’ll rephrase the case. I still have, you know, very vivid memories about this, but I tell my residents about this case. When I was a fellow, there was a young patient in his early forties, a father of several children, a young family man who had a big right MCA stroke and really was progressing to the point that it was clear that he needed a hemicraniectomy or he was going to die. Discussed this with my attending, who said I should consult neurosurgery. At the time, the neurosurgical service had a transition to practice service for these emergencies - and so, these were fairly young, chief residents or early-year attendings. And the person came in, went into the patient's room, and I didn't even know about it, and came out and then just said, “Family decided for CMO”. I was very surprised and shocked and was trying to understand how this happened, and this provider, all he said was, “Well, it's all how you put it to the family. I told him that he probably shouldn't be a vegetable. They didn't want him to be a vegetable, and so this was the only option.” And, so, I was very shocked, and the patient did progress to die within a few days. And, so, that was a dire example of how biased prognostication can drive families to maybe an unnecessary outcome. Dr Monteith: And what’s CMO? Dr Muehlschlegel: I’m sorry. Comfort measures only - so, essentially, a withdrawal of life-sustaining therapies. Dr Monteith: Yeah. That is a good example of that and how our bias can inform families and maybe not with the exact amount of data to support that, as you outlined so nicely in your article. Dr Muehlschlegel: And I do want to emphasize, I don’t want to generalize that all providers are like that, but it is an example that really still sticks in the back of my mind, and I think, you know, we need to shine a light at how we do this and how we do it right or wrong. Dr Monteith: And wouldn’t it be nice to just have more objective measures (right?) to guide us? So why don’t we talk about existing tools that are used to help guide neuroprognostication? Dr Muehlschlegel: Yeah, so I think, in general, we can break down prognostication to two pieces (and I outline that in the article as well). So, one is, kind of, a derivation of prognostication in the head of a physician or, you know, clinician – and what may go into that is how the patient presented, examination, radiology or other diagnostics, biomarkers, you name it. But, then the second part of it (that also is really important) is how we put it to the family, right? Because we can influence families in a way that we may not even be aware of, and I think we all have unconscious biases, and how we talk to families is really importan

In this episode, Gordon Smith, MD, FAAN speaks with Casey S.W. Albin, MD, author of the article “Neuromuscular Emergencies,” in the Continuum® June 2024 Neurocritical Care issue. Dr. Smith is a Continuum® Audio interviewer and 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. Albin is an assistant professor of neurology and neurosurgery in the departments of neurology and neurosurgery, division of neurocritical care at Emory University School of Medicine in Atlanta, Georgia. Additional Resources Read the article: Neuromuscular Emergencies 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 Guest: @caseyalbin Transcript  Full 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, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, 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 by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening.   Dr Smith: Hi. This is Dr Gordon Smith. I'm super excited today to be able to have the opportunity to talk to Dr Casey Albin, who will introduce herself in a second. She's well known to Continuum Nation as the Associate Editor for Media Engagement for Continuum. She's also a Neurointensivist at Emory University and wrote a really outstanding article for the neurocritical care issue of Continuum on neuromuscular emergencies. Casey, thanks for joining us. Tell us about yourself. Dr Albin: Sure. Thank you so much, Dr Smith. So, yes, I'm Casey Albin. I am a Neurointensivist. I practice at Emory. We have a really busy and diverse care that we provide at the Emory neuro ICUs. Just at the Clifton campus, there’s over forty beds. So, although neuromuscular emergencies certainly do not make up the bread and butter of our practice - I mean, like many intensivists, I spend most of my time primarily caring for patients with cerebrovascular disease - this is a really interesting and just kind of a fun group of patients to take care of because of the ability we have to improve their outcomes and that some of these patients really do get better. And that's a really exciting thing to bear witness to. Dr Smith: I love finding neurointensivists that are interested in neuromuscular medicine because I share your interest in these patients and the fact that there's a lot that we can do for them. You know, how did you get interested in neurocritical care, Casey? Dr Albin: You know, I was always interested in critical care. It was really actually the neurology part that I came late to the party. I was actually, like, gearing up to apply into emergency medicine and was doing my emergency medicine sub-I (like, that was the route I was going to take), and during that sub-I, I just kept encountering patients with neurologic emergencies - so, you know, leptomeningeal carcinomatosis and obstructive hydrocephalus, and then a patient with stroke - and I realized I was just gravitating towards the neuroemergencies more so than just any general emergencies. And I had really enjoyed my neurology rotation. I did not foresee that as the path I was going to take, but after kind of spending some time and taking care of so many neurologic emergencies from the lens of an emergency department, sort of realized, like, "You know, I should go back and do a neurology sub-I.” And so, kind of, actually, late in the game is when I did that rotation and, like, dramatically changed my whole life trajectory. So, I have known since sort of that fourth year of medical school that I really wanted to focus on neurocritical care and neurologic emergencies, and I love the blend of critical care medicine and the procedural aspect of my job while doing it with the most interesting of all the organ systems. So, it's really a great blend of medicine. Dr Smith: Did you ever think about neuromuscular medicine? Dr Albin: Uh, no. Dr Smith: I had to ask. I had to ask. Dr Albin: No, I mean, I do really love neuromuscular emergencies, but I've known for forever that like, really wanted to be in an acute care setting. Dr Smith: You know, I think it's such a great story, Casey, and I know you're an educator, too, right? And, um, we hear this from learners all the time about how they come to neurology relatively late in medical school, and it's been really great to see the trajectory in terms of fellowship determination dates and giving our students opportunities to make their choice, you know, later during their medical school career. And I wonder whether your journey is an example of what we’re seeing now (which is more and more students going into neurology because we’re giving them the free space to do that), and then also in terms of fellowship decisions as well (which was what I was alluding to earlier)? Dr Albin: Yeah, absolutely. I think having more exposure to neurology and getting a chance to be in that clinical environment - you know, when you are doing the “brain and behaviors” (or whatever your medical school calls the neurology curriculum) - it is so hard and it's so dense, and I think that that's really overwhelming for students. And then you get into the clinical aspect of neurology, and sure, you have to know neurolocalization - and that is fundamentally important to everything we do - but the clinical application is just so beautiful and so much fun and it's so challenging, but in a good way. So, I totally agree. I think that more students need more exposure. Dr Smith: Well, I mean, that's a perfect segue to something I wanted to talk to you about, which is you brought up the beauty of neurology - which is, I think, you know, neurologic formulation, really – and we talk a lot