October 2024 Pain Management in Neurology Issue With Dr. Nathaniel Schuster

Spine pain is one of the most common presenting concerns in health care settings. It is important for neurologists to understand strategies for evaluating and managing patients with spine pain. In this episode, Katie Grouse, MD, FAAN, speaks with Vernon B. Williams, MD, FAAN, author of the article “Spine Pain,” in the Continuum October 2024 Pain Management in 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. Williams is the director of the Center for Sports Neurology and Pain Medicine at Cedars-Sinai Kerlan-Jobe Institute in Los Angeles, California. Additional Resources Read the article: Spine Pain 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: @VernWilliamsMD 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 Grouse: This is Dr Katie Grouse. Today I'm interviewing Dr Vernon Williams about his article on spine pain, which appears in the October 2024 Continuum issue on pain management in neurology. Welcome to the podcast, and please introduce yourself to our audience.  Dr Williams: Oh, well, thanks for having me. My name is Vernon Williams and I'm a neurologist here in Southern California. Dr Grouse: So, I want to start off today by asking, what do you feel is the key message from your article? Dr Williams: So, I think the key message is that we want to make sure people understand that there's really a distinction between abnormal imaging, tissue damage, nociception, and this experience of spine pain. So, the concept is that nociception is different from the clinical experience of pain; nociception, meaning the electrical signaling from these, quote unquote, pain generators and that kind of thing. But it's really an incomplete framing. We really want people to understand that the experience of pain is colored by a number of other things, things like genetics, biochemical factors, behavior and psychological factors, social factors, those kinds of things. So that's one of the big messages, this distinction between nociception and this clinical experience of pain.  Dr Grouse: Why do you think it's important for neurology clinicians to read this article? Dr Williams: Well, I think, you know, for one thing, spine pain is very common. So, it is likely that neurologists will encounter patients who come to see them because of that chief complaint. But I think that if we want to really be successful at treating spine-related pain, then we really have to know all of that basic information, the basic knowledge that we came to learn as residents and medical students or what have you. But it's also important to know that that knowledge is necessary, but it's insufficient. You really also have to confront pain from the standpoint of these other things, these other behavioral factors, psychological factors, social factors, and you got to kind of combine those things to be the most successful in treating this very common condition.  Dr Grouse: You know, you mentioned earlier about the difference between tissue damage pain and nociception. I find this to be, you know, a really great lens thinking about these concepts to view this topic and your article specifically. Can you go a little more into what the difference between, specifically, pain and nociception really is? Dr Williams: Yeah. I mean, so when we talk about nociception, in many ways we're talking about the electrical activity. And so, there's the stimulation of these nerves, in the periphery typically, and that electrical signal is transmitted, you know, from those nociceptive fibers into the spinal cord. And it's headed from the first-order neuron to the second-order neuron and axons in the spinal cord and eventually reaches the brain. But essentially the concept is that it's not pain at that point. It's not pain until those signals reach the cortex and they are experienced in some context. And that context really colors whether or not, and to what extent, people experience pain or suffer pain as a result. So, when we think about nociception, we tend to think about kind of tissue damage or the threat of tissue damage. And in clinic, we tend to kind of focus on that and we look for relationships between abnormalities on imaging studies that could be causing those kinds of electrical signals. And we tend to focus less on that second but critical aspect of things, and that's that individual 's personal experience, which is colored by a number of different things: their attention, their expectation, colored by how we interact with them, our verbal and non-verbal communication with them. And again, like we talked about: their history, who are they, their genetics, their behavioral history, their psychological history and those kinds of things. So, it's really this combination of things that we have to be aware of when we're treating spine pain. And I think the tendency is for us to focus on the first half and less on the second half. Dr Grouse: Absolutely. I certainly think our training and our focus on localizing the lesion may in some ways hurt us in that sense because we really focus so much on the first and not so much the second. Would you say that's probably right? Dr Williams: Yeah, I mean, that's part of our heritage as clinicians, particularly neurologists. It's, where's the lesion? And so, what happens when there is no, quote unquote, lesion? What happens if there are multiple potential lesions? And so, these kinds of concepts, I think, become really important, and the context in which you're examining and evaluating that patient becomes important. And I think they are at least as important as the potential pain generator or the nociceptive signal.   Dr Grouse: Now, you mentioned earlier something about sort of how we approach the patient and the language we're putting out, the body language. I found the concept of nocebo and maladaptive pain-related neuroplasticity to be absolutely fascinating when I was reading your article, and I was really surprised to learn that clinicians can really contribute to this effect unknowingly through their body language, verbal language, nonverbal messaging, and even how they're interpreting the test results? When a patient comes to see you with chronic back pain, how do you approach the whole process to minimize this effect and, really, to set the stage for more constructive and therapeutic evaluation? Dr Williams: Yeah, Katie, I think that's… it's tough because our culture is so, you know, it's so ingrained in our culture to look for a structural abnormality as an explanation for an individual 's symptoms. And so, I find myself struggling with that all the time, not only discussing why we're ordering an imaging study, but, if that person comes back and I'm describing to them the abnormalities on that imaging study, I've got to be very careful about describing them in the context of what we expect. And so, I'll typically try to use words like, well, you've got some wear-and-tear changes that we all get, as compared to saying, well, you've got a disc herniation abnormality at L five S one that's causing your pain. That statement could have a negative effect on that individual's framing of what's going on. Maybe that L five S one disc is contributing to their symptoms and maybe it isn't. Maybe it's been there or for years and maybe it's new. And even if it is new, does that mean, in that patient's mind, that now they've got an abnormality that has to be fixed or else they will continue to have pain? And so, kind of trying to keep all of those things in mind is why we want to kind of color that interaction. And I mentioned both verbal and nonverbal interaction and communication with the patient, because I think that they are picking up on all of these signals. Some of them are very obvious and some of them are very subtle. But keep in mind their brains, their nervous systems are primed to interpret all of these signals, both verbal and nonverbal. And that's going to have a downstream - or upstream, I would say - effect on their framing and how they interpret the interaction and what they think it means for them and their future. So, you know, it's kind of a big thing to think about when you- every time you walk in a room, but it's an important thing to think about when we're communicating with patients.  Dr Grouse: It's absolutely fascinating and has really made me go back and think about, gosh, are there ways that I could have done things better to really message this in a more helpful way? And on that note, do you have any tips or tricks on how to put out that that messaging, both verbal and nonverbal; to be, you know, to avoid those pitfalls of kind of reinforcing the wrong message about tissue damage? Dr Williams: Yeah. I mean, so one of the main things is trying to be very purposeful about educating people on the difference between tissue damage or potential tissue damage and pain. And so being careful not to use statements like, well, I think your pain is coming from this disc or this structural abnormality because again, we want to try to separate those things. They are different. I think that, you know, how we discuss imaging studies is very important because you want people to understand that an imaging study is just that. It's anatomy and it doesn't equal function, it doesn't equal what they experience in terms of sensory symptoms and pain. But I think the goal is to try to be very purposeful and maybe even reexamine how we discuss those things or when we discuss those things. One of the things I've found helpful is kind of the order in which I perform my clinical assessment. So traditionally, I was taught, like many, take the history, do the physical examination, and then start to discuss and educate patients. Right? Here's the test I want to order, here's what I think may be going on, so on and so forth. I think in some cases it's more beneficial to take the history and, before the physical examination, discuss what I'm thinking, taking that opportunity to discuss the differences between nociception, tissue damage, the experience of pain, the importance of movement, so on and so forth. And then do the physical examination so that that person has some idea of what is it that he's looking for. How is this going to inform his opinions and recommendations and so on and so forth. But also provide them with the concept that movement, for instance, is safe unless they have certain kinds of red flags on their history. I'm encouraging movement and I'm encouraging them to recognize that some of these movements they may have predicted would have been painful for them actually aren't painful, and they may start to internalize the concept that they can do it once without paying, that probably means that they're not damaging themselves every time they perform that movement. And if they can do one pain-free rep, that's important, and that may counteract the concept that they are damaging themselves every time they move and every time they feel pain, that means that there's tissue damage. So, what we talk about, how we talk about it and even when we talk about it during the course of that evaluation may have some negative or positive effects. And it may be beneficial to kind of think about those things and whether or not our typical approach might be the best or maybe we can improve on that or adjust that, particularly in certain situations and with certain patients. Dr Grouse: That’s absolutely fascinating, and great tips I think that all of our listeners will want to incorporate as we're approaching this patient population. You know, in your article, I also wanted to talk about, you mentioned some really interesting treatments for pain is that I think would include, or would, fall under the category of neuromodulation. Can you summarize some of these options for us? Dr Williams: Yeah. I mean, so I think that the concept of neuromodulation, I tend to think of it in a very holistic sense. And so not only focusing on the application of external stimuli and that could be, you know, electrical stimuli, magnetic stimuli, cryo, analgesia, those kinds of things in order to turn up or down nervous system activity, electrical signals, what have you. I think of neuromodulation in a global sense. I think in a way, cognitive restructuring and education, in a way, is a form of neuromodulation. It's affecting how that individual frames the concept of their pain, structural changes versus experience, so on and so forth. But generally, I'm talking about these kinds of things. So, there are some very interesting approaches with electrical stimulation and it doesn't necessarily have to be permanent implantation of a stimulator as we tend to think about with spinal cord stimulation, but there are some interesting temporary peripheral nerve stimulators that that can be very helpful for various kinds of spinal pain. And then there's also these technologies that I find fascinating. Some of them are in the wearables category. So, combining the education and framing and cognitive restructuring with things like virtual reality, there are some interesting programs that combine some predictive modeling with virtual reality, such that an individual has goggles on, they are participating in some activity that requires them to move in a certain direction and move to a certain extent that may or may not match what they are seeing visually in the goggles. So, you can kind of begin to kind of dissociate their expectation of when they may experience pain as a function of their movement from what actually happens. So, these kinds of things, I think, are really interesting ways to augment our traditional approaches to pain, physical therapy, rehabilitation, medications, some kinds of injections, with these additional approaches that really have an effect on the nervous system as opposed to just focusing on what I would call kind of the mechanical anatomy, the joints and the discs and what have you, with traditional approaches. Dr Grouse: It's really exciting to hear about some of these new options that can be tried to help with this neuromodulation and sort of cognitive restructuring. Of course, understanding that there's some things that we do ourselves that do this in the clinic encounter, which I think is a great reminder. I wanted to touch on, in your article, you had mentioned that we really have to be aware as clinicians, that health inequities and disparities and even the social determinants of health have inevitable effects on spine pain. How can our listeners better recognize and ensure equitable care for this patient population, particularly in light of the fact that many of these therapies that we've just been talking about can be difficult to access even in the best circumstances? Dr Williams: Well, you know, thanks for asking that question. I think that's a great question. I think from the standpoint of, you know, health equity and addressing, you know, disparities and that kind of thing, the first thing is to just acknowledge and recognize that these things are present. And even, you know, though we may have the best intentions, there may be scenarios where our practices are affected and our patients are affected by these kinds of things. So, I think the first thing is the acknowledgement. And then the second thing is kind of trying to figure out if there are things that we can do as individual practitioners, or our offices can do or the entities that we interact with, maybe that's a hospital system or what have you to address these kinds of things. So, we know, for instance, from the standpoint of race and ethnicity, there's disparities with respect to African Americans, with Hispanics and other ethnic minorities and the kind of care they receive. We know that access resulting from insurance coverage and geographical limitations, that kind of thing can be significant. And interestingly, it doesn't necessarily mean that the person is uninsured. So, for instance, we will often see individuals who've had work injuries and who are covered by the workers’ compensation system have certain limitations placed on what they have