December 2025 Neuropalliative Care Issue With Dr. Maisha T. Robinson

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Maisha T. Robinson, MD, MSHPM, FAAN, FAAHPM, who served as the guest editor of the December 2025 Neuropalliative Care issue. They provide a preview of the issue, which publishes on December 2, 2025. Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota. Dr. Robinson is the Chair of the Division of Palliative Medicine and an assistant professor of neurology at Mayo Clinic in Jacksonville, Florida. Additional Resources Read the issue: continuum.aan.com Subscribe to Continuum®: shop.lww.com/Continuum Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @LyellJ Guest: @neuropalldoc Full episode transcript available here Dr Jones: Most of us who see patients with chronic progressive neurologic disease are aware of the value of palliative care. The focus on symptom management and quality of life is a key aspect of helping these patients. But how many of us are comfortable starting the conversation about palliative care or care at the end of life? Today we have the opportunity to speak with a leading expert on neuropalliative care, Dr Maisha Robinson, about how we can better integrate neuropalliative care into our practices. Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about subscribing to the journal, listening to verbatim recordings of the articles, and exclusive access to interviews not featured on the podcast. Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today I'm interviewing Dr Maisha Robinson, who is Continuum's Guest Editor for our latest issue of Continuum on neuropalliative care, and our first-ever issue fully dedicated to this topic. Dr Robinson is an assistant professor of neurology at Mayo Clinic in Florida, where she is Chair of the Division of Palliative Medicine, and she also serves on the AAN Board of Directors as Chair of the Member Engagement Committee. Dr Robinson, welcome. Thank you for joining us today. Why don't you introduce yourself to our listeners? Dr Robinson: Well, Dr Jones, thank you for having me. Really a pleasure to be here. I'm Maisha Robinson at the Mayo Clinic in Jacksonville, Florida. I spent my time as a neurohospitalist, a general palliative care physician, and a neuropalliative care physician. Dr Jones: So, this is a topic that at Continuum, we have heard about from subscribers for a long time requesting a fully dedicated issue to palliative care. And we've titled this neuropalliative Care. So, we want to respond to our subscribers and bring them content that they're interested in. I also think that palliative medicine is a big education gap in our specialty of neurology and something that we have room to improve on. So, let's start with the basics, Dr Robinson. Palliative medicine has been around for a long time, but this concept of "neuropalliative care" feels relatively new. What is neuropalliative care? Dr Robinson: That's a great question. Generally, what I would say is palliative care, first of all, is really just a specialty that focuses on trying to improve quality of life for people that have a serious or advanced medical condition. And neuropalliative care is really palliative care for people with neurologic conditions. And you'll see a number of neurologists doing neuropalliative care, but also there are internists as well, and people from other specialties, who focus on patients with neurologic disease and really trying to improve their quality of life. Dr Jones: Got it. And so, it's really the principles of palliative medicine in a specialty-specific context, which I think is important for us given the prevalence of chronic disease in our specialty. And I was obviously reading through these articles in this issue, and in the really wonderful articles, there are some themes that came up multiple times in various different articles. And one of them was obviously the importance of communication with patients and families. I think, and I'm speaking a little bit from personal experience here, many physicians feel uncomfortable bringing up the discussion of palliative care. And I'm sure that is something that reflects on your practice, too. How often do you have a patient who shows up to clinic and they ask you, why am I here? Dr Robinson: It happens all the time, because colleagues who are referring patients are nervous to tell them that they're sending them to palliative care. But we try to tell people it's really just to normalize it, to say that the palliative care team is going to see you, they're going to help with some symptoms, they're going to help you think about big picture, and they're going to be sort of an added layer of support to your team. And I think if people approach it from that standpoint, then patients and family members will say, that sounds great, I need a little extra support. Dr Jones: So, I think most neurologists have a threshold at which they would feel more comfortable having specialty support, having a palliative medicine specialist to help them in symptom management with the patient. For the palliative care that they provide themselves---and we want our subscribers to read this issue and feel more comfortable with delivering some palliative care on their own---how would you encourage them to begin that conversation? How should they initiate that conversation with a patient about working more toward palliative management of symptoms? Dr Robinson: So, one of the things we recommend is really introducing an approach to palliative care very early in the disease process. So, discussions about big picture and goals of care, discussions about who might help make medical decisions if the person can't make them for themselves. Those kinds of things can be discussed very early on. And in fact, that's palliative care. And then they can talk to patients more about the fact that as the disease progresses, there may be an additional team that can help walk along alongside the neurologist in helping you prepare for what's to come. You know, I think it's very important for patients and family members who feel like you're not abandoning them, but you're adding additional resources. And so, I like the way that we often will suggest to people to say partner or collaborate or bring in extra resources with the palliative care team. I think patients and family members will respond to that. Dr Jones: Yeah. So, by talking about it early, you kind of, at least, help to avoid that problem of the patient perceiving the introduction of palliative care as the quote-unquote "giving-up problem." Is that right? Dr