about the elegance of the neurologic examination. But one of the things I really liked about your article was its old-school formulation – you talk about the importance of history, examination, localization, pattern recognition – I wonder if, maybe, you could give us some pearls from that approach and how you think about acute neuromuscular problems and the ICU? Dr Albin: Absolutely. I really do think that this is the cornerstone of making a good diagnosis, right? I will tell you what’s really challenging about some of these patients when they are admitted to the ICU is that we are often faced with sort of a confounded exam. The patient may have been rapidly deteriorating, and they may not be able to provide a good history. They may be intubated by the time that we meet them. And so not only are they not able to provide a history themselves, but their exam may be confounded by the fact that they're on a little bit of sedation, or they were aspirating and now they have a little bit of pneumonia. I mean, it can be really challenging to get a good neurologic exam in these patients. But I do think the history and the physical are really where the money is in terms of being able to send the appropriate test. And so, when I think about these patients who get admitted to the neuro ICU, the first thing that we have to have is someone who can provide a really good collateral history, because so much of what we're trying to determine is, "Is this the first presentation, and this is a de novo (new) neuromuscular problem?” or “Had the patient actually had sort of a subacute or chronic (even) decline and they’ve been undiagnosed for something that was maybe a little bit more indolent, but (you know, they had an abrupt decline because, you know, they got pneumonia, or they have bloodstream infection, or whatever it was allowing them to sort of compensate) they have no longer been able to compensate?”. And so, I really do think that that's key. And when I am hearing the story the first time, that's really one of the focuses of my history – is, "Was this truly a new problem?”. And then, when we think about, you know, "Where do we localize this within the nervous system?”, it's actually quite challenging because, you know, patients with acute spinal cord pathology may also not present with the upper motor neuron findings that are classic for spinal cord pathology. And so I think, again, it's a little bit recognizing that you can be confounded and we have to keep a broad differential, but I am sort of examining for whether or not there's proximal versus distal (like, the gradient of where they’re weakest), is there symmetry or asymmetry, and then, are there other, sort of, features that go along with helping us localize to something to the nerves (such as sensory symptoms or autonomic symptoms)? So when I think about, you know, where we're putting this, you can put anything in sort of the anterior horn cells or to the nerves themselves, to the neuromuscular junction, and then to the muscles. And teasing that out, I put in some figures and tables within the article to help kind of help the reader think about what are features of my patient's exam, my patient's history, that might help me to put

Neurologic infections become emergencies when they lead to a rapid decline in a patient’s function; however, neurologic infections are often challenging to recognize. In this episode, Aaron Berkowitz, MD, PhD, FAAN, speaks with Alexandra S. Reynolds, MD, author of the article “Neuroinfectious Emergencies,” in the Continuum® June 2024 Neurocritical Care issue. Dr. Berkowitz is a Continuum® Audio interviewer and professor of neurology at the University of California San Francisco, Department of Neurology and a neurohospitalist, general neurologist, and a clinician educator at the San Francisco VA Medical Center and San Francisco General Hospital in San Francisco, California. Dr. Reynolds is an associate professor in the departments of neurosurgery and neurology at Icahn School of Medicine at Mount Sinai Health System in New York, New York. Additional Resources Read the article: Neuroinfectious Emergencies Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Transcript Full 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, a companion podcast to the Journal. Continuum Audio features conversations with the guest editors and authors of Continuum, 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 by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening.     Dr Berkowitz: This is Dr Aaron Berkowitz, and today, I'm interviewing Dr Alexandra Reynolds about her article on neuroinfectious emergencies, which is part of the June 2024 Continuum issue on neurocritical care. Welcome to the podcast, Dr Reynolds. Um, would you mind, please, introducing yourself to our audience?   Dr Reynolds: Sure. Thank you for the invitation. I’m Alex Reynolds, and I am a neurointensivist at Mount Sinai Hospital in New York City.   Dr Berkowitz: Fantastic. Thanks for joining us. Dr Reynolds has written a really comprehensive article with lots of clinical pearls for the evaluation of patients with neurologic infections. So, to start off, when should we consider a neurologic infection as the cause of a patient's neurologic symptoms?   Dr Reynolds: That is a, really, much more complicated question than I think you recognize. I feel like a lot of it has to do with the risk factors of the patient. So, certainly, you know, a lot of times, we think about a patient who comes in with fever and altered mental status, and that's sort of the patient we're thinking about as having an intracranial infection – but, I do think there are a lot of risk factors that, sort of, may push us in that direction even if the patient doesn't have a fever or even if the patient doesn't seem like meningitis (for example). So, you know, a lot of patients nowadays are immunosuppressed, either because of infections or because of the therapies that we're using as immunosuppressants (so, autoimmune diseases, transplants, bone marrow patients). And then, I think, any patient who has had an intracranial procedure or a spinal procedure, we sort of just have to have in the back of our mind that surgical procedures come, by definition, with risk of infection (and so, that’s always something to think about). And then, certainly, anything in terms of endemic risk factors (so a patient who has come from a country that has an endemic infection), we need to just be a little bit more broad about what we're thinking about in that patient population.   Dr Berkowitz: That's very helpful. You mentioned something I wanted to pick up on. We always think fever, of course we're going to be thinking about a neurologic infection, but some types of neurologic infections and in some patient populations, it's possible to have an infection of the nervous system with no fever, sometimes even no white count. What other clues should be considered, or when would you think about pursuing infection even in patients who don't have a fever or an elevated white count?   Dr Reynolds: So, certainly, in patients who have imaging that’s a little abnormal. I think, oftentimes, the patients that I’ve seen with sort of indolent infections have a subdural collection that just doesn’t look quite right or doesn’t make sense with the clinical history (you know, you can have P. acnes infections that go on for months that people really don’t necessarily notice) - so any imaging, oftentimes on MRI, you’ll see, sort of, diffusion restriction where you don’t really expect to see it. So, those sorts of patients might be ones where if the story is just not really fitting, you might want to think about infection. So, I think it's also important to remember that patients who have procedures elsewhere in the body can sort of seed themselves, and either by direct spread or by hematogenous spread, those infections can kind of seed the CNS - so, patients with valve procedures in the heart, patients who have intraabdominal procedures, there really is no reason that those infections can't travel to the CNS as well. And so, I was sort of always taught, you know, if the story doesn’t make sense, then you have to consider infection, even if the patient doesn’t have a white count or fever. So, I think just having, sort of, that suspicion in the back of your mind that if you can't really make sense of the story, then consider an infection.   