access to, often resulting in lots of frustration from those patients. And that's a reality that we sometimes have to work really hard to overcome. Socioeconomic status, provider bias. And again, this is something that we have to kind of do some internal searching to say, hey, am I approaching these individuals on a on a more equal and equitable basis, or am I also subject to some of the biases that that I've been exposed to and trying to overcome that? So, I think that's a huge part of the context. And when we talk about how we learn, whether we're talking about spine pain or anything else, I'm a believer in that kind of cycle of pedagogy that includes content-based information, which is kind of the very basic foundational information, that includes things we can memorize and definitions we can memorize. And that may include things like what we've talked about relative to kind of the nociception and pain pathways, so on and so forth. But then there are concepts, and we've talked about the concept of verbal communication and nonverbal communication, the concept of cognitive restructuring and neuromodulation as an approach. But then context is kind of that last level, probably the most significant level in terms of how we can integrate all this information and really master information. And that context has to do with things like social determinants and disparities and the reality that these things have an effect on how we evaluate and manage patients and the success with which patients can be managed. And so, I appreciate that question, I think it’s a great question, because it gets that kind of the reality of what does this look like in real life as opposed to just on the page or just in a textbook. Dr Grouse: Well, that's really helpful and certainly something that we can all keep in mind as we try to be more aware of this, and I like the idea of just acknowledging it and just having it there, knowing that this exists and helping that inform how we approach these patients. I wanted to ask you, what do you think the biggest controversy is currently in the evaluation and management of spine pain? Dr Williams: You know, I think that there's a couple of controversies that are interesting. Nowadays, one of them has to do with the utility of some of the things that have been performed and done most frequently for spine pain, and that's things like epidural injections, facet injections, some of the interventional procedures. There's some controversy among some as to whether or not these things are effective, you know, what role they have in treatment because some people will say, oh, is there any long-term effect from these kinds of procedures? Even patients will sometimes say, hey, listen, I'm not sure if I want an injection because isn't that just temporary, or, isn't that just a band aid? But I think that when we talk about pain from the perspective of it potentially being a progressive disorder and trying to be aggressive with managing pain so that we are less likely to see some of the chronic manifestations that occur with maladaptive neuroplasticity it's important to be aggressive with stopping no subceptive signals, reducing an individual 's experience of pain, optimizing their function, and having a positive effect on the ability to treat and eliminate pain, even if that means with epidural injections or blocks or what have you, as long as they're safe and effective. I think that there are some controversies evolving related to some of the regenerative procedures that have been done for other kinds of musculoskeletal pain. So, for instance, PRP and stem cells, you know, people have been doing those for knees and muscle tears and what have you. And of course, that technology has kind of evolved into potential approaches for spine pain. People are often interested in whether PRP or stem cells may help their spine pain. And so, I think that's another area of potential controversy because there hasn't been a ton of, you know, high-level evidence, although there are some, you know, there's some studies out there and there's some evidence that they may be of benefit. And I think the role of stimulators and implants for axial pain is another area of potential controversy. Those are probably the biggest things in this area of spine pain that are topics of controversy. There are things that have people talked about for years in terms of chiropractic care versus traditional medical care. But I think right now it's the utility of these kinds of interventional procedures, the role of regenerative procedures and injections, and then the role of more aggressive interventions like permanent implantation of stimulators and that kind. Dr Grouse: Is there anything coming on the horizon in the field of managing spine pain that we should be looking out for? Dr Williams: Well, you know, I am still bullish on the concept of neuromodulation and we've talked about that peripheral nerve stimulation, spinal cord stimulation, and then other wearables, VR, so on and so forth. I think that those things will continue to evolve, and I think that technologies continue to evolve that are likely to help with spine related pain. Some of them are very interestingly related to the ability to strengthen multifidus muscles and improve muscular function in individuals with spine pain. But I think that's one area - neuromodulation - that we'll continue to see evolution. I think that- I'm interested to see what the role of regenerative injections and regenerative procedures may play. And then just like every other field of human endeavor, artificial intelligence, machine learning, those kinds of things are likely to have a significant effect on how we diagnose an individuals, on treatment options for various individuals, and even a predicting outcome from various treatment. So those, I think, are examples of areas that we'll see continued growth and evolution with respect to spine pain. Dr Grouse: Well, I'm very excited to see what comes down the pipeline and both vastly more to come, I'm sure. So, thank you so much, Vernon, for joining us. I really enjoyed reading your article. I really enjoyed talking about this topic. I think I've learned a lot and I hope that our listeners will take the time to read this article. It's really, really helpful. Dr Williams: Well, I appreciate the opportunity. I really enjoy participating in this process. The interview was fun, so thanks a lot for having me. I really appreciate it. Dr Grouse: Again, today I've been interviewing Dr Vernon Williams, whose article on spine pain appears in the most recent issue of Continuum on pain management in neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today. Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continnpub.com/AudioCME. Thank you for listening to Continuum Audio.

Neurologists bring special skills to pain evaluation and management and are well equipped to appreciate both the focal and diffuse nature of pain. By using expert knowledge of the nervous system and implementing relevant therapies, neurologists can succeed at and find meaning in optimizing patient outcomes. In this episode, Allison Weathers, MD, FAAN, speaks with Beth B. Hogans, MD, PhD, author of the article “Principles of Pain Management,” in the Continuum October 2024 Pain Management in Neurology issue. Dr. Weathers is a Continuum® Audio interviewer associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio. Dr. Hogans is an associate professor in the department of neurology at Johns Hopkins School of Medicine and an associate director for education and evaluation at the Geriatric Research Education and Clinical Center at the VA Maryland Health Care System in Baltimore, Maryland. Additional Resources Read the article: Principles of Pain Management 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 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 Beth Hogans, author of Principles of Pain Assessment, Diagnosis, and Management from the October 2024 Continuum issue on pain management and neurology. Welcome to the podcast, and please introduce yourself to our audience.   Dr Hogans: Good afternoon. My name is Beth Hogans. I'm a neurologist. My faculty appointment is at Johns Hopkins School of Medicine in the Department of Neurology, where I'm an assistant professor. I also serve at the Baltimore VA Medical Center, where I'm the Associate Director of Education and Evaluation for the Geriatric Research, Education and Clinical Center, as well as a neurologist.   Dr Weathers: Thank you so much for, again, being with us today and taking the time to speak with me. I was really struck by how broadly applicable this topic is, not only to all neurologists, but to all physicians and even to all of our listeners, given how prevalent these conditions are. Nearly all physicians involved in direct patient care treat some type of pain disorders, and we all experience pain at some point, though hopefully not chronic pain. Well, usually like to start with a question - again, it feels especially pertinent here in getting to speak with you - what is the most important clinical message of your article? Dr Hogans: So, I'm going to say there's two key messages. The first one is that all pain has a differential diagnosis, and the second one is that all meds work better with non-pharmacological and whole-health comprehensive management incorporated. So that's why I structured the article around the ideas of assessment, diagnosis and management. It's a pretty sort of traditional, basic approach to how we look at clinical problems, but we definitely want to start with proper assessment, go on to a thoughtful differential diagnosis, and then move towards a management plan that is not just, you know, one stop shop, but actually kind of brings several aspects together. Because pain is so multidimensional; you know, it's represented in multiple places in the brain as well as other levels of the nervous system. And so, I think we're still in an era, and we may stay in an era, of, you know, needing something to go along with medication in many cases.   Dr Weathers: I think those are two absolutely critical points for our listeners to keep in mind, both, again, keeping that broad differential, and - we'll get more into management in a bit, but again - that dual strategy of both the pharmacologic and the non-pharmacologic. And again, going down a little bit more there on that management track, a really recurring theme that I picked up in your article is the importance of interprofessional collaboration in the assessment and the management of patients with pain. In the abstract, you actually use the phrase “remarkable” for the diversity of health professions, which I really loved. What other clinicians do you work with in diagnosing and managing pain conditions, and what are their roles in the care of these patients? Dr Hogans: So, something you hear over and over again at pain meetings is, “there is no I in team.” They say that all the time. And it's one of the things I really love about pain, is that we get to work with great colleagues who have their own perspectives, approaches and therapies for pain. So, in my particular practice, which I do focus kind of more at the interface between neurological and musculoskeletal pain because of my passion and interest for spinal pain, you know, ranging from neck to tailbone, but most especially in the lower back. Physical therapy, clinical psychology, sleep sedicine, nursing, pharmacy, rehab… Podiatry is something that people don't often think of, but is really important for getting spine mechanics correct… Ergonomics. But I want to just say something about clinical psychology because there may not be enough clinical psychologists in the United States, but we as neurologists are also brain doctors. You know, we have to stay within our scope of practice. But there's a move now to talk about psychologically informed physical therapy. So why don't we talk about psychologically informed neurology? I think we could do an even better job of kind of leveraging our knowledge of the brain and how it works to kind of bring that into our practice. And so, people with pain often need a lot of empathetic support, for example, as well as knowledge about their condition. So, I would encourage people to build local networks of folks that they refer to and work with. Because when I was a younger doctor, physical therapists taught me a lot of what I know now - because I didn't get it at med school, although by the time I got to residency, I had some really great teachers. But clinical psychology, PT, sleep medicine, those are, like, almost all-the-time collaborators for me. And then like I said, nursing, pharmacy, rehab, podiatry, et cetera, et cetera, prosthetics… those things are all important for pain. Dr Weathers: I was struck by the quote, “one of the things I really love about pain.” That's a great line, and understand how it was meant, but I think - again, a really great quote, but I think you make such important points and, really, it is such a critical team approach. And I love all of those roles you called out. And I was struck in listening to your really thoughtful answer about how I've spoken with several other authors of actually very different topics, but about how we're thinking now about a trauma-informed care approach to many neurological conditions and the similarities with this patient population, how it likely informs very much the approach to this patient population as well and probably the significant potential.   Dr Hogans: A hundred percent! And so, for example, one of the things that probably does factor in for chronic pain - not in everyone, but in, let's say, many cases - is a prior exposure to trauma, whether it's PTSD or adverse childhood events. And so that's why, you know, clinical psychology is, like, very high up on my list of collaborators. And one of the things that I really like - you could say love - about working in the BA system is the ready availability of mental health co-management. So, I would say about a third of my patients in neurology are co-managed by mental health. And what it does is it sort of defuses a lot of what would otherwise come into the visit and be my job as a neurologist to manage, if not treat, right? I still have to manage, you know, someone who comes in with untreated mental trauma or mental health conditions if they're coming into that visit, and I'm trying to open the topic of whether mental health co-management could be helpful. That can sometimes, strangely enough, antagonize people. We’re still in an era of substantial stigma. But I can just say the practice of neurology, together with appropriate mental health co-management, is far superior than going alone. Dr Weathers: Absolutely. And how fortunate that for a lot of your practice, your patients do have those resources available to them. And I think it speaks to the importance of those resources, that all of our patients should really have that availability, and the importance of access. Dr Hogans: Right. So, at Johns Hopkins, we also have exceptional access to, you know, some of the world 's best clinical psychologists. And I've been really privileged to work with my colleagues in clinical psychology. The challenges that - in some of my roles, I interact with trainees and learners who are in clinics that are not as well resourced. And therein lies just tremendous heartache and difficulty. We've been trying to build some resources. There are federal resources that can help to open those conversations and maybe take some of the initial steps towards things like cognitive behavioral therapy, acceptance commitment therapy, mindfulness-based stress reduction. There's many of these psychological therapies that are proven to be effective for pain and chronic pain, and yet we haven't really had that conversation as a society about, how do we get people connected with those therapies? Many of them can be delivered on a larger scale. And I think we just need to think a lot more thoughtfully about, how can we have more of a public health approach to chronic pain and wellness? Dr Weathers: Absolutely. Such really important points. So, we've talked about the really kind of important, obvious points for what we very much kind of know to be accurate. I want to talk now about, what are the most common misconceptions that you've encountered in treating patients with pain disorders?   