Robinson: Correct. Because we also don't want to see people who are just being referred to us for end-of-life care. Palliative care is about much more than that. But if patients will Google palliative care, they may see hospice come up. And so, introducing the concept early and discussing some palliative topics early will allow the patient and family members to think that, okay, this isn't because I'm at the end of life. This is just because my clinician wants to make sure that I have all the bases covered. Dr Jones: This was also mentioned in several of the articles, the studies that have shown how frequently palliative care is initiated very near the end of life, which is usually, I think, perceived as a missed opportunity, right? To not wait so long to take advantage of what palliative care has to offer. Dr Robinson: That's correct. And the benefit of palliative care is that oftentimes we work alongside an interdisciplinary team, a team that could be quite helpful to patients and their support systems throughout the course of the disease. So, we have chaplains, we have nurses, we often have other clinicians, advanced practice providers as well, who work with us. We have spiritual advisors as well. And the patients and family members could benefit from some of those resources throughout the course of the disease. Who they might need to meet with may vary depending on what the disease is and how they're doing. But there's definitely some benefit to having a longitudinal relationship with the palliative care team and not just seeking them out at the end of life. Dr Jones: So- that's very helpful. So, it'll obviously vary according to an individual provider's level of comfort, right, where they're comfortable providing certain palliative management care versus when they need to have some assistance from a specialist. Are there types of care or are there certain thresholds that you say, wow, this patient really should go see a specialist in palliative medicine or neuropalliative care? Dr Robinson: So, I think that if there are, for instance, refractory symptoms, where the neurologist has been working with a patient for a while trying to manage certain symptoms and they're having some challenges, that person may benefit from being referred to palliative care. If patients are being hospitalized multiple times and frequently, that may suggest that a good serious-illness conversation may be necessary. If there are concerns about long-term artificial nutrition, hydration, or functional and cognitive decline, then some of those patients have benefited from palliative care. Not only the patient, but also the caregiver, because our team really focuses on trying to make sure that we're walking through the course of disease with these patients to ensure that all of the needs are managed both for the patient and the family member. Dr Jones: Got it. And that's very helpful. And I know that we talk about a lot of these decisions happening in an ideal environment when there's good access to the neurologist and good access to a palliative medicine specialist or even a neuropalliative medicine expert. In your general sense, I- and maybe we'll talk a little bit here in a minute or two about the growing interest in neuropalliative care. But in terms of access, in terms of availability of really, truly neuropalliative expertise, what is your sense of how widely available that is in the US? Dr Robinson: There's a shortfall of palliative care clinicians in the United States. Everybody who needs a palliative care clinician won't have access to one. And I think your point about the primary palliative care is so important. That's really what we encourage all clinicians, neurologists, neurosurgeons, even, physiatrists, the neurology care team members need to be comfortable with at least initiating some of these conversations. Because, to your point, not everyone's going to have access to a palliative care physician. But by reading issues such as this one, attending some courses---for instance at the American Academy of Neurology meetings---, doing some online trainings, those types of things can be helpful to bring any neurology clinician up to speed who certainly may not have access to a palliative care physician. Dr Jones: So, I know---and this is in part from my own conversations with patients in my own practice---there are a number of fears that patients have when they have a chronic disease, something that's progressive or something that we don't have a curative treatment for. But I think one of, if not the most common fear among patients is pain, and pain that can't be managed adequately during the course of chronic illness or at the end of life. One of the interesting concepts that I saw mentioned in a few of the articles in this issue is this concept of total pain. So, not just the somatic pain that I think we tend to think of as clinicians and patients tend to think of as patients, but a more holistic definition of pain. Walk us through that and how that relates to palliative medicine. Dr Robinson: So, Dame Cicely Saunders, the modern-day founder of palliative medicine, really described this biopsychosocial model for pain. And so, you're right, it's not just physical pain, but it's psychological pain, it's spiritual pain. And oftentimes when we are taking care of patients with neurologic disease, they may have some physical pain, but a lot of them are thinking about, for instance, the things that they will miss, which may cause some internal discomfort. Things that they're grieving, the life they thought they were going to have, the person that they used to be, the life they used to have, and what they anticipated their life as being. And some of that can cause people to have not only the spiritual discomfort, but also some psychological discomfort as well. And so, when we're thinking about how to provide rehensive care to these patients, we have to be thinking about all of these aspects. Dr Jones: It's really helpful. And I guess the more you can identify those, the more you can either help yourself or find the right expert to help the patient. I thought that was an interesting expansion of, of my view of how to think about pain. And another observation that came up in several of the articles was a lack of high-quality clinical trial evidence to inform a lot of the interventions in neuropalliative care. Some of them are common-sense, some of them are based on clinical experience or expert advice. In your own practice, if there was one key knowledge gap to close---in other words, if there was one pivotal