Dr Berkowitz: Yeah. So, obviously, fever, white count, those would clue us in that a patient with new neurologic symptoms (signs) may have an infection as a cause. But, as you said, they may not be present in patients who have had any type of neurosurgical procedure (or you've just taught us even non-neurosurgical procedures elsewhere in the body) that could have led to bacteremia. And then, you mentioned earlier, also patients who are immunocompromised may develop a neurologic infection without fever or white count, and our threshold is certainly lower to pursue that possibility in that population as well. Other points on that before we move on?   Dr Reynolds: I had an attending that told me if you're thinking about a lumbar puncture, you better just do it – so, I think those are wise words to sort of live by. If you're thinking about an infection, you better just work it up.   Dr Berkowitz: Yeah. I think that's right. I heard something similar that if you're standing around on rounds debating whether the patient should get a lumbar puncture, probably, if you've talked about it that much, you should probably do it. I think we've heard the same things in different places. Along those lines of who needs a lumbar puncture, many patients with systemic infections can develop a headache, even if it's just from systemic infection (you don't necessarily have meningitis and cephalitis), and many patients, particularly older patients, develop confusion in the course of systemic infections, like pneumonia and urinary tract infections. And as neurologists, we are often consulted on these patients because they are confused, they are febrile, they may have an elevated white count, and people start to wonder, Could this patient have meningitis? Could this patient have encephalitis? In many cases, at least in my experience (I'm curious to hear your experience), it turns out that these patients have a systemic infection and the confusion and/or headache are related to that systemic infection, not a primary neurologic infection - but based on that topic we just discussed about, if you've talked about lumbar puncture enough, probably best to do it. How do you think about these patients who are, for example, admitted to a medical service for fever and confusion, may or may not have had a systemic source identified, but the suspicion is there? How do you think about which of those patients need a lumbar puncture, or what clues you into thinking to have a higher concern for meningitis, encephalitis, abscess, other neurologic infections in this context?   Dr Reynolds: It's such a good question, because I think, especially as we get older, you know, even things like nuchal rigidity might be hard to assess in a patient who’s sort of started to fuse their spine - so, I think it can be really challenging. I think, you know, always go back to basics. Is there any new laterality that doesn't really make sense? Is there a sort of disconnect between imaging and how the patient looks? And it can be so confounded, because these are patients who are also on antibiotics (which themselves can be neurotoxic), and so, it can be really hard to sort of parse that out. But, I do think that there are some less invasive things you can try to do first to sort of help risk stratify your patient. So, you know, certainly, getting a CAT scan and just making sure that everything looks as you would expect it to look - there's no, sort of, hydro out of proportion to what you might expect. I’ve definitely seen patients who have meningitis that we caught because they have just a little bit of pus in the ventricles that was interpreted as intraventricular hemorrhage. And you sort of just have to sit there and think, like, Does that make sense, or is it an

Despite validated models, predicting outcomes after traumatic brain injury remains challenging, requiring prognostic humility and a model of shared decision making with surrogate decision makers to establish care goals. In this episode, Lyell Jones, MD, FAAN, speaks with Jamie E. Podell, MD, an author of the article “Traumatic Brain Injury and Traumatic Spinal Cord Injury,” in the Continuum June 2024 Neurocritical Care 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. Podell is an assistant professor in the department of neurology, program in trauma at the University of Maryland School of Medicine in Baltimore, Maryland. Additional Resources Read the article: Traumatic Brain Injury and Traumatic Spinal Cord Injury 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: @LyellJ Guest: @jepodell Transcript Full 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, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, 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 by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening.   Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr Jamie Podell, who has recently authored an article on traumatic brain injury and traumatic spinal cord injury in the latest issue of Continuum on neurocritical care. Dr Podell, welcome. Thank you for joining us today. Why don't you introduce yourself to our audience and tell us a little bit about yourself?   Dr Podell: Thanks, Dr Jones. It's great to be here. As you mentioned, I'm Dr Podell. I'm neurocritical care faculty at University of Maryland Shock Trauma. I have a primary interest in traumatic brain injury, both from a research and clinical perspective. I previously have more of a cognitive neuroscience background, but I think it kind of ties into how I think about TBI and outcomes from traumatic brain injury. But what I really like doing is managing acutely ill patients in the ICU, and I think TBI really affords those kinds of interventions, and it's a really rewarding kind of setting to take care of patients. Dr Jones: Yeah, and I really can't wait to talk to you about your article here, which is fantastic. For our listeners who might be new to Continuum, Continuum is a journal dedicated to helping clinicians deliver the best possible neurologic care to their patients, just like Dr Podell was talking about. We do that with high quality and current clinical reviews, and Dr Podell's article - it's a massive topic - traumatic brain injury and traumatic spinal cord injury. And, you know, as we start off here, Dr Podell, we have the attention now of a massive audience of neurologists. If you had one most important practice change that you would like to see in the care of these patients who have trauma, what would that practice change be? And, I think, maybe, we'll give you two answers, because you cover TBI and you cover spinal cord injury. What would be the most important practice changes you'd like to see?   Dr Podell: So, this isn't that specific, but I think it's really important. I think we need more neurologists, and specifically neurointensivists, managing these patients. I think there's a lot of variability across institutions and how acute severe TBI and spinal cord injury patients are managed. They're often in surgical ICUs, and neurology may be involved in consultation but not in the day-to-day management. But I think what we're seeing is that, you know, there's a lot of multisystem organ dysfunction that happens in these patients, and that has a really strong interplay with neurologic recovery and brain function. And I think, you know, neurointensivists are very well equipped to think about the whole body and how we can kind of manipulate and really aggressively support the body to help heal the brain with special attention to, kind of, the nuance of any individual patient's brain injury. Because TBI is extremely heterogeneous and there's not just a cookie-cutter script for how these patients can be managed, I think, you know, people like neurologists, neurointensivists who have a lot of attention to the nuance - that's really helpful in their management.   Dr Jones: I'm so glad you said that, and not just because I'm a neurologist who's a fan of neurologists, but I do think there are some corners of neuroscience care where neurologists could be a little more present - and trauma definitely seems like one of those, doesn't it?   