Dr Hogans: Yeah. So, this is where, you know, physician as advocate for the patient really comes into play. So, I think the number one misconception that I and many of my colleagues encounter: that pain is the patient 's problem, or that that pain reflects an excessive sensitivity. I think one analogy that I use with students that helps to kind of piece this apart is the immune system, right? There are people who have immunodeficiencies that they're not sufficiently protected from the environment, and then there are - lots of people have allergies where their immune system is sort of hyper-alerted to things that are not a true threat. And the pain system is exquisitely regulated. The neurology of the pain system is fascinating and compelling, and once you learn a little bit about it, you can apply it at the bedside, time after time after time. So, number one: pain is real. And there is an association between strong pain and increased risk for chronic pain. And then sort of the flip side of that is that malingering or, you know, fictitious pain is probably a lot like other functional disorders in that it's part of a complex. So, I think we need to do a lot more work to discover, you know, quote, what is pain that people think is amplified or manufactured and how can we frame that in a clinical context rather than just casting blame or- we already mentioned stigma. You know, stigmatizing people does not help. And there are people who have real pain problems that are really severe and disabling, and neurologists can actually help support those people as they encounter their environment. Dr Weathers: I really love that response. And I think you're right in that we do so often, in the medical system, tend to stigmatize these patients, even as we say the right things and we, I think, talk about it and we recognize… and yet, still, it's almost these unconscious biases. I think, as good as we've gotten in some areas, it's still hard to separate them. It's almost kind of one of the last unspoken, still-acceptable ones in some ways that oh, they must be drug-seeking or, you know, to your point, you use the word, kind of malingering, that they’re somehow, you know, either at fault or that there's some nefarious behavior going on there. And I think you made such really important points that we have to change our way of thinking that it is such a common and, frankly, wrong misconception that a lot of us really carry around and it's really hard to break. We have to kind of recognize these biases in ourself and really fight against them when we encounter these patients. Dr Hogans: I think part of how we got there is the opioid crisis. Dr Weathers: Yes. Dr Hogans: You know, unfortunately we still do not have a fantastic understanding of opioid durability. Like, how long does opioid analgesia last? Not from, like, hour to hour, but, like, from month to month. Roger Cho has done some awesome work looking at long-term efficacy of opioids, and it's surprisingly modest. And yet, opioids have this profound kind of behavioral impact, that they really are highly reinforcing. And so, once they're in the conversation, you find yourself in, like, almost this life-or-death struggle between, you know, am I going to get opioids at this visit? How many? You know, if not, why not; are you going to decrease? And so those of us who are working today, you know, and have been working for the last five years, have been through this terrible struggle. And that struggle is not yet resolved. But once opioids are kind of off the table or neutralized, then we actually have a conversation that is really, you know, A: how good of a clinician are we? Do we really understand what our patient is going through? And how can we bring, like Hippocrates said, you know, get the system to bear on the problem and not just, you know, try to throw drugs at it. So I think that, really, pain challenges us to be our best selves and to, you know, really be clever and kind and helpful. And it is a really great opportunity to help. And as I said, the mechanisms of pain are fascinating neurologically. So, it kind of satisfies some of what we come to work for, but I think it's not all done yet. One of my challenges has been, I wrote an article in 2011 with one of my trainees where we counted up the number of hours documented in the double AMC database for med schools, and we found that the modal value for US medical schools at that time was four. So out of four thousand curricular hours, there were four pain hours. And when you think about the prevalence of pain, that's just a drop in the bucket. So, you know, it's getting better, but we need to come up with some new strategies. So I wrote, I've written three books now. The latest one is really designed to give that intro-level knowledge of pain. But also, obviously, the Continuum article, I wanted to kind of set the table, lay the foundation, and give people some core knowledge to get started with. Dr Weathers: And again, a fantastic article. If our listeners haven't read it, I strongly encourage them to go back because I think you did just that. And as you were just talking, I was thinking about that, especially for those of us who, you know, depending on when in your training was, you know, mine started in the early 2000s. We've kind of lived through that era with the pendulum swinging. Where was, you know, the signs were posted in each clinic room. You know, don't forget to ask, you know, your provider about your pain meds, and it was the sixth vital sign, and all of that. And then the pendulum swung very quickly and very severely the other way, where it was, you have now created this problem, right? We have all caused this epidemic and we're supposed to immediately take these meds away, right? And now to your point, you know, we've all been in these situations with opioids where that was all that was talked about, right? So, you know, we've all been on call and now you're getting the call overnight from people trying to get their opioids filled when, you know, not their prescriber because they knew if they called - or family members, as soon as you got prescribing rights, were now calling and asking. And we've all been in these very hard situations. Dr Hogans: Just because you have a hammer doesn’t mean that everything is a nail. Dr Weathers: I know. So, in trying to negotiate and navigate, you know, these very rough situations… And I think now we're reaching kind of this new era where, to your excellent point, realizing that there are a lot of other solutions. And I love how you framed it, that this is really where we can be our best selves as providers. And actually, to that point, so - as I've mentioned on this podcast many times, clinically, I'm a neuro-hospitalist and I actually wanted to get your opinion as one of the foremost experts. So, a challenging situation I'm also often faced with in my clinical role is when a patient with a chronic pain condition such as diabetic neuropathy or lumbar radiculopathy is admitted to the hospital, often with a totally unrelated condition that either results in a new acute pain, but often also exacerbates their underlying chronic pain, what's your approach to the assessment and management of similar cases? I know our listeners will return again and again to that fantastic approach you laid out in Figure 1.1 with the coordination of the pharmacologic and non-pharmacologic therapies, as we've talked about several times just throughout our conversation, how important both of those approaches are. But a lot of those options are unfortunately limited in the in-patient setting. So how do you balance those? Dr Hogans: So, there's a whole other toolkit that comes into play for acute pain or sort of pain palliation. And you actually have some important allies in the hospital. It turns out that nurses, generally speaking, have some more education than do most physicians about pain. And the nurses that I encounter really see themselves as genuine, sincere advocates for the patient 's interest. They're at the bedside, they're working very closely, and their training actually does, I think, give them a number of tools and a set of inspirational ideas that build towards patient comfort. So, if you communicate with nursing staff about your desire to provide more comfort for the patient, whether it's padding, positioning, activities such as, you know, having them participate in something, you know, whether it's just having a family member, you know, take them for a walk, whether it's in a wheelchair or having an older adult sit by the nurse's station just to give some form of distraction. Ice, you know, cool packs and hot packs, you know, supportive toweling or pillows, all of that can really help. Years ago, nurses used to actually be trained in giving massages, and that can provide some comfort. You know, supportive touch is kind of how we frame that nowadays. But the other piece that you have is, in many cases, PT is getting involved much earlier in the patient, you know, rehabilitation course. And remember that motion is lotion. So, our endogenous analgesia system, which actually involves both endogenous opioids and endogenous cannabinoids, can be activated through many forms of motion, as well as immobility is actually a cause of pain itself. So, you just, you break out your in-patient tool kit and, you know, there are other tools and there's other allies that you want to think about in that context. Dr Weathers: Those are all really great tips, many of which, I know, as you said, a lot of us tend in our thinking to go right to pharmacologic strategy, so wouldn't even be considered, but I think really thoughtful, and that we do have at our fingertips. So- Dr Hogans: I wish I had thought to put them in the article. Dr Weathers: No, they were fantas- but again, why we podcast, agree for complimenting the article… we encourage people to take advantage of both. Well, this has been wonderful, and I know I have learned so much, even more than was in the article. I always like to end on a hopeful note, so I would love to hear what developments in the field of pain that you're most excited about. What do you think is coming down the pipe? Dr Hogans: Well, I think, like a lot of people, I've been waiting for the opportunity that's happening right now, which is, there's a massive investment in pain science being made by the NIH. Finally. You know, we've moved from, you know, just like, little things here or there, commercial kind of entities, to, we now have large NIH dollars flowing into pain. I'd like to see not only a focus on small molecule development, which will ultimately lead to better pharmacological agents, but I'd also like to see a thoughtful approach to non-pharmacological therapies, whole health approaches. Things like healthy communities, safe exercise spaces for all ages, more nutritious food, yoga, Tai chi. We know from Skelly and Cho's article in 2020 that there are many, many non-pharmacological therapies that actually work for chronic pain. There’re some things we still don't know. Like, do older adults respond as well as middle-aged adults? And how can we get NPTs - non-pharmacological therapies - more accessible to people who are subject to disparities? I think part of what happened during the opioid era is that you could get, you know, a bottle of pills for a four-to-ten dollar co-pay and physical therapy was twenty dollars a shot. And we know PT will get you to a better place, but that person that you're talking to may not have three hundred dollars to go to a course of PT. And we need to figure out, you know, how do we do this better, safer, more healthfully. Dr Weathers: And, I think, forgetting even the co-pay; it's the coordination, the time off work, all of it, right? So it's, I think, all of those challenges, but I think all of that are such important points about - and I think, that's really where I'm hopeful. Right? The emphasis, we talked a little bit about trauma-informed care earlier in our conversation, but the focus now on addressing the underlying social disparities of health and overall healthcare disparities, I think, is so promising. Dr Hogans: We need to think about the long-term consequences for human health; and pain has a terrible impact on human health for many reasons, and, I hope, will continue to be the focus of effort for years to come. Dr Weathers: Absolutely. Well, that is such an important statement to end on. Thank you again, Dr Hogans, for such a fantastic conversation and again, such an overall excellent article. Dr Hogans: Thank you, Dr Weathers, it was great to speak with you today again. Dr Weathers: Today I've been interviewing Dr Beth Hogans, whose article on principles of pain assessment, diagnosis, and management appears in the most recent issue of Continuum on pain management and neurology. To learn more about the topics of pain assessment and other topics of pain management, don't forget to listen to Continuum Audio episodes from this and other issues. Thank you to our listeners for joining today. Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

In this 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 phenomenon, but it becomes a clinical problem when the pain is unmanageable or out of proportion to the patient's coping skills, and it seems to have evolved - at least in terms of our understanding of it, how it impacts people's lives. It's not just a physical or biological process, right? There are psychological factors here, there are social factors here. How does that inform your thinking about management of pain?   Dr Schuster: Yeah, so, I think that that's one of the most important running themes throughout this issue of Continuum that readers will find, is that there's a movement away from the biomedical model towards the biopsychosocial model in thinking about patients. And, at least for myself, when I was coming out of neurology residency, my training was much more on the biomedical model and on medication treatments. And throughout this issue, what you'll find is discussions of the importance of the biopsychosocial model, having pain psychology as being a component of the treatment for so many of these patients. That medications alone (for many of our most challenging patients) won't be the answer by themselves - that you'll need to have involvement of physical therapy, of pain psychology. And we have an article written by the pain psychologist who I work with at UCSD, Dr Mirsad Serdarevic, which I think will be very interesting for so many neurologists. It's also wonderful that we have an article on facial pain that's written by a neurologist, Dr Meredith Barad, together with a dentist, Dr Marcela Romero-Reyes. So, it really takes a team to treat so many of these very challenging patients who we are treating in our neurological practices.   Dr Jones: Yeah, thanks for that. I realize that with a complex problem, a lot of times you need more than one area of expertise, right? It's a team process and a team effort. When you think about your own practice, Dr Schuster, when do you bring in other specialists or other perspectives in the management of patients with pain?   Dr Schuster: So, one of the articles that I really enjoyed reading in this forthcoming issue of Continuum is the one from Dr Narayan Kissoon on widespread pain syndromes. These patients who have widespread pain syndromes very often are the patients that I'm referring to our pain psychologist. Neurologists can do so much for these patients by making the right diagnosis. So often, these patients might be treated by one specialist for one organ system, another specialist for another organ system, and they can have so many different specialists, and they can be going from institution to institution. And a neurologist is in a really good position to be able to take the full history, put everything together and say, “I think you have a chronic overlapping pain condition. I think you have central sensitivity syndromes” - to be able to talk to them about their central nervous system being amped up, and that there are treatments that we can give them to help to treat these conditions, fibromyalgia and others, that affect so many of our patients who we encounter in neurologic practice. So, the International Association for the Study of Pain now has this term, nociplastic, and some people use the term neuroplastic to talk about these central sensitivity syndromes, and while not all neurologists maybe are hearing those terms used yet in clinical practice, I think it gives us a good framework - and between Dr Kissoon's article, as well as Dr Beth Hogans’ article on general principles of pain, I think that those will give the practicing neurologist a lot of good updates as to how our thinking about these patients has evolved.   Dr Jones: I know, as clinicians, we have a very cause-and-effect kind of component to our training, right? Here is the problem, here is the lesion, here is the result, and what do I do about it. I think patients also want to know what is the cause of the pain, and I think it's, maybe, historically been frustrating when someone clearly has pain and there's not a single factor, especially a removable factor, that causes it. So, I think, hopefully, having this language that we can use to communicate it with our better understanding of pain, hopefully that will help. Does that help you in your practice when you're talking to patients, when you explain what's going on? Is that well-received in general?   Dr Schuster: Yeah, you know, I think a lot of doctors are afraid to talk about fibromyalgia, for example, with patients. And what I'm finding in my practice, actually, is that a lot of patients are liberated when they can receive a diagnosis, such as fibromyalgia, that they can read about, they can learn about treatments for it, they can join support groups online and find that they're not alone - indeed, this condition affects 2 to 4% of people, and that very well could be a underdiagnosis. It keeps them from looking to different specialists for each painful body part and potentially having unneeded surgeries - and surgeries that might make things worse. So, I think physicians are understandably concerned because there is stigma - there's stigma around a lot of painful conditions, and there's stigma around some of the treatments that we use to treat these patients - and I think that physicians who are sensitive to that can sometimes be hesitant, but I'm really surprised how often patients are just really appreciative to get the right diagnosis.   Dr Jones: And you mentioned a minute ago that things have changed even since you came out of training, and, obviously, training is really important to know how to manage these problems. In my own world, I've seen, I think, an increase in the interest in pain management as a subspecialty among neurology trainees. There's obviously something that grabbed you, something that pulled you into this field. What's been your path to being a pain specialist?   Dr Schuster: Yeah, so I was a neurology resident at Ronald Reagan UCLA Medical Center, and fortunately, there, they have a few pain neurologists - and also, in the community, we have a few other pain neurologists as well that I had the great fortune to work with. And I was so impressed, especially those who are doing both pain and headache treatment, that you were able to help so many people treating very high-prevalence conditions - very often, younger patients, people who are going through school, building families - and being able to really reduce their disability, improve their quality of life and the quality of lives of their families is very gratifying. So, I encountered that as a neurology resident. I had their mentorship. And then, I applied for both headache and pain fellowships, and I did both a headache fellowship and a pain fellowship - and I think that that's been a wonderful combination for my career. To have that mix of patients has been really wonderful for preventing burnout. I think having a combination of slightly different patient populations between the headache population and the pain population, as well as, of course, those who have comorbid headache and pain conditions, has been very gratifying to treat people with these conditions. Not that many neurology residents think about doing a pain fellowship, and I wrote, together with my good friend and colleague Jacob Hascalovici, back in 2018 (that was published in the Green Journal), an article on pain neurology as an emerging subspecialty within neurology - and certainly, I would encourage any neurology residents who are interested in potentially pursuing a pain fellowship to read this article. There's such a need for neurologists in the pain field.   Dr Jones: It can be a little bit of a self-fulfilling prophecy, right? So, obviously, role modeling was important to you, right? You could see the practice when you were in training, when you could still make the decision, and if there aren't enough pain neurologists (which I think we can agree that there aren't), there are probably a lot of trainees who don't have that window into what that practice can be like, which, again, makes it kind of a barrier to folks entering the field - so, hopefully, being more comfortable with it will help our listeners and our readers, you know, integrate this into their practice and see it as a path forward for their own careers if they're interested. One last question for you, Dr Schuster, is - you know, looking into the future, obviously, when we have more options to treat these patients, it's rewarding and engaging and exciting - what do you think the next big thing in pain management is going to be? What should our listeners know that's coming down the road for these patients?   Dr Schuster: Yeah, so the interventional segment and the neuromodulation treatments are really changing a lot these last few years, and I believe are going to keep on evolving with new treatments coming down the pathway. And so, we have two wonderful and really nicely balanced articles on these topics: one of them from one of my former mentors from my UCLA days, Dr Vernon Williams, wrote one on spine pain, and he talks about the interventional pain treatments; and another from Dr Prasad Shirvalkar on neuromodulation for painful neuropathic diseases. And these are really wonderful articles for the neurologist who wants to learn about what treatments are available that, they might not personally be doing these, but that they can refer to colleagues - and these are changing a lot. Epidural steroid injections, for example: helpful for a lot of patients, but there's so much more to the interventional pain field than just that, and I think our practicing neurologists will learn a lot about, “Oh, what can neuromodulation be useful for within the pain field?” And, of course, because there's industry involvement in neuromodulation research, you need somebody who's really good at being very balanced, and I think Dr Shirvalkar did an incredible job about writing a really balanced article about the neuromodulation options that we have for patients with neuropathic pain disorders.   Dr Jones: It's exciting stuff. I think there's a lot to look forward to. I think the update that our readers and listeners will have from this issue will be extremely helpful for themselves in their practice and for their patients. For people who are audiophiles, each of these articles will have a corresponding podcast, so we'll refer people to that. And with that, Dr Schuster, I want to thank you for joining us for a really thorough, fascinating discussion on the field of pain neurology and our brand-new issue on pain neurology. And again, we've been speaking with Dr Nat Schuster, Guest Editor for Continuum’s most recent issue on pain neurology. Please check it out. And thank you to our listeners for joining today.   Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information, important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. Thank you for listening to Continuum Audio.

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 able to accomplish. So, it is very challenging - I think that's a very important call-out. What do you think is the easiest mistake to make when treating patients with autoimmune neurologic disorders, and how should our listeners avoid it?   Dr Smith: Yeah, that's an excellent question. One of the most common mistakes I see is either overvaluing diagnostic testing or not ordering the appropriate diagnostic testing for the clinical syndrome in any given patient. And where this comes into play, really, is the fact that when we order diagnostic testing in the United States for immune-mediated neurologic disorders, these autoantibody panels are available to us that test for a multitude of autoantibodies all at the same time, and if we don't choose the appropriate test for the clinical syndrome that the patient is there with, we run the risk of getting a positive result for an antibody that's unrelated to the syndrome we're seeing in the patient – and no test is 100% specific (or 100% sensitive, for that matter), but these low-specificity issues when you indiscriminately test really can cloud the clinical picture and delay getting the appropriate diagnosis. And so, I really think that one of the biggest mistakes is seeing maybe a low-positive result for an antibody that does not match the clinical syndrome if you go back to the books and use your resources to figure out if that result is meaningful - overvaluing that antibody result and maybe plowing forward with a treatment plan that involves a long course of immunomodulatory therapy is a pretty significant mistake. And then, on the flip side is that because these panel tests, you order them as a block, and you think that you ordered the right thing - or you think that whoever you asked to order the order for you ordered the right thing – and so often, people say the panel was negative, and they don't look at the individual results of the antibodies that were tested in the panel, and because different antibody panels are designed to test for different clinical phenotypes. I see the error where a clinician thinks that all of the antibodies necessary to test for were tested for and negative, and now they feel like their hands are tied. And so, it's both this overvaluing the diagnostic testing and forgetting to question the testing results if they're not what you expect once you get more clinical data - I think both of those are pretty big mistakes. And continuing, again, always be curious, always recheck results, and don't take laboratory values in an EMR that are in black and white as the stone-cold truth that tells you your answer - you have to stay curious about the patient, their history, their neurologic presentation, their response to treatment over time, and really keep assessing. My other soap box here about diagnostic testing is that, historically, a lot of the antibodies that we test for were called paraneoplastic (and that's because they were some of the first antibodies discovered, so, they were some of the earliest ones that we developed tests for), and clinical reference laboratories continue to offer paraneoplastic panels for historical reasons and because a lot of people think that that's what they want. But, paraneoplastic panels, in and of themselves, are not representative of a specific clinical phenotype - they just diagnose patients who have a high risk of malignancy associated with an antineural antibody. And so, most of the clinical reference labs I know of - certainly at ARUP, we have a notice on our testing page, I know Mayo Clinical Laboratories also has a notice that says, “Paraneoplastic panels are not generally the recommended panel to test for antineural antibodies. Consider ordering the phenotype-specific panel that fits the patient's clinical syndrome”. And I think that's super important – we still have paraneoplastic stuck in our head for historical reasons, and it is almost never the right answer.   Dr Weathers: It's really interesting. At my organization, you know, we actually have had some really thoughtful conversations about, do we really restrict it (you know, as part of lab stewardship efforts) - and, you know, these are expensive, and to your point, they can be frankly, really dangerous, you know, to really send somebody down this wrong path with a lot of surveillance, committing them to immunomodulatory therapies, and take you in completely the wrong direction when, actually, your low test probability was very low. So, I think that is an excellent one to really call out and for people to be very thoughtful of - and the way, again, to avoid it is to be very thoughtful about the panels. And for people, certainly, they are very convenient, but people need to be really aware of what's in them and what they are ordering and how to interpret them. And I love that advice about not just thinking about the wholesale as negative - really, you know, for many of us, they are still coming in as scan documents, you know, click into them, read every line, really understand what those results mean.   Dr Smith: And I would also say that I think people don't realize, but clinical reference laboratories would love for you to reach out when there are questions. So, if you don't understand the diagnostic testing that was performed or result, you pretty much all have hotlines. You can call and reach out to an expert in the testing and ask them some questions, and don't be afraid to reach out to your colleagues who might have more experience. We love hearing from people with questions and helping to direct them to the right testing and help them get the answers that they really want to for their patients.   Dr Weathers: I think that is a great plug. Before you order, preferably, before you send in.   Dr Smith: I do like when I hear from people before mistakes were made. Yes. That's nice.   Dr Weathers: It’s a great point.   Dr Smith: When you order these panels, you do run the risk of having these low positive results that may or may not be clinically meaningful. And we do recommend that most of the diagnostic testing be ordered in both serum and CSF. And so, a good example of a mistake that can be made is a very low-positive NMDA-receptor antibody in serum - maybe it was ordered for a patient with cognitive decline or confusion (maybe not under the ideal clinical scenario for ordering), and then it's negative in the CSF. So, an NMDA-receptor positive, negative in the CSF, not the right clinical picture, people can get really jazzed and want to treat an NMDA-receptor encephalitis, that in that case, really isn't meeting diagnostic criteria, and there are excellent diagnostic criteria that have been developed and published for that disorder and for several other autoimmune neurologic disorders, and I think going back to those criteria and really questioning yourself before you start blindly down a path based on a lab result is really important.   Dr Weathers: I think that's excellent advice, too, always keeping that in mind that just because you have gone down this path and gotten that result doesn't mean that you are stuck and committed to it. Always keeping that criteria in mind, always going back, always checking it is really important as well. Moving on from mistakes to kind of an adjacent question, what do you think is the biggest controversy right now when it comes to the treatment of patients with autoimmune neurologic disorders?   