Dr Podell: Yeah, I think it's tough, because some patients with severe TBI and spinal cord injury can have a lot of multisystemic trauma with, you know, pulmonary contusions, intraabdominal pathology - you need to go to the OR for their other injuries, and so I think it really makes sense to have kind of a collaborative multidisciplinary approach to these patients, but I think neurologists should play a very big role in that approach, however that's done (there are lots of different ways that it's done). But I think having a primary neurology-trained neurointensivist – I know I’m biased, but I think that’s where I’d like to see the field moving.   Dr Jones: And, obviously, neurocritical care is an intuitive place for neurological trauma care to start, and even with the sequelae of downstream things, I think neurologists could be more engaged. I wonder if neurology hasn't historically been as involved because it's sort of gravitated to surgical specialists. And I think part of it is, you know, trauma is not usually a diagnostic mystery, right? The neurologist can't pretend to be Sherlock Holmes and try to figure out what's going on when it was pretty clear what the event was, right?   Dr Podell: Right. Yeah, I agree with both of those points. I think, for one, I think postacute care is also a big area where neurologists can be involved more - and patients kind of fall through the cracks. A lot of times, these patients will just follow up with a neurosurgeon and get a repeat head CT and it’ll look stable. We started implementing post-TBI neural recovery clinics, which I think other places are starting to do as well, and I think that's kind of a good model for getting neurologists involved - but also, rehab specialists are involved in that. But in terms of, yeah, the diagnostic mysteries and stuff, I think there still can be some, though, with TBI. Yes, obviously, the initial primary insult is obvious, but the secondary pathology that can happen in patients is really nuanced, and it is so variable, and, sometimes, it does take that detective eye to see, “Oh, this patient has one cerebrovascular injury, their risk of stroke to this territory? How are we going to manage it? and thinking about all the kind of sources of secondary decline that are possible. I think it takes that neurology detective sometimes to think about, too.   Dr Jones: Yeah. We never stop pretending to be detectives, right?   Dr Podell: Yeah.   Dr Jones: And on a related note, you know, in your article, you mentioned some of the novel serum and electrophysiologic and imaging biomarkers that are being used to care for these patients. How are you using those in your practice, Dr Podell?   Dr Podell: That's a good question. I think, unfortunately, as with a lot of clinical care, the clinical care does kind of lag behind the research and what we know what we can learn about these patients and their outcomes through retrospective studies. So, to be completely honest, you know, even the serum studies that I mentioned in the article (like GFAP, UCH-L1) - those kind of things, that's not clinically available at our institution. We don't use those. I think a lot of the imaging biomarkers that we see, some of them are coming from more advanced imaging – like, we're talking about FMRI - that requires a lot of post processing (so, again, we're not necessarily using that clinically). But what I would say is that we use imaging to kind of try to predict what complications patients might be at risk of and to try to predict their clinical course. And I think it comes down to trying to break down the heterogeneity of these patients and to try to kind of lump them into different bins of, “What's this patient at risk for?”, “What's their trajectory going to be like?”, “When can I start peeling back how aggressive I am with this patient?”. And, so far, I don't think any of the markers that we have are really clear black-white prescriptive indicators of what to do (I don't think we're quite there yet). So, again, I think we just kind of use all of the data in combination to come up with a management plan for these patients. I think some of the markers, (like some of the electrophysiologic markers), looking at EEG for things like background can provide prognostic information, especially in patients who are comatose that you're wondering a

The critical care management of spontaneous subarachnoid hemorrhage (SAH) is similar to that of other acute brain injuries, with the addition of detecting and treating delayed cerebral ischemia. Recent trials are influencing practice and providing guidance for standardizing management. In this episode, Kait Nevel, MD speaks with Soojin Park, MD, FAHA, FNCS, author of the article “Emergent Management of Spontaneous Subarachnoid Hemorrhage,” in the Continuum June 2024 Neurocritical Care issue. Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana. Dr. Park is an associate professor of neurology (in biomedical informatics) at Vagelos College of Physicians and Surgeons, Columbia University in New York, New York and medical director of critical care data science and artificial intelligence at NewYork-Presbyterian Hospital in New York, New York. Additional Resources Read the article: Emergent Management of Spontaneous Subarachnoid Hemorrhage 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 Guest: @soojin_soojin Full episode transcript   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, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, 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 by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening.   Dr Nevel: This is Dr Kait Nevel. Today, I'm interviewing Dr Soojin Park about her article on emergent management of spontaneous subarachnoid hemorrhage, which is part of the June 2024 Continuum issue on neurocritical care. Welcome to the podcast. It's so great to be talking to you today.   Dr Park: Thank you so much, Kait. Nice to be here.   Dr Nevel: Before we get started, could you introduce yourself for the audience?   Dr Park: Sure. So, I am an Associate Professor of Neurology - also in Biomedical Informatics - at Columbia University here in New York City. I trained in vascular neurology and neurocritical care.   Dr Nevel: Great. And so, I always like to ask at the beginning of these interviews, you know, if we could take away one thing from your article — and this is specifically (I'll direct this) towards the neurologists out there that are covering inpatient consults and ER consults — and so, for our clinical neurologists listening out there, what is the most important thing that you think that they should take away from your article?   Dr Park: So, I guess the most important thing for the general neurologists out there is that it may have been a while since they were aware of some updates that have occurred. There are some recent trials that are influencing practice and will potentially influence practice in the next few years that readers should really know about, and it provides a little bit stronger guidance to drive more standardized management. There have been two recent guidelines published this year. But there remain several gray areas for management where you need to be a bit more nuanced, and so I'm hoping the article gives the readers a framework to deliver more expert care.   Dr Nevel: Yeah, and I really, of course, always urge the listeners to go back and read the article and reference the article, because I do think that you do that really nicely and are clear when there are things where there's more higher-level, evidence-based reasons for things and where there's, kind of, just more expertise and guidelines on certain things. So, could you tell the listeners a little bit more about yourself, what interests you about subarachnoid hemorrhage specifically, and how you approach that interest and clinical background in writing this article?   Dr Park: So, I mentioned that I trained in both vascular neurology and neurocritical care back when many people used to do that. As a result, I’ve trained or practiced in four different academic medical centers who have specialized neurointensive care units. And the patients with subarachnoid hemorrhage tend to have a substantial ICU length of stay, and the neurointensive care that we provide can have a very large impact on patient outcome. And what I saw, though (practicing across four different centers), was that the management of patients with subarach can be quite variable across institutions and across patients within institutions, and it's reflective of a couple of things. One, there's, like, complexity in detecting ischemia, even when your patient is a captive audience in their ICU room. Second, there's many clinical mimics that occur (the patients with subarachnoid hemorrhage, they have a risk for), such as hydrocephalus, seizure, and things like delirium. And then, finally, there's limitations in the technology that we even have available in terms of monitoring these patients. But, for me, it was this complexity and the variability of management that kind of posed an opportunity, and it really sparked my curiosity early on and has sustained me. So, I'm particularly interested in the role that, kind of, the complex analysis of existing monitoring technologies can play to improve outcome for patients with subarachnoid hemorrhage, and that's where the marriage of both being a neurointensive care physician and a biomedical informatics person comes in.   Dr Nevel: Yeah. That's really interesting, and I could see that, because I always felt, even during my training, that some of the management and, you know, what diagnostics were even ordered to follow patients throughout the ICU was expertise based and seemed to vary without a lot of really solid, again, high-level studies, guiding what was done. So how do you marry the bioinformatics with your interest in SAH?   Dr Park: Right. So, I have two grants on - basically, I guess you would say AI, but really data science - on how we can manage patients with bleeds, specifically ICH and subarachnoid hemorrhage and hydrocephalus. So, we use data that comes from the monitors and we process that in a multimodal fashion and apply signal processing and machine learning and we build predictive analytic tools. So, I'm very interested in this pipeline of developing clinical decision support (information that we don't really have), and we're trying to glean from all the data and turn it into information that clinicians might use. The problem in subarachnoid hemorrhage patients is that a lot of what we're looking for is subclinical - so, it's not quite obvious, either because you can't possibly be in the room to be constantly monitoring for it (and, currently, the best monitor is the human, is examination), but, specifically in patients who have disordered consciousness, even the examination can be somewhat limited, and that’s where we rely upon some of our neuromonitors. So, my interest has come in taking those multimodal monitors - but even nonneurologic monitors (stuff about your physiology, like your heart rate and blood pressure, et cetera) - and able to find signals that might tell us that a patient is getting into a dangerous zone. So, that’s what my research portfolio has been 100% about - it’s about subarachnoid hemorrhage patients and trying to optimize management, both for prevention and intervening in a timely fashion.   Dr Nevel: Wow. That’s really interesting and would be so wonderful, it sounds like, for this patient population, if, you know, something was able to be identified that you could easily monitor to kind of predict or catch things early. So, kind of segueing from that, what do you think are the most — and you outline these nicely in your article, and I’m going to reference the listeners to, I believe it’s the first table (table 5-1) - but what are, just like in general, the most important initial steps a clinician should take when managing somebody with an aneurysmal subarachnoid hemorrhage?   Dr Park: So, I think it’s sort of along the timeline. So, at the time of presentation of a patient with subarachnoid hemorrhage, the focus you should have should be really on differentiating the etiology of the subarachnoid hemorrhage. At the same time, if the patient has any coagulopathies, you should manage that coagulopathy reversal, blood pressure management, and then detection and management and treatment of hydrocephalus. That’s first and foremost. But then there is a longer timeline of neurocritical care management, and that’s really centered on prevention, detection, and treatment of delayed cerebral ischemia, and that can occur anytime from onset of subarachnoid hemorrhage to two to three weeks out. And then that period of neurocritical care is made challenging because you have early brain injury (which is the period of seventy-two hours after onset), cerebral edema, and then, like we talked about, disordered consciousness. This kind of knowing how to augment your management strategies with monitoring or imaging is really key.   Dr Nevel: Yeah. And you, you know, spend some time in your article really going

Management of stroke due to large vessel occlusion (LVO) has undergone unprecedented change in the past decade. Early identification and aggressive treatment are important in mitigating negative effects on patients’ prognoses. In this episode, Allison Weathers, MD, FAAN, speaks with T. M. Leslie-Mazwi, MD, author of the article “Neurocritical Care for Patients With Ischemic Stroke,” in the Continuum June 2024 Neurocritical Care issue. Dr. Weathers is a Continuum® Audio interviewer and an associate chief medical information officer at Cleveland Clinic in Cleveland, Ohio. Dr. Leslie-Mazwi is a professor and chair in the department of neurology at the University of Washington in Seattle, Washington. Additional Resources Read the article: Neurocritical Care for Patients With Ischemic Stroke 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 Transcript Full transcript available

In neurocritical care, the initial evaluation is often fast paced, and assessment and management go hand in hand. History, clinical examination, and workup should be obtained while considering therapeutic implications and the need for lifesaving interventions. In this episode, Aaron Berkowitz, MD, PhD FAAN, speaks with Sarah Wahlster, MD, an author of the article “The Neurocritical Care Examination and Workup,” in the Continuum June 2024 Neurocritical Care issue. Dr. Berkowitz is a Continuum® Audio interviewer and professor of neurology at the University of California San Francisco, Department of Neurology and a neurohospitalist, general neurologist, and a clinician educator at the San Francisco VA Medical Center and San Francisco General Hospital in San Francisco, California. Dr. Wahlster is an associate professor of neurology in the departments of neurology, neurological surgery, and anesthesiology and pain medicine at Harborview Medical Center, University of Washington in Seattle, Washington. Additional Resources Read the article: The Neurocritical Care Examination and Workup Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Guest: @SWahlster Full Episode Transcript Sarah Wahlster, MD   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, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, 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 by clicking on the link in the Show Notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the Show Notes. AAN members: stay tuned after the episode to hear how you can get CME for listening.  