Dr Smith: You know, one of the big controversies that I see and I'm concerned about is that we've gotten into a habit of treating the way we've always treated based on expert opinion, and while experts have their opinions based on a lot of experience, they don't take the place of well-designed randomized controlled clinical trials - and in rare diseases (like autoimmune neurologic diseases), it can be really challenging to conduct those trials, especially in the face of people who have a pathway that they always do with their patients. If they have a NMDA-receptor encephalitis patient, they feel very comfortable doing their standard of care with IV steroids and then either plasma exchange or IVIG, and then possibly (and very often), I see following with a B-cell inhibitor, like rituximab, as sort of just a “kitchen-sink” approach to treatment. And while I understand the passion and the desire to make a really sick patient sitting in front of us better as fast as possible, I don't think we have adequate evidence to support that being the “one-size-fits-all kitchen-sick” approach for treatment. And I really am passionate about all clinicians all over the world, supporting randomized controlled clinical trials that are well-designed with the backing of experts in the community, so that when we look at a patient and tell them that we recommend a course of treatment, we're recommending it based on the best quality evidence available, not just what everyone's always done before. I think we can do better than that. And I think there's some controversy in this. Some people think that it doesn't make sense, we already know the answer, but I would say we haven't asked the right question and thoroughly investigated enough. And this is especially important with children, right? We know pediatric patients often don't have well-designed clinical trials to guide their treatments - but in NMDA-receptor encephalitis, many of the patients are children, and I think that they deserve to be involved in well-designed clinical trials in order to support the recommendations that we make for treatment.   Dr Weathers: And in addition to children, think about all of the other patient populations that have traditionally not been well represented in trials, right - pregnant patients, patients of color (historically very underrepresented in trials) - many, many other patient populations that have not been adequately represented.   Dr Smith: Absolutely. Yeah. I think we need to really care about that and face that problem head on and speak to it. We can't just say this is the way we've always done things, so we're going to keep doing it that way. I think we owe it to our patients and ourselves, when we look our patients in the eye, to say that we have good evidence to support the recommendations we're making.   Dr Weathers: I think we have already answered this question in many ways with each of the questions we've already talked about, but is there any other strong arguments that you can make for why it's important for neurology clinicians to read your article?   Dr Smith: Dr Clardy and I spent a lot of time working on this article, trying to put together a piece that will be a resource that people could turn to again and again. I don't think that this article is something that you should read from top to bottom and think that you've absorbed and digested everything, right? So, what we work to do was to really provide a structure and a framework to think about the treatment of immune-mediated neurologic diseases. So, rather than memorizing specific drugs for specific conditions, we developed sort of a space where you could talk about B-cell targeting therapies and the different ways we can target B-cells, we talked about complement inhibitors, neonatal FC receptors, and, really, just at a high level, how these drugs work and how they're targeted, so that going forward in three, four, five years, what I believe we'll know more about each of the individual diseases mediated by antineural antibodies. When we understand what causes that disease, we'll be able to go to a resource like this and choose rationally based on mechanism of action, a drug to treat our patient - even if it's in a patient with such a rare disease that we don't have the luxury of a clinical trial to guide our choices.   Dr Weathers: That's a really excellent point - and I know I've said it a few times, but I think you guys did such a really excellent job at really laying it out in a way that makes it this really comprehensive, really easy-to-use resource at that point of care for providers to be able to do exactly that. Well, I always like to end on a hopeful note, so, this is always my favorite last question – but, what do you think is the next breakthrough coming in the treatment of patients with autoimmune neurologic diseases?   Dr Smith: Yeah, I think in the near future (I certainly hope, at least) that the next breakthrough is going to be in really being able to deliver personalized care based on what we understand about the mechanisms of a patient's rare disease. So, again, right now, I find we're kind of left with the “kitchen-sink” approach because we know so little about the mechanisms that drive each of these unique neurologic diseases and we don't have enough information from clinical trials to inform rational treatment decisions, so we go with these broad approaches - and I really think that in the near future, with work being done by a lot of people (dedicated people over the world) on biomarkers and things that predict either onset of disease or relapse or disease severity or really looking at basic fundamental mechanisms that drive disease, we're going to be able to make more rational choices in the treatment of these patients and mobilize the resources that are expensive, but valuable for the right patient at the right time.   Dr Weathers: That is a very exciting and hopeful future to look towards. Thank you, Dr Smith, for joining me on Continuum Audio. It was wonderful to get to spend this time with you again. Again, today, I've been interviewing Dr Tammy Smith, whose article on therapeutic approach to autoimmune neurologic disorders, written with Dr Stacey Clardy, appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.   Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

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 also what I would say to a learner or a more experienced neurologist who might be reading the article, kind of pick out the little things that you might add to your own kind of approach to - you know, when you see that person with an ataxia, remember that Sjogren syndrome is one of the things you might consider that could be a treatable cause, or you want to see a sensory neuronopathy, don't just think paraneoplastic – again, Sjogren syndrome. So, kind of pick out those little pearls and add them to your approach to that patient that we all see, and I think that would be my biggest takeaway.   Dr Nevel: Yeah. Thank you. So, kind of like, keep this information from the article in mind so that you keep rheumatologic disorders in mind as a possibility when you're approaching a patient with whatever neurologic symptoms they're presenting with. So, what do you think is challenging? You kind of already mentioned a little bit, you know, just that it stretches us maybe into the medicine arena and so maybe stretches our medical knowledge, especially as we become more subspecialized or focused in neurology - but what is challenging about identifying, diagnosing neurologic symptoms as being related or due to an underlying rheumatologic disorder?   Dr McCombe: Absolutely. Yeah. Well, as you said, you know, it forces us to kind of face that medicine stuff that we might not be as comfortable with, but I think what else is challenging is that, sometimes, those medical clues aren't there. For the rheumatologic disorders for the most part, they are. Sjogren’s is potentially a little bit different in that, potentially, the symptoms are less obvious or a little bit more subtle. But, in particular, with neurosarcoidosis, there's a distinct proportion of the patients that won't, in fact, have any systemic complications of their underlying disease, and so, you have to think about it even when the clues aren't there. That's why you have to add it to those kind of differential diagnoses where it might be considered, because those systemic clues that we all rely on when we do our review of systems and we ask about rashes and joint pain and lung issues, and these sorts of things may not be there - and so, you still have to think about it even when it might be completely isolated to the central nervous system.   Dr Nevel: What is our understanding of why some patients with rheumatologic disorders develop neurologic involvement? Do we have an understanding? Do we know why some patients do and some patients don't? I know that's, you know, kind of, uh - that's a tough question, but that was something that I thought of as I was reading your article, like, why does this happen to some people?   Dr McCombe: Absolutely. I mean, I think, potentially, it's a little bit more clear for some of them, like rheumatoid arthritis, because, typically, if you develop a CNS complication of this, it's, in fact, just because you've had the disease for a very long time, and often, it's uncontrolled, and so you think about the disease “spreading” now to the central nervous system - but for other conditions, like neurosarcoidosis, it is much less clear, and even if you look at the epidemiologic patterns for that, it makes it even more muddied in that in some populations, it appears that they develop more central nervous system disease, whereas in others, less. And so, why that is the case and why certain individuals might develop this complication of these diseases I think is yet to be seen.   Dr Nevel: Yeah, that's always the crux of things if we can figure out the why, then maybe we could prevent it, right?   Dr McCombe: Million-dollar question always.   Dr Nevel: Always. So, what do you find the most intriguing about neurologic involvement of rheumatologic disorders?   Dr McCombe: Well, I think one of the things that, really, I mean, for neurosarcoidosis in particular, so many patients do so well, and that's what I really like about it. You know, you see patients who present with an incredible burden of disease radiologically, and yet, don't look nearly as sick as they should when they're sitting in front of you. And then, you start them on therapies and some of them do so well, and even those with relatively devastating deficits, or moderate disease who do have neurologic symptoms, have a remarkable improvement in their neurologic symptoms with treatment. And so, that's always something that's quite rewarding when you get to see these patients in follow-up, and they're generally quite thankful because they're doing so well. And it's different from many of the neurologic diseases that we treat. I mean, in autoimmune neurology, we're lucky because we do have a number of diseases that are quite treatable and patients can have wonderful outcomes. But, you know, it's always scary when we see patients with devastating neurologic signs and it's great to see improvement with treatment. And so, that really draws me to it.   Dr Nevel: Yeah, absolutely. That's really rewarding when you're able to help somebody get better in such a profound way.   Dr McCombe: Mm hmm.   Dr Nevel: What is one common misconception about neurologic manifestations of rheumatologic disorders? Or what do you think is not well understood by treating clinicians?   Dr McCombe: I think probably one of the things I see the most is, sometimes, an undertreatment of the patient. And so, I see patients who, you know, other clinicians may have seen and have made the diagnosis, and perhaps it's a lack of confidence in the diagnosis and so they kind of want somebody else with a subspecialty to kind of confirm the diagnosis, but that treatment hasn't been initiated despite pathological confirmation on biopsy of another tissue. And these patients, like I alluded to before, they do well, but you need to treat them and you need to treat them adequately, and when their symptoms are quite impairing, you need to treat them adequately now. And so I think, sometimes, that delay in starting a second-line therapy and relying on steroids for too long - those sorts of things can really expose a patient to a lot of different side effects and to a lot of different complications that they may not have had, too. So, that's why I spent some time focusing on the treatment, because I think just gaining a little bit of comfort with some of these more common second-line medications is a good thing, because starting those early, I think, makes sense because you can really save the patient a lot. And then, the other thing, too, is that when you're using steroids, think about all of the systemic things that you're causing - think about the increased risk of infection and the fact that you need to prophylax for certain infections, think about bone health, think about protecting the lining of someone's stomach - so not only kind of thinking about your disease in isolation and what you need to do for treatment, but that you need to ensure that you're appropriately prescribing the patient all of the things they need to do to protect themselves during these times.   Dr Nevel: Yeah. I think that's so important. And I'm glad that you brought that up, because I think, unfortunately, many of us have seen a patient who ended up having PJP pneumonia (or something like that) because they weren't put on antibiotic coverage for prolonged steroid use or, you know, bone health - all of that is really important to think about. So, this may be entering a territory where there's no, you know, great evidence, but you mentioned, you know, starting kind of that maintenance or second-line agent - when do you decide to do that in patients? And maybe we can focus (since it gets a little broad), but, you know, in a patient with neurosarcoidosis, let's say - when you're starting the steroids, when do you decide, okay, this person is also going to need a maintenance therapy? Is that something that you do at the beginning when you're starting the steroids, or is that something that you think about later on depending on how their course goes?   Dr McCombe: Yeah. In my practice, I do it at the outset - again, because I'm quite focused on, you know, as soon as I get them on it, getting people off steroids - and so I start essentially almost all of my patients on it unless there's some other contraindication or complication to their disease. And because I deal with central nervous system complications in the vast majority of my patients, I'm starting a TNF-a inhibitor as well as methotrexate, and that's because I see a lot of patients with cord disease and significant brain disease, and so I want to treat them kind of more aggressively from the outset. And so, typically, they'll be on steroids, um, a TNF-a inhibitor, as well as methotrexate, and then I just back off, actually, as they do well. And so, I try to taper the steroids quite quickly over the course of just a number of weeks, or kind of two to three months at most. I maintain the TNF-a inhibitor, and then in some patients, depending on how they're doing, I might eventually stop the methotrexate. Some patients tolerate it so well that we don't for a number of months - other patients want to try to minimize their medications as quick as they can. So, that's my personal practice. In the province where I live, we don't have to worry about access to these medications, and so I understand that that might be an issue in some centers where people practice and have different access and different funding. Of course, I live in a country where we have universal healthcare, and in our province, I have very good access to these medications and they're funded from my patients regardless of socioeconomic status, and so I have the luxury of making these choices and I understand that other people might not, but that's my personal practice and I find it works quite well in the vast majority of patients.   