Dr Berkowitz: This is Dr Aaron Berkowitz, and today I'm interviewing Dr Sarah Wahlster about her article on examination and workup of the neurocritical care patient, which is part of the June 2024 Continuum issue on neurocritical care. Welcome to the podcast, Dr Wahlster. Can you please introduce yourself to the audience? Dr Wahlster: Thank you very much, Aaron. I'm Sarah Wahlster. I'm a neurologist and neurontensivist at Harborview Medical Center at the University of Washington. Dr Berkowitz: Well, Sarah and I know each other for many, many years. Sarah was my senior resident at Mass General and Brigham and Women's Hospital. Actually, Sarah was at my interview dinner for that program, and I remember meeting her and thinking, “If such brilliant, kind, talented people are in this program, I should try to see if I can find my way here so I can learn from them.” So, I learned a lot from Sarah as a resident, I learned a lot from this article, and excited for all of us to learn from Sarah, today, talking about this important topic. So, to start off, let's take a common scenario that we see often. We're called to the emergency room because a patient is found down, unresponsive, and neurology is called to see the patient. So, what's running through your mind? And then, walk us through your approach as you're getting to the bedside and as you're at the bedside. Dr Wahlster: Yeah, absolutely. This was a fun topic to write about because I think this initial kind of mystery of a patient and the initial approach is something that is one of the puzzles in neurology. And I think, especially if you're thinking about an emergency, the tricky part is that the evaluation and management go hand in hand. The thinking I've adapted as a neurointensivist is really thinking about “column A” (what is likely?) and “column B” (what are must-not-miss things?). It's actually something I learned from Steve Greenberg, who was a mutual mentor of us - but he always talked me through that. There's always things at the back of your head that you just want to rule out. I do think you evaluate the patient having in mind, “What are time-sensitive, critical interventions that this patient might need?” And so, I think that is usually my approach. Those things are usually anything with elevated intracranial pressure: Is the patient at risk of herniating imminently and would need a neurosurgical intervention, such as an EVD or decompression? Is there a neurovascular emergency, such as an acute ischemic stroke, a large-vessel occlusion, a subarachnoid hemorrhage that needs emergent intervention? And then other things you think about are seizures, convulsive/nonconvulsive status, CNS infection, spinal cord compression. But I think, just thinking about these pathologies somewhere and then really approaching the patient by just, very quickly, trying to gather as much possible information through a combination of exam and history. Dr Berkowitz: Great. So, you're thinking about all these not-to-miss diagnoses that would be life-threatening for the patient and you're getting to the bedside. So, how do you approach the exam? Often, this is a different scenario than usual, where the patient's not going to be able to give us a history or maybe necessarily even participate in the exam, and yet, as you said, the stakes are high to determine if there are neurologic conditions playing into this patient's status. So, how do you approach a patient at the bedside? Dr Wahlster: So, I think first step in an ICU setting (especially if the patient has a breathing tube) is you think about any confounders (especially sedation or metabolic confounders) - you want to remove as soon as possible, if able. I think as you do the exam, you try to kind of incorporate snippets of the history and really try to see - you know, localize the problem. And also kind of see, you know, what is the time course of the deterioration, what is the time course of the presentation. And that is something I actually learned from you. I know you've always had this framework of “what is it, where is it?” But I think in terms of just a clinical exam, I would look at localizing signs. I think, in the absence of being able to do the full head-to-toe neuro exam and interact with the patient, you really try to look at the brainstem findings. I always look at the eyes right away and look at, I think, just things like, you know, the gaze (how is it aligned? is there deviation? is there a skew? what do the pupils look like? [pupillary reactivity]). I think that's usually often a first step - that I just look at the patient's eyes. I think other objective findings, such as brainstem reflexes and motor responses, are also helpful. And then you just look whether there's any kind of focality in terms of - you know, is there any difference in size? But I think those are kind of the imminent things I look at quickly. Dr Berkowitz: Fantastic. Most of the time, this evaluation is happening kind of en route to the CT scanner or maybe a CT has already happened. So, let's say you're seeing a patient who's found down, the CT has either happened or you asked for it to happen somewhat quickly after you've done your exam, and let's say it's not particularly revealing early on. What are the sort things on your exam that would then push you to think about an MRI, a lumbar puncture, an EEG? You and I both spend time in large community hospitals, right, where “found down” is one of the most common chief concerns. In many cases, there isn't something to see on the CT or something obvious in the initial labs, and the question always comes up, “Who gets an MRI? Who gets an LP? Who gets an EEG?” - and I'm not sure I have a great framework for this. Obviously, you see focality on your exam, you know you need to look further. But, any factors in the history or exam that, even with a normal CT, raise your suspicion that you need to go further? Dr Wahlster: It's always a challenge, especially at a community hospital, because some of these patients come in at 1 AM where the EEG is not imminently available. But I think - let's say the CT scan is absolutely normal and doesn't give me a cause, but as an acute concerning deterioration, I think both EEG and LP would cross my mind. MRI I kind of see a little bit as a second-day test. I think there's very rare situation where an acute MRI would inform my imminent management. It's very informative, right, because you can see very small-vessel strokes. We had this patient that actually had this really bad vasculitis and we were able to see the small strokes everywhere on the MRI the day later, or sometimes helps you visualize acute brainstem pathology. But I think, even that - if you rule out a large-vessel occlusion on your CTA, there's brainstem pathology that is not imminently visible on the CT - it's nothing you need to go after. So, I do think the CT is a critical part of that initial eval, and whereas I always admire the neurological subspecialties, such as movements, where you just – like, your exam is everything. I think, to determine these acute time-sensitive interventions, the CT is key. And also, seeing a normal CT makes me a little less worried. You always look at these “four H” (they're big hypodensity, hyperdensity, any shift; is there hydrocephalus or herniation). I think if I don't have an explanation, my mind would imminently jump to seizure or CNS infection, or sometimes both. And I think then I would really kind of - to guide those decisions and whether I

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Ariane Lewis, MD, who served as the guest editor of the Continuum® June 2024 Neurocritical Care issue. They provide a preview of the issue, which published on June 3, 2024. 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. Lewis is a professor of neurology and neurosurgery and director of the Division of Neurocritical Care at NYU Langone Medical Center in New York, New York. Additional Resources Continuum website: ContinuumJournal.com Subscribe to Continuum: shop.lww.com/Continuum More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @LyellJ Full episode transcript  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, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, 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 by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the Show Notes. Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr Ariane Lewis, who recently served as Continuum's guest editor for our latest issue on neurocritical care. Dr Lewis is a Professor of Neurology and Neurosurgery at NYU, where she serves as the Director of the Division of Neurocritical Care. Dr Lewis, welcome. Thank you for joining us today. Why don't you introduce yourself to our listeners? Tell us a little bit about yourself. Dr Lewis: Thank you so much for having me, Dr Jones. It was a pleasure to be an editor of this issue, and I'm really excited for it to come out. As you mentioned, I'm a Professor of Neurology and Neurosurgery at NYU. I'm also a fellow of the American Academy of Neurology and a fellow of the Neurocritical Care Society. I serve on the Ethics Law and Humanities Committee for the AAN. I was a past chair of the Ethics Committee for the Neurocritical Care Society and also the past chair of the Ethics Committee at NYU. Dr Jones: So, pretty diverse professional interests. And I was going to ask you about the ethics - that feels like something that ties in pretty well to neurocritical care. I imagine that expertise comes in handy, right? Dr Lewis: Yes, absolutely. My area of expertise is related to brain death and ethical, social, and legal complications related to brain death determination. Dr Jones: Got it. And when we were talking before we started recording here, you're from the New York area and a lifelong Yankees fan, is that right? Dr Lewis: Yes, that's correct. Dr Jones: How are they going to do this year? Dr Lewis: We're hoping we're going all the way. Dr Jones: Okay. Dr Lewis: In a while. Dr Jones: Our listeners heard it here first. So, the issue – let’s get into the neurocritical care topics – phenomenal issue, full of detailed diagnosis and management strategies for patients with, you know, all manners of severe neurologic disorders requiring critical level of care. With your perspective (which is a unique perspective) - you've just edited a full issue on neurocritical care, you got to delve into all the topics - what were you most surprised to learn, Dr Lewis? Dr Lewis: Well, you know, I think that one of the most exciting things about this issue is the fact that, in addition to dealing with the typical topics related to neurocritical care - like hypoxic ischemic brain injury and stroke and intracerebral hemorrhage and subarachnoid hemorrhage, of course - the issue delves into some very unique topics related to neurocritical care. There's an article written by Dr Barry Czeisler that focuses on emergent management of tumefactive and aggressive demyelinating disorders, Dr Casey Albin wrote about neuromuscular emergencies, and doctors Maciel and Busl wrote about neuroonc emergencies – and I think that these areas are really important areas for neurologists and trainees to know about, and they’re not talked about all that often. And these topics are often focused on, of course, by other subspecialties, but the perspective of a neurointensivist related to these topics is infrequently addressed. So I think that these are really the most exciting aspects of this issue, because it’s something so unique in terms of the spin on these topics. Dr Jones: Fantastic. And what else can we look for in this issue? What other topics can our listeners and readers expect to find there?  Dr Lewis: So, the issue starts off with the examination and workup of the neurocritical care patient. Dr Sarah Wahlster and Nick Johnson from the University of Washington did an awesome job really bringing the reader into the topic of neurocritical care as they address an overview of neuroemergencies, red flags related to life-threatening conditions, herniation syndromes, vascular territories, and mechanisms and management of acute neurodeterioration, and they summarize monitoring modalities in neurocritical care and clinical and radiographic scales and scores that are commonly used in neurocritical care – and that’s a really nice overview to introduce the reader to this issue. The rest of the issue focuses on a wide range of topics pertaining to the emergent management of neurocritical care issues, including hypoxic ischemic brain injury (which was addressed by Dr Steinberg from the University of Pittsburgh),  management of stroke due to large vessel occlusion (which was addressed by Dr Leslie-Mazwi from the University of Washington), management of ICH (addressed by Dr Murthy from Weill Cornell), and then also management of spontaneous subarachnoid hemorrhage (addressed by Dr Soojin Park). Dr Clio Rubinos addressed emergent management of status epilepticus. Emergent management of TBI and spinal cord injury was addressed by Dr Podell and Dr Morris from the University of Maryland. And then neuroinfectious emergencies – which, again, is another unique topic in this issue – was  addressed by Dr Reynolds from Mount Sinai. And then the issue concludes with a paper that focuses on prognostication and neurocritical care by Dr Susanne Muehlschlegel from Johns Hopkins University.  Dr Jones: Yeah. And what a great list of authors and expertise. And really, you know,  having seen these articles, really just phenomenal guidance on a lot of different subtopics. And I imagine – you know, this is a dynamic area, there’s a lot of evidence – but, you know, sometimes, there are controversies or debates or unresolved questions in the field. Having just reviewed and edited the issue, what do you think the biggest debate or controversy is in neurocritical care right now?  Dr Lewis: So there’s definitely a lot of controversies that are addressed in each of these individual articles. For example, in the paper on subarachnoid hemorrhage, Dr Soojin Park provides a summary that compares the guidelines on management of subarachnoid hemorrhage that were written by the Neurocritical Care Society and the American Health Association / American Stroke Association in 2023 and really walks through what’s similar and what’s different between these guidelines. For the most part, they are very similar, but there are areas of differences. Additionally, in terms of management of acute neuroemergencies related to neuromuscular issues (in some cases, it’s not clear whether to treat patients with IVIG or with plasmapheresis), Dr Casey Albin creates a nice summary addressing these issues in terms of what are the pluses and minuses associated with each of these medications. Additionally, there are a number of novel therapies that are not traditionally considered for various neuroemergencies that are walked through in each of the individual articles. For example, in the paper that focuses on management of status epilepticus, Dr Rubinos addresses alternative therapies, like immunomodulatory agents or neuromodulation, for management of super-refractory status epilepticus. So, I think, in addition to addressing the more traditional therapies for various neuroemergencies, the issue really goes above and beyond to address novel interventions.  Dr Jones: That’s fantastic. And obviously, it continues to be a rapidly evolving area.  When you look out to the horizon – and the next generation of care for patients with critical neurologic illness – what do you see on the horizon? What should our listeners and readers be aware of to watch out for?  Dr Lewis: I think one thing that is really important to be aware of related to patients with neuroemergencies is the Curing Coma Campaign (which is organized by the Neurocritical Care Society), which focuses on research in terms of improving the clinical management, the prognostication, and the care of patients and addresses the goals for  improving recovery for patients who are comatose. And obviously, coma can be due to a wide range of different etiologies (many of which are described in this issue), and so I think that their work as we move ahead will be incredibly important and interesting to see how things evolve in that domain. Dr Jones: We will be on the lookout for the Curing Coma Campaign – sounds like a great initiative. And, I think, medicine is a team endeavor, right? We were talking about the Yankees earlier (baseball) as a team sport – so is medicine. When you think about the importance of teams, it’s hard to imagine a setting where it’s mo