Dr Nevel: Yeah. And you bring up a really good point that, you know, access to some of these medications for patients with CNS manifestations of sarcoidosis, neurosarcoidosis, sometimes can be challenging to treating the patient with medications that you feel like would be best for them. But that's wonderful that you don't have those access issues where you live. How long do you typically continue the TNF-a inhibitor in patients, since you mentioned, you know, tapering off the steroids, tapering off the methotrexate, potentially depending on patient tolerance and course. What's your approach to the TNF-a inhibitor?   Dr McCombe: Yeah, so, of course I follow them clinically, and then radiologically as well, and it's really satisfying if you can see the resolution of their symptoms as well as resolution of the abnormalities and the MRI, so I let that guide me a little bit. But, in most patients, I keep them on therapy for about one to two years, and then at that point, see if I can cease it in some patients. And I, again, continue to follow them radiologically and clinically after I cease it so that I can ensure that I'm catching their disease more quickly if it does come back and then can just reinitiate therapy, but in lots of patients you're able to stop the medication and they have persisting, kind of, disease freedom after that, and so they don't need to be on anything.   Dr Nevel: Yeah, great. And I'm almost hesitant to focus so much on neurosarcoidosis. (It was the rheumatologic manifestation that you talked about the most in your article.) I'm going to put in a plug for everybody to read your article so that they can read about neurologic manifestations of rheumatoid arthritis, Sjogren’s, lupus, Behcet’s - many more things. But focusing on neurosarcoidosis, it can be difficult in my experience to definitively diagnose, and people who have neurosarcoidosis particularly, and people who don't seem to have any systemic manifestations or, you know, imaging findings consistent with sarcoidosis - can you share your approach with us? And you outlined this in your article nicely, too, but your personal approach to patients with suspected neurosarcoidosis, and how you make that clinical decision to treat somebody with possible neurosarcoidosis, somebody who maybe you're not able to get pathologic evidence on?   Dr McCombe: Absolutely. Yeah, those ones are difficult. And, you know, whenever possible (as I mentioned in my article), I think pathological evidence of a diagnosis is important, because then when you find yourself a year down the road and a treatment path and you have uncertainty, it's much more difficult to consider continuing medications that can have quite a number of side effects when you're not absolutely certain about that diagnosis. But, in some patients, you know, I've had patients who might have nondiagnostic biopsies (if you attempt to do a biopsy), or they have disease in a site that really just isn't amenable to biopsy, or they have some other reason they can't have a biopsy. So, how I approach that is that, you know, if you think about possible neurosarcoidosis similar to any other nondiagnosed, you know, blow out-like lesion (for lack of a better term) in the CNS, if it's steroid-responsive, I think that kind of going down a path of treating it as a steroid-responsive lesion is kind of the approach that I take - so the diagnosis in the chart might be possible neurosarcoidosis, but in the back of my mind, I'm just thinking of kind of a steroid-responsive nondiagnostic or idiopathic lesion. So, I then follow that up typically with something like methotrexate (so, a more broader- spectrum immunosuppressant-type medication), and if the methotrexate is able to maintain the response that the steroids initiated, then eventually get them off the steroids. And so, you know, if I think about my patients that I've treated in the past, if they have a diagnosis of possible neurosarcoidosis, I probably don't start a TNF-a inhibitor as quickly in them, because in the back of my mind, I'm always wondering what type of inflammatory lesion this is, but that steroid responsiveness really helps me decide to start a second-line or maintenance therapy and then, typically, in those patients, as I mentioned, I'll start something like methotrexate a little bit more soon.   Dr Nevel: Yeah, great. Thanks for sharing that with us. So, what do you think comes next in this field? What excites you? Where do you think our next kind of development or understanding or breakthrough, whether it's diagnostic or treatment-wise?   Dr McCombe: I think, in the field, you know, any immunologic diseases, we've been really gaining a much better understanding of pathophysiology, and that's honestly what excites me the most, when you can know precisely what part of the immune system is at play here (whether it's, you know, complement-mediated or antibody-mediated) and then being able to then rationally choose medications based on a really clear understanding of the disease is something that I think is kind of novel in a way. For so many years, we would use kind of big broad-spectrum immunosuppression - even in multiple sclerosis, still, we use medications that, historically, we've found to be helpful - but we don't have a great understanding sometimes of why the medicines work. So, kind of going at it from the other way, where we're actually determining what is the exact pathophysiology of disease and then making a rational approach to a therapy, or choosing a therapy based on that, I think is what excites me the most, and I think we'll gain a better understanding of even a broader swath of diseases and be able to make those choices more often. That's what I like about this field.   Dr Nevel: Great. Well, thank you so much for sharing that - and looking forward to the future in this area of neurology. And thanks so much for talking with me today and sharing your story and your expertise and knowledge.   Dr McCombe: Well, thank you for having me. It's been fun.   Dr Nevel: And I encourage all the listeners to read your article. Again, today, I've been interviewing Dr Jennifer McCombe, whose article on neurosarcoidosis and neurologic involvement of rheumatologic disorders appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining today.   Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

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 IgG4-mediated condition), but the same concept applies to other IgG4-mediated diseases, such as MuSK myasthenia, where having an antibody result can guide your treatment towards B-cell depleting therapies instead of sort of trying the typical regimen that you try for other myasthenia gravis patients.   Dr Monteith: And you mentioned where I was reading that, sometimes, nerve conduction studies and EMG can be useful to then narrow the autoantibody profiles. Oftentimes, in the inpatient service, we order the autoantibodies much faster, because it's sometimes harder to access EMG nerve conduction studies - but talk about that narrowing process.   Dr Dubey: Yeah. And it goes back to the point you just made where we end up sending, sort of, sometimes (and I'm guilty of this as well), where we just send antibodies incessantly, even knowing that this particular patient is not necessarily likely to be an autoimmune neurological disorder, and that can be a challenge, even if the false-positive rate for a particular test is, let's say 1% - if you send enough panels, you will get that false-positive result for a particular patient. And that can have significant effects on the patient - not only unnecessary testing or imaging (depending on what type of antibody it is), but also exposure to various immunotherapies or immunosuppressive therapies. It's important to recognize red flags – and that's one of the things I've focused on in this article, is talking about clinical, as well as electrodiagnostic, factors, which make us think that this might be an autoimmune condition, and then, subsequently, we should consider autoantibody testing. Otherwise, we can be in a situation - that 1% situation - where we may be sort of dealing with a false-positive result, rather than a true-positive result. In terms of EMGs, I think I find them extremely useful, specifically for neuropathies, distinguishing between demyelinating versus exonal, and then catering our antibody-ordering practices toward specific groups of antibodies which are associated with demyelinating neuropathies (if that’s what the electrophysiology showed) versus if it's an exonal pathology (considering a different subset of antibodies) - and that's going to be extremely important.   Dr Monteith: You're already getting to my next question, which is what are some of the limitations of autoantibody testing? You mentioned the false-positivity rate - what other limitations are there?   Dr Dubey: So, I think the limitations are both for seropositive, as well as seronegative, patients. As a neurologist, when we see patients and send panels, we can be in a challenging situation in both of those scenarios. Firstly, thinking about seropositives - despite the growing literature about neurology and antibodies, we have to be aware, at least to some extent, about what methodologies are being utilized for these antibody tests. And what I mean by that is knowing when you're sending a sample to a particular lab, the methodology that they're utilizing - is that the most sensitive, specific way to test for certain antibodies? We've learned about this through some of the literature published regarding MOG and aquaporin-4, which has demonstrated that these antibodies, which we suspect are cell surface antibodies, not only generate false-positive, but also false-negative results if they are tested by Western blots or ELISAs. Similar can be applied to some of the cell surface antibodies we are investigating on the autoimmune neuromuscular side (we have some sort of unpublished data regarding that for neurofascin-155). Secondly, it's also kind of critical when you're getting these reports to kind of have a look at what type of secondary antibodies are being utilized, an example being we talked about neurofascin-155, and I mentioned these are IgG4-predominant diseases, so testing for neurofascin IgG4 and knowing that particular patient is positive IgG4 rather than neurofascin pan-IgG. That's an important discrimination, and important information for you to know, because we have seen, at least in my clinical practice, that patients who are positive for neurofascin IgG4 follow the typical story of autoimmune neuropathies - the ones who are not (who are just neurofascin-155 IgG-positive), oftentimes can have wide-ranging phenotypes. The same applies to neurofascin-155 IgMs. And then (not for all antibodies, but for some antibodies), titers are important. A good example of that is a3 ganglionic receptor antibodies, which we utilize for when we're taking care of patients who have autoimmune dysautonomia - and in these cases, if the titers of the antibodies are below .2 nmol/L, usually, those don't have a high specificity for AAG diagnosis. So, I get referred a lot of patients with very low titers of a3 ganglionic receptor antibodies, where the clinical picture does not at all look like autoimmune autonomic ganglionopathy. So, that's another thing to potentially keep in mind. And then, on the seronegative front, it's important to recognize that we are still sort of seeing the tip of the iceberg as far as these antibodies or biomarkers are concerned, specifically for certain phenotypes, such as CIDP. If you look at the literature, depending upon what demographics we're looking at or sort of racial profiles we're looking at, the frequency of these autoimmune neuropathy biomarkers range from 5% to 20%, with much higher frequency in Asian patients - so, a good chunk of these diseases are still seronegative. In the scenario where you have a very high suspicion for an autoimmune neuromuscular disorder (specifically, we'll talk about neuropathies, because that's why we utilize tissue immunofluorescence staining on neural tissues), I recommend people to potentially touch base with that tertiary care lab or that referral lab to see if they have come across some research-based antibodies which are not clinically validated, which can give you some idea, some additional supportive idea, that what you're dealing with is an autoimmune neuromuscular disorder. So, we have to keep the limitations of some of these antibody panels and antibody tests in mind for both positive, as well as negative, results.   Dr Monteith: So, you've already given us a lot of good stuff, um, about titer seronegativity and false-positive rates. And, you know, also looking at the clinical picture when ordering these tests, utilizing EMG nerve conduction studies, give us a major key point that we can't not get when reading your article.   Dr Dubey: I think the major key point is we are neurologists first and serologists later. Most of these patients, we have to kind of evaluate them clinically and convince ourselves at least partly that this might be an autoimmune neuromuscular disorder before sending off these panels. Also, I find it useful to narrow down the phenotype, let's say, in a particular neuropathy or a muscle disease or a hyperexcitability syndrome. So, I have a core group of antigens, autoantigens, or autoantibodies, which I'm expecting and making myself aware of - things beyond that will raise my antenna - potentially, is this truly relevant? Could this be potentially false-positive? So, clinical characterization up front, phenotypic characterization upfront, and then utilizing those antibody results to support our clinical decision-making and therapeutic decision-making is what I've tried to express in this article.   Dr Monteith: And what is something that you wish you knew much earlier in your career?   Dr Dubey: It's a very challenging field, and it's a rapidly evolving field where we learn many things nearly every year, and, sometimes, we learn things that were previously said were incorrect, and we need to kind of work on them. A good example of that is initial reports of voltage-gated potassium-channel antibodies. So, back in the day when I was actually in my medical school and (subsequently) in my residency, voltage-gated potassium-channel antibodies were closely associated with autoimmune neuromyotonia, or autoimmune peripheral hyperexcitability syndromes. Now, over time, we've recognized that only the patients who are positive for LGI1 or CASPR2 are the ones who truly have autoimmune neuromuscular disorders or even CNS disorders. The voltage-gated potassium-channel antibody by itself, without LGI1 or CASPR2, truly doesn't have a very high specificity for neurological autoimmunity. So, that's one example of how even things which were published were considered critical thinking or critical knowledge in our field of autoimmune neuromuscular disorders has evolved and has sort of changed over time. And, again, the new antibodies are another area where nearly every year, something new pops up - not everything truly stands a test of time, but this keeps us on our toes.   Dr Monteith: And what's something that a patient taught you?   Dr Dubey: I think one of the things with every patient interaction I recognize is being an autoimmune neurologist, we tend to focus a lot on firstly, diagnosis, and secondly, immunotherapy - but what I've realized is symptomatic and functional care beyond immunotherapy in these patients who have autoimmune neurological disorders is as important, if not more important. That includes care of patients, involving our colleagues from physical medicine and rehab in terms of exercise regimen for these patients as we do immunotherapies, potentially getting a plan for management of associated pain, and many other factors and many other symptoms that these patients have to deal with secondary to these autoimmune neurological conditions.   Dr Monteith: I think that's really well said, because we get excited about getting the diagnosis and then getting the treatment, but that long-term trajectory and quality of life is really what patients are seeking.   Dr Dubey: Yeah, and as you pointed out, most of the time, especially when we are in inpatient service, or even when we're seeing the patients upfront outpatient, we are seeing them, sometimes, in their acute phase or at their disease not there. What we also have to realize is, what are the implications of these autoimmune neurological conditions in the long term or five years down the line? And that's one of the questions patients often ask me and how this can impact them even when the active immune phase has subsided - and that's something we are actively trying to learn about.   Dr Monteith: So, tell me something you're really excited about in your field.   Dr Dubey: I think, firstly (which is pretty much the topic of my entire article), is novel antibodies and new biomarker discoveries. That's very exciting - we are actively, ourselves, involved in the space. The second thing is better mechanistic understanding of how these antibodies cause diseases, so we can not only understand diseases, we can also try and understand how to target and treat these diseases - this is being actively done for various disorders. One of the disorders which continue to remain a challenge are T-cell mediated diseases, where these antibodies are just red flags or biomarkers are not causing the disease, but it's potentially the T-cells possibly attacking the same antigen which are causing disease process, and those are often the more refractory and harder-to-treat conditions. I'm hoping that with some of the work done in other fields (such as rheumatology or endocrinology for type one diabetes), we're able to learn and apply the same in the field of autoimmune neurology and autoimmune neuromuscular medicine. And then, the final frontier is developing therapies which are antigen specific, where you have discovered that somebody has a particular antibody, and if that antibody is pathogenic, can I just deplete that antibody, not necessarily pan-depleting the immune system. And there is some translational data, there's some animal model data in that area, which I find very exciting, will be extremely helpful for many of my patients.   Dr Monteith: So, very personalized targeted therapies?   Dr Dubey: Correct. Without having all the side effects we all have to kind of take care of in our patients when we start them on, let's say, cyclophosphamide, or some of these really, really, significantly suppressive immunosuppressive medications.   Dr Monteith: Well, thank you so much. I learned a lot from reading your article to prepare for this interview, but also just from talking to you. And it's clear that you're very passionate about what you do and very knowledgeable as well, so, thank you so much.   Dr Dubey: Thank you so much. Thank you for inviting me to do this. And thank you for inviting me to contribute the article.   Dr Monteith: Today, I've been interviewing Dr Divyanshu Dubey, whose article on autoimmune neuromuscular disorders associated with neural autoantibodies appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining us today.   Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information, important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

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 celebrities in the world having this rare disease - you know, the downside of the increased awareness, as we've said. So, moving on from the diagnosis to treatment - again, you do a, obviously, you know, an incredible job in the article, really going through the treatment options and your algorithms - what would you say is the most common misconception you've encountered in treating patients with this disease?   Dr Dalakas: The most common is now (with the publicity) is that it is a disabling disease. Well, it is disabling, but if you treat the disease correctly and early on, I'm not saying we’re curing the disease - many diseases (autoimmune diseases), we help a lot, so there are some we make the patient feel normal, but the disease is there - so, if we start the correct therapy early, a good number of patients respond very well. But by the time the patients come to us, they are so stiff, they walk like a statue, or they come in a wheelchair - of course, it's difficult to reverse this, although we have been very happy to see patients with immunotherapies to get out of the wheelchair, to walk, to enjoy normal activities. So, we have made enough progress with the therapists to help a good number of patients. Now, what is the first therapy we do? Well, is what we call the antispasmodics - these are drugs that relax the stiffness that patients have, sort of a symptomatic therapy. It's not going to address the disease itself, but we address the symptoms. And of course, the symptomatic therapy in SPS is not just to relax the patients - it is related to the so-called GABAergic inhibition. So, the drugs that we use (like the benzodiazepines, or the baclofen, et cetera), these are the drugs that work on the GABAergic pathways. So, it is symptomatic therapy, but it works also on the mechanism, so it's not just a relaxing basis - but since the patients have a lot of phobias, the benzodiazepines also help the phobias. The anxiety and the phobias make the patients worse - they make them more stiff. And in the beginning, they go to psychiatrists because they are so phobic - they're phobic to walk. They hear something, they get so stiff. And I have patients coming at the National Airport in Washington to come to there needing aids in getting out of the plane - some of them get so stiff, they have to get an ambulance to come to the hospital because they're stiff everywhere. So, these phobias and anxiety have triggered a lot of my interest to the point of asking the investigators at the National Institute of Mental Health to see if there is any such thing like autoimmune phobias, because these patients have an autoimmune disease, so, well, maybe we can treat the phobias of immunology - well, we did not find anything, but I just sort of brought the idea maybe we have an autoimmune phobia. But on the other hand, when the patients get better, the phobias are reduced and they're more comfortable to walk. So, it's a very interesting complexity of the symptoms altogether.   Dr Weathers: That is – and, actually, that leads into my next question somewhat, that, as I mentioned in your introduction, you are the world expert in this rare disease. How did that happen? You talked about it a little bit just now. But how did you develop this particular interest and expertise? What drew you to this particular disease?   Dr Dalakas: Yes. It's interesting. I was interested in autoimmune neuromuscular diseases (many of them) and neuropathies and myopathies, and one day, I had a good friend of mine who was the clinical director of NINDS at that time, Dr Hallett. So, he saw patients in the movement disorder clinic and they had stiff-person (I don't know why they went to the movement disorder, but they went there), and Dr Hallett said, “Well, this is an autoimmune disease. You should work on this.” And then, I started seeing one or two patients, and I was very impressed. Really, the symptomatology is so interesting. The patients are suffering, and they sort of give the impression that they're neurotic. So, it's just a combination of when you listen to the symptoms, I was very impressed with the depth of the discomfort that they have and without seeing anything - but, when you examine the patient, you see the stiffness and nothing else. They're not weak, like, we see patients with MS, with myopathies, with neuropathies - they have weakness. They may use a cane, they may use two canes, they may use a walker, because they're stiff. So, it's a different disability than you see in patients who are weak. So, this really made me so interested to understand the mechanism - what's going on here - and that's the reason I started and I put the protocol. And then, we did a lot of immunological studies to understand the mechanism, electrophysiological studies to look at these agonist and antagonist muscles - and of course, we named it also. You know, in the beginning, the syndrome was described as stiff man (stiff-man syndrome), and they're all women. They are most of them, women. In fact, there is an article in a major journal, three women with stiff-man syndrome - and this was many years ago. So, stiff-person will be a more proper term. And then we're seeing a lot of patients or more women, but also we have enough men.   Dr Weathers: So, we've talked a lot about the change with this disease in public awareness. How has that changed your day-to-day life - has it (with the change in public awareness)? Are you bombarded with media requests?   Dr Dalakas: Well, it has stimulated me to write more about the disease and more articles, but also to highlight certain things that were not known before. For example, I had recently a paper on late-onset stiff-person. So, people, we see now patients who develop stiff-person at the age of seventy - they are above sixty or so, overall - and they have more severe disease. These patients also have not good tolerance to the medications we use - so, it's a more challenging group, so it is important to make the diagnosis even in patients with late-onset. These people do less well, because, first of all, they're all misdiagnosed, because if you're a little stiff at the age of sixty-five or seventy - well, you have a bad back, so you all have degenerative disc disease, so you don't think of stiff- person in that age. So, the stimulus was to identify some other issues with the stiff-person. The other is to think of new trials - and I have been working on two new trials. They're not out yet. I'm working to see how best to apply the new therapies. And also, it came up the idea of what are the best ways to assess, objectively, to assess the response, because this is an issue from the beginning. When I did controlled trials at the NIH, and we had established the so-called stiffness index to see how stiff they are measurably, but it is still subjective. It's not really objective, it's not (weakness to measure). So, we have gait analysis, we have the time to walk. So, I think establishing objective criterion to assess response to therapy, it’s an important one - and so, I have been working on this how to make it more objective or as subjective as we can.   Dr Weathers: I think that's fantastic. And you actually, I think, have already answered my question - which is, what is the next breakthrough coming in the diagnosis and management of patients with stiff-person syndrome and the GAD antibody-spectrum disorders - and I think it's going to be the outcomes of these trials. Is there anything else that you're really excited about coming along in this field?   Dr Dalakas: Well, I think that the hope is, then, better immunotherapy, because the patients respond to IVIG based on the controlled study. We did one with anti-B-cell therapy - it was not statistically positive, but we had some placebo effects, because that second trial included some patients who did not have severe disease, so it was difficult to assess mild response. So, I'm interested in other similar immunotherapies, and we were approaching companies to see if they can sponsor such a trial. I think the publicity helps a lot, because if I was going to approach a company before the publicity, nobody would be interested in - there's no, you know - it's money-driven, so they will not do it. But at the NIH, I did it, because NIH had the grants there to sponsor the trials. So, I think the publicity will help us. And I know talking to companies, there are one or two companies that they have expressed a lot of interest, and, hopefully, we can do some new trials and go work on it, but I don't have any clear drug at the moment. I cannot discuss a real drug.   Dr Weathers: Of course, of course, more to come, but still very exciting. And so, still to learn more about you - again, you're so well known, obviously, for what you've done for the field of neurology. What do you like to do outside of seeing neuromuscular patients in your research career? What do you do for fun for your hobbies?   Dr Dalakas: Well, I have two hobbies. One is I'm an art collector of abstract expressionism. So, I go to a lot of auction houses, and I bid often for certain artists that I'm very interested, some French artists, some at the New York School of Modern Art. The eras of the forties and fifties of the abstract expressionism - so that's my collection and my interest in not missing auctions. And the other was I have a interest in wine collection – but, so, most of the time, I read art and I collect art.   Dr Weathers: That is a great answer. I appreciate art. I am not (fortunately) at the auction and collecting stage yet, but that I will have to learn from you. That's wonderful.   Dr Dalakas: Yeah. I'm originally from Greece, and I have also a professorship at the University of Athens, and also I go there. I also have some European artists in my collection.   Dr Weathers: That's wonderful. We have one more modern piece that we've been lucky enough to have.   Dr Dalakas: Yeah, I started with the impression impressionistic art, but I evolved into abstract.   Dr Weathers: Who is your favorite artist?   Dr Dalakas: Well, it's, you know, Rothko and Newman. So, these are very expensive artists, of course, so I can, but in that school, so these artists are not alive now, but people who are working with Rothko and Newman in the other group - so, there are four or five of them that I collect.   Dr Weathers: I feel like we need a whole separate interview just to talk about that.   Dr Dalakas: But, they are very stimulating, because the colors talk to you, and it's not like an impressionistic piece that, sort of, their flowers are nice, et cetera - so the colors talk to you differently.   Dr Weathers: They do. I love Rothko. Well, thank you, Dr Dalakas, for joining me on Continuum Audio. This has been a wonderful conversation. Again, today, I've been interviewing Dr Marinos Dalakas, whose article on stiff-person syndrome and GAD antibody-spectrum disorders appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining us today.   Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