Indomethacin-responsive headache disorders are rare conditions whose hallmark is an absolute response to the medicine and include paroxysmal hemicrania and hemicrania continua. In this episode, Gordon Smith, MD, FAAN, speaks with Peter Goadsby, MD, PhD, FRS, author of the article “Indomethacin-Responsive Headache Disorders,” in the Continuum® April 2024 Headache issue. Dr. Smith is a Continuum® Audio interviewer and 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. Goadsby is a professor of neurology at King’s College London in London, United Kingdom and professor emeritus of neurology at the University of California, Los Angeles in Los Angeles, California. Additional Resources Read the article: Indomethacin-Responsive Headache Disorders Subscribe to Continuum: continpub.com/Spring2024 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 Guest: @petergoadsby Transcript 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, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, 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 by visiting the link in the Show Notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the Show Notes. AAN members: Stay tuned after the episode to hear how you can get CME for listening. Dr Smith: This is Dr Gordon Smith. Today, I've got the great pleasure of interviewing Dr Peter Goadsby on indomethacin-responsive headache disorders, which is part of the April 2024 Continuum issue on headache. Dr. Goadsby is a Professor of Neurology at King's College London, in London, United Kingdom and a Professor Emeritus of Neurology at the University of California, Los Angeles, which is located in Los Angeles, California. Dr Goadsby, welcome to the podcast. Well Peter, I'm super excited to have the opportunity to talk to you. And I think, before we begin, we probably ought to expand on your introduction. I think there may be three or four neurologists who don't know who you are, and I think they should know who you are because you've got a really amazing story. These are exciting times in headache, right? And a lot of that's because of your work and you've been widely acknowledged for that; you received the appropriately named “Brain Prize,” which (if I'm correct) is the largest neuroscience award in the world; got to meet Danish royalty; you’re - more recently, the ABF Scientific Breakthrough Award, which is super excited. So, particularly interested in hearing about your Continuum article. But before we get there, I think it would be really great to hear your story. How did you get into this in the beginning, and what's inspired you along the way to the many achievements you've had? Dr Goadsby: Why, it's a very kind introduction. People have been nice to me. It has to be said, Danish royalty were very nice, I have to say, and the very jolly chap, the Prince of Denmark. I got into neurology - I guess it's all about mentoring for me. I got into neurology because I got into medical school pretty much by accident. I really wasn't that interested and heard a lecture by James Lance, who was Professor of Neurology, University of New South Wales, at the time. He was talking about a nondominant parietal lobe. I'd seen the case as a medical student; it sort of just seemed weird to me and I wasn't that interested. But he set out this way of thinking about things to try and understand why a clinical presentation is what it is - what he described as a physiological approach to clinical neurology. He described a number of things, but he described that in this lecture and then gave a reference to some work that Mountcastle did on nondominant parietal recordings from awake behaving monkeys in the Journal of Neurophysiology. And I thought to myself, “Wow, this is really interesting - you could really get to the bottom of something,” and had that sort of “puzzle-y” thing going on. And I thought Lance was just wonderful, so I became interested in that. And then eventually I asked him about research - actually, I asked him about research after a lecture he gave on migraine, and the explanation of the time was some circulating substance - probably just as silly now. I went up to him afterwards and said to him, I thought the explanation he was giving was wrong. Like, here was a global person - he described Lance-Adams syndrome; this was someone who trained at Mass General, trained at Queen Square; was the first professor of neurology in Australia. I was just – like, it was a stupid thing to do. But I couldn't resist myself - I told him I thought it was wrong. And he's very polite, and he said, “Well, perhaps you could come and help us by doing some research.” And I thought, “Okay, that's a very nice response.” Interestingly, his daughter described him as unfailingly polite at his funeral. Of the many things you'd say about him, he was a kind person. Whether it's science or just the way you practice - that word (kind) - you can know as much about a subject as you like, but if you're not kind to patients, you're probably in the wrong game. He taught me to be curious about a problem and got me interested in headache, and to be kind in clinical practice - just kind – and I think they were very important lessons. So, I got into it because of excellent mentoring, and I’d like to think I've helped some others along the way. Dr Smith: Well, you certainly have helped a lot of people, Peter, and what a great story. I'm reflecting - I think the first vignette in The Man Who Mistook His Wife for a Hat was a right parietal syndrome - wasn't it? You've read that book? Dr Goadsby: Yes, I have. And I've met Sacks. When Sacks came to Australia, he wanted to see Lance, and Lance said, “Fine, but you have to meet me between the morning round and the afternoon clinical meeting.” And he got him to come and have lunch with him in the hospital cafeteria at the Prince Henry Hospital and invited me to this lunch. And I sat there and watched them chat. But it was a measure of Lance and how people were interested in him that Oliver Sacks had to get in a taxi and come out to a hospital cafeteria to have lunch if you wanted to have a chat. Because it was - it was a privilege to train with the person. You know, I've done okay, but I only do okay if you've got – you know, you can work with patients, you've got great collaborators, and you've got someone you can get advice from (a great mentor). Dr Smith: Yeah, that's actually really great words of wisdom for the residents and fellows and junior faculty listening to this. Maybe we should actually talk about your article, which was really great. Your article was on indomethacin-responsive headaches - and we can maybe talk about some specific questions - but what's the main take-home point? If our listeners needed to take or were to take home one point from your article, what would it be, other than it's indomethacin-responsive (that's in the title)? Dr Goadsby: Yeah, it's what it says on the jar. Well, I think the one thing to take home is that there are forms of headache that seem relatively pedestrian, like one-sided headache that feels like it ought to be migraine that's strictly one-sided, and a small percentage of them respond almost like switching a light off to indomethacin. So, I think you have to have a high index of suspicion. And I’m sure I give indomethacin to ten, twenty times as many people - or thirty - who end up (or even more, probably) who end up having a response. But we do it for a short period of time. For those who get the response - I can tell you, when they come back, they're crying, their partners crying, or the other day I saw one, their child's crying, because all of a sudden, you've basically fixed the problem up. So, the message would be, if you've heard about something and it feels a bit “maybe, could be” - you've heard this indomethacin thing - just do it for a couple of weeks. The worst thing that can happen is nothing (nothing happens). For a couple of weeks, they're not going to have a problem with the tummy (and I'm not advocating taking people with a active gastric ulcer, trying to bump them off). But you cover them properly, you give them a short trial, and occasionally in your practice, you will be so rewarded by that - you will dance home. Dr Smith: Well, this is going to be my next question. There are very specific criteria, right, for defining cluster, SUNCT, SUNA (and there was a really great Continuum Audio conversation I had with Mark Burish I'll refer our listeners to about cluster, SUNCT, and SUNA), but the indomethacin-responsive headaches - and even migraine - that sounds to me, as someone who's not a headache person, like, that could be challenging to sort out. If you see someone who has consistent, unilateral headache, do you just do an indomethacin trial, or do you select based on other criteria from the classification system? Dr Goadsby: I'd like to think I was aware of the criteria, and I am. But the longer I practice, the more I'm inclined simply to give the indomethacin and get