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 article in Brain from 2018, where we also discuss parallels (immunogenetic parallels) with targets seen in genetic disease or in autoimmune disease, and there are actually some examples for cerebellar ataxia, and some of the targets are, indeed, the same for the antibodies and mutation. And some targets are a little bit more difficult, because for those, the antibodies would probably not be pathogenic, but it's more like an autoimmune overall target but it's T-cell mediated. But, for example, water-gated, um, calcium channels - we have antibodies and we have mutations. Or, another example would be glycine receptor antibodies give you acquired hyperekplexia, whereas the mutations give you hereditary hyperekplexia. So, there is, indeed, a bit of an overlap between autoimmune and genetic disorders, but often, also, like, the age at onset (because that might be the next question, the age at onset), and maybe family history and associated features, should help to distinguish the two. I think more from the pathophysiological point interesting, rather than clinically too confusing.   Dr Smith: Wow, that's really cool. So, another question I have is regarding antibody panels, right? And so, I think, oftentimes (at least around here), folks confronting an unusual phenotype will send the Mayo panel - they'll send autoimmune encephalitis or a paraneoplastic panel – and, you know, I think one of the challenges I have thinking about the spectrum of phenotypes that you described, I mean, if you recognize “Aunt Minnie”, then you know where to go, but it seems to me that there's a lot of these that maybe folks don't recognize “Aunt Minnie”. What is the diagnostic utility and pearls and pitfalls of ordering these panels when you're not really certain? In other words, is there a risk of a false positive if the pretest probability is low? So, I guess that's a long question, but do you have guidance about when we should and maybe when we should not be ordering these panels? So, you know, undifferentiated ataxia that's chronically progressive - should we be sending a panel or not? Patients who are later-onset acute, maybe so. So, what's the guidance on when to order the panel?   Dr Balint: It's a tricky topic also for many people in our practice, because, of course, as you said, we don't want to miss something, but, indeed, with any test which you order with a low pretest probability and which is not quite appropriate, you might have false positives, and that might cause much additional trouble in security, or maybe unnecessary and invasive immunotherapy with adverse effects – so, it's really important to think well about antibody testing. And, generally speaking, like always in medicine, we shouldn't order random tests, and antibody panels and neuronal antibodies are not designed as a screening test, so you need to have a phenotype and a reasonable suspicion - and clinical acumen is really key, and that's why also the article is so much focused on the phenotype. It's clearly not that any movement disorder patient who enters the outpatient clinic should get a blood test for antibodies that will likely cause harm, and it has been shown that these antibodies can be falsely positive, both in other diseases but also in healthy controls, and much depends also on which tests you use (but, let's not go into too much detail over here) - so, generally speaking, I would say if you have a suspicion of an autoimmune disease clinically (I mentioned some scenarios where you would think of an autoimmune disorder). And then, ataxias are, of course, a bit tricky, because often, we don't have too many other handles there, and there's still also a significant number of acquired late-onset ataxia where we don't know what the cause is. I think in the ataxia scenario, if I don't have a good answer or explanation, I would order antibody tests a bit more freely - I mean, if you do it properly, you do the serum and the CSF, and that also increases your sensitivity but also the specificities, so I wouldn't then just do the serum, but then go for serum and CSF. In other movement disorders, it depends also a little bit on the phenotype. So, somebody with a phenotype fitting well with Parkinson's disease, I wouldn't do any testing. Somebody with clear PSP phenotype without any red flags or not-fitting features, it is very unlikely to have an antibody finding, and this has been shown also in cohorts. But, if you have something which is not fitting in the phenotypes - for example, you have somebody where you think it might be a PSP phenotype with predominantly axial Parkinsonism falls, but you notice that the oculomotor disturbance is not a vertical gaze palsy, but a horizontal gaze palsy – so, it's not really fitting phenotype as you know it. That's a scenario where would probably think of antibody testing. Then, if you do the testing theorem - and CSF, in general, is gold standard - there are some antibodies where theorem is good enough (like, for example, with aquaporin-4 antibodies), but the reason why we do serum and CSF, as I mentioned, is the increased sensitivity and specificity. And nowadays, in the antibody world, we have something similar to the genetics - we have the variant of unknown significance and in the neurology world, we coin the term “antibody of unknown significance” to also give a name to the problem that, sometimes, we get a test result and it is difficult to interpret. Another handle over there would be to try to confirm the test result in another test method. So for example, if you have a cell-based assay with an antibody finding, you would like to confirm that on immunohistochemistry - the staining pattern is in keeping with that.   Dr Smith: So, Bettina, that was a really great and comprehensive answer to the question with a lot of pearls packed into it, and I think the idea that, you know, oftentimes, it's helpful to do both serum and CSF testing is important - also looking for staining to further confirm the diagnosis. And, I think one of the things that I was struck by in your response was the example of a PSP patient who instead of vertical gaze palsy had horizontal gaze palsy as a red flag, and I think a lot of our listeners are probably familiar with the idea that maybe hyperkinetic movement disorders might be autoimmune, or certainly rapidly progressive ataxia, but at least I don't think of Parkinsonian syndromes as often. I know there are some that we need to consider. Maybe you can give us some pearls about when we should consider antibody testing in a patient who has a Parkinson syndrome?   Dr Balint: So, I will not cover now the paraneoplastic Parkinsonian syndromes (because they typically develop as rapidly that you would anyway think about it, hopefully), but go more into those conditions which might mimic degenerative disease - and one of the most interesting antibodies in this regard is IgLON5, and you will be aware that it has been discovered in 2014 in patients who shared a characteristic sleep movement disorder (non-REM parasomnia). The spectrum has broadened a lot, and one possible manifestation is that it could come into the differential of Parkinsonian syndromes - so, for example, if you have axial Parkinsonism and a gaze palsy, you are in a PSP phenotype, but the red flag would be maybe if the eye movement disorders are not really fitting with the PSP phenotype. Also, in PSP patients, we don't expect parasomnias at night. If the bed partner is, for example, complaining that the patient is moving in his sleep and doing movements, then this would be a red flag, and in this context, you would think of IgLON5. IgLON5 could also give you Parkinsonism and cerebellar ataxia, and they might have dysautonomia, and, of course, with a sleep movement disorder, you are now in the ballpark of MSA phenotypes; however, if there are additional features (like, for example, fasciculations) which you don't expect in MSA, that would be, again, the red flag. So, typically, even in those differentials, there are some red flags on handles which would point you to the diagnosis - it is not that it completely mimics the phenotype of our default degenerative disease, but, sometimes, you need to hunt a little bit for those handles.   Dr Smith: So, Bettina, that's really interesting. I wanted to ask you about IgLON5, and in particular, the sleep phenotype, but, you know, I wonder whether there's a risk of just confusing this with REM sleep behavior disorder and a chronic Parkinsonian syndrome - what's the time course of this, and any other wisdom in terms of how to differentiate it from, you know, a more common neurodegenerative problem?   Dr Balint: So, the spectrum of sleep disorders in IgLON5 is actually a bit broad. The characteristic thing is the non-REM sleep parasomnia with the finalistic fine movements, but classic REM sleep behavior disorder has also been reported in these patients. And one of the tricky things is IgLON5 is a slowly progressive disease (some patients had symptoms for a decade prior to diagnosis), so it's really an important differential of autoimmune disease - but as mentioned, the features not fitting in, and they are typically also the cardinal features. So, gaze palsies are very frequent, ptosis, bulbar symptoms, vocal cord palsy, sleep movement disorders which might not fit to the original phenotype, and breathing problems (for example) so severe that they require a tracheostoma – so, these are some red flags which would alert you to this diagnosis of anti-IgLON5 disease.   Dr Smith: I'm curious, Bettina, how do you keep up on all of this and keep it all straight? Right, there's a lot of information, and as I was reading your article, you've got these wonderful tables - and in fact, this whole issue for our listeners feels that way. I've read several of these articles now, and I'm just curious what your strategy is to stay up to date and stay organized. You have to be very organized to be an autoimmune neurologist, it seems to me.   Dr Balint: And having a little bit of OCD helps clearly, as always, in neurology. I think it is just that I started to be interested in this area for a while and I have in my head the clinical phenotype to most important associated antibodies, and as the field continues, I just add up on that panel. But, I don't want people to be discouraged - you're right, many antibodies, but I think the point is not to know each and every antibody but to know in which scenario to think of an autoimmune syndrome and then to know where to look it up.   Dr Smith: Well, I think that's a great way of ending our conversation, Bettina. I think your article does a great job of that, and one of the things I love about Continuum is these articles serve as point-of-care tools. I think our conversation will also serve as a useful framework, because I think you've talked a lot about how to organize your thinking, and, you know, pearls for when we should be thinking about these disorders which are uncommon, but you certainly don't want to miss one because the therapy can be very effective. So, Bettina, thank you so much for joining me. This has been a really great conversation.   Dr Balint: Thank you so much, Gordon. Thank you very much for your good questions.   Dr Smith: So, again, today, I've had the great pleasure of interviewing Dr Bettina Balint, whose article on ataxia and other autoimmune movement disorders appears in the most recent issue of Continuum, which is on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thanks to our listeners for joining us today.   Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

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 a great topic to study in the future, I think.   Dr Smith: This is a really interesting area, and one that's really benefited by significant therapeutic development. I wonder if you might look a little bit in the future and tell us, maybe, the agent, or perhaps the target, that you're most excited about therapeutically that's coming down the road these days?   Dr Sechi: There are trials ongoing for MOGAD, which is the real need in terms of treatment, because for NMO, we already have three, four drugs that have been approved and which efficacy have been demonstrated by randomized clinical trials, and those are B-cell depleting agents, IL-6 inhibitors, and complement inhibitors. For MOGAD, this is still a gray zone, because the optimal treatment strategies remains to be defined. There are ongoing trials that are quite promising on IL-6 inhibitors and the inhibitors of the neonatal Fc receptor (which is also used in myasthenia gravis as you know). And something that seems to be quite effective - a good option for long-term treatment in these patients and relapse prevention - is also the periodic administration of IVIG (intravenous immunoglobulin), which is a nice option, for instance, in the children where you want to avoid immunosuppressants of other types. So, I think IL-6 is going to show to be very effective in the end. We'll see. We'll see.   Dr Smith: So, I wonder if I might just give you a vignette and get your thoughts about, kind of, acute management, right? I just took care of a patient who had a longitudinally extensive myelitis and she was essentially paraplegic and actually came in progressing fairly rapidly, and we, of course, started her on IV methylprednisolone, sent off the proper diagnostic testing - the question I have is, how quickly do you advance therapy and go to IVIG or plasma exchange when you're encountering these, right? It takes, you know, I think the turnaround time is, you know, often about a week to get these tests back (at least several days) - I mean, should we be going very quickly to plasma exchange in someone who has a severe phenotype? Is it okay to do three to five days of IV methylprednisolone and wait for the results to come back? What's the right approach?   Dr Sechi: I think this is a great question, actually. You know, management of the acute attacks probably is the most important thing, you know, to allow a good recovery, and I think timing of PLEX administration should be very short - so, the threshold for PLEX should be low, especially when the attack is severe, and this has to be done regardless of antibody testing results, which is typically not available before one or two weeks (at least a year in Italy), I think, in many hospitals. So, I think the risk-benefit ratio of administering PLEX is in favor of treatment in these patients, because the side effects (the potential side effects) are very rare and can be prevented. Some diseases, they can mimic NMO or MOGAD - they're very rare, and they can really worsen with PLEX. As an example, we can say spinal cord infarction can worsen, maybe, because of hypotension due to PLEX. Or some very rare infections, like one case, a bad case of intramedullary spinal cord abscess that looked really similar to an AQP-4 IgG-related LTM - and it was bad, because the patient had no fever, no signs of infection, the CSF culture was negative initially, so we ended up doing a biopsy after failure of PLEX and steroids. So, it is recommended to start within the first three to five days, preferentially, in severe cases, and this is great for the outcome of the patient, so, I do recommend PLEX as a second treatment option. And I'm not sure about IVIG acutely. There is some data on MOG, but it's still controversial - it works a lot when PLEX fails, but it can be considered after PLEX, of course. And there are some very rare patients that do not improve, even after IV methylprednisolone, PLEX, or IVIG, and so, you need to consider some rescue therapies. In those patients, it's kind of complicated, because there are some options, like IL-6 inhibitors seem to be quite effective and quite fast-acting for MOGAD attacks, and also eculizumab and complement inhibitors can be an option in patients with AQP-4 - but maybe less in patients with MOG. So, these are the possibilities (very quickly).   Dr Smith: So, you mentioned FcRn inhibitors a moment ago, and I wonder, do you see a future where - and I think you were mentioning them as maybe more chronic therapy? Correct me if I'm wrong.   Dr Sechi: Yeah, yeah.   Dr Smith: Do you foresee a role for these agents in acute management? I mean, there are some that, you know, very quickly lower immunoglobulin levels, though just looking out in the future, you think that these sort of infusion therapies that we think about chronic therapy (you mentioned, you know, complement inhibitors) are going to be useful in acute management?   Dr Sechi: Yeah, it depends. It's a good option to try. I'm not sure about the time to action. It's very dependent on that, because IL-6 inhibitors and complement inhibitors are very fast-acting (I think they can be effective already within twelve hours, 24 hours, which is good), but it's reasonable that, also, Fc inhibitors can be an alternative in the future. As far as I know, there is not much in the literature, but it's good to try in the future in case, acutely.   Dr Smith: Well, exciting times indeed. Elia, thank you so much for a great discussion. I thoroughly enjoyed this. I look forward to visiting you soon, and I want to congratulate you on a really great article that's very interesting and very clinically useful.   Dr Sechi: Well, thank you, Dr Smith. This is my pleasure, and thank you for great questions. I had a great time and hope the readers of Continuum will like the article and the nice figures we have put together. So, thank you, thank you very much.   Dr Smith: Well, again, congratulations. And for our listeners today, I've been interviewing Dr Elia Sechi, whose article on aquaporin-4 antibody-positive NMOSD and MOGAD appears in the most recent issue of Continuum, which is on autoimmune neurology. It's a very exciting issue. Please check out Continuum Audio episodes from this and other issues of Continuum. And thanks to you all for joining us today.   Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.