trial that we could do to answer one question in helping patients with chronic neurologic disease---what would you say is the main gap? Dr Robinson: I think the real gap is, who needs palliative care and when? That seems very simple. We have tried things such as automatic triggers for palliative care, for instance, in patients with ALS, or we've said that maybe all glioblastoma patients should see palliative care. But is that true? Are we utilizing the resources in the best possible way that we can? We're not sure. And so, you'll see these practices doing things all a little bit different because we don't have a best practice and it's not really standardized about when people should see palliative care, or why, for instance, they should see palliative care, or who should see palliative care. And I think if we could help drill that down, we can provide some better guidance to our colleagues about when and why and who should see palliative care. Dr Jones: It's a really kind of a fundamental, foundational, who needs the service to begin with or who needs to care. Okay, that's- that is a big gap. So, one of the interesting concepts that I read- and it was in Benzi Kluger's article on neuropalliative care for patients who have movement disorders. I think it's a concept that is interesting, really, maybe in the management of patients with a lot of different chronic, progressive neurologic diseases. And it's this idea of stealing victories or bringing joy to patients. In other words, not just managing or trying to minimize some of the negative aspects or symptoms of disease, but looking for opportunities to bring something positive to their experience or improving their quality of life. Tell us a little more about that, because I think that's something patients would appreciate, but I think neurologists would appreciate that, too. Dr Robinson: Dr Kluger loves to talk about sustaining and finding joy in patients who have really serious or advanced neurologic conditions. He likes to talk about stealing victories, which can relate to the fact that patients and their loved ones can find even some benefit despite having a serious or advanced neurologic condition. Neurologists and neurology clinicians also can steal victories in their patients when they notice, for instance, that they've gained a new skill, and they've lost a skill that they used to love because of the advancing disease. And this is just an opportunity for not only the patients and family members, but also the care providers to recognize that in the midst of decline, there are positive things to be found. Dr Jones: I think it gives patients a sense of maybe reclaimed autonomy when they can say, well, there's maybe nothing I can do to cure this disease in the conventional sense, but I can maybe go on this trip with my family, which has been something I've always wanted to do. Or, I can do these things, so I can attend certain events that I want to. And I think that autonomy and independence aspect of that, I think that I think that was really meaningful and something that I'm going to bring back to my own practice in my care of patients who have ALS, for example. When you think about neuropalliative care---and you've been a leader in this area, Dr Robinson---what do you think the biggest change in neuropalliative care has been over the last few years? Dr Robinson: I think there's a growing cohort of people who are recognizing that there is some benefit in having dedicated specialists who focus on palliative care for patients with neurologic disease. When I said I was going to do neuropalliative care, somebody asked me, why would a neurologist be interested in palliative care? Over the last decade and a half, we've seen that shift. And not only are our colleagues recognizing the benefit, but also patients and caregivers are. Some are even asking for palliative care. I think people are recognizing that not only having their primary neurologist or neurology clinician taking care of them, they have this extra layer of support, and this extra team really focused on quality-of-life issues can be beneficial. Dr Jones: So, one of the things that I think you and I have both seen, Dr Robinson, is a growing interest among neurology trainees in palliative medicine. And maybe that's anecdotal, but in my own practice, I've seen more and more trainees express an interest in this. For neurology residents who are interested in this as a component of or maybe a focus of their career, what would you recommend to them? How should they go about this? Dr Robinson: Yes, it used to be that every neurology resident interested in palliative care would call me or email me or send me a message, but now there are so many that I can't keep up. We're excited about the growing number of people interested in neuropalliative care. What I would say to those people is that you can really try to hone your skills by, for instance, doing a rotation with the palliative care team at your hospital, if there is one. If there isn't one, you might even ask to spend some time with the local hospice agency, which may be helpful to you. If you're attending some of the national meetings---for instance, the American Academy of Neurology meeting---you may want to go to a course and learn a little bit about palliative care. There are a couple that are offered every year. There is an education opportunity for education in palliative and end-of-life care as well. And so, there are a number of resources that you can find in addition to this issue of Continuum as well. Dr Jones: I find it gratifying that trainees ask about this. And I'm sorry, I think I've probably sent a bunch of trainees your way for advice about this, and you've been incredibly generous with your time and expertise. So, I find it very gratifying that our neurology trainees are interested in this area, because it's an important area of medicine. It's also probably a challenging practice just from the cognitive load and the emotional load of caring for patients who are moving through a progressive illness. What is your thinking about how to have a sustainable career in palliative medicine? What is your approach to that? Is it for everyone? Dr Robinson: Yeah, the issue with palliative care is that we do see some very challenging situations, and frankly some very sad situations. But I actually love what I do because I think that we're helping patients and their family members during very, very difficult times. I feel like this is why I went to medical school, to try to be there for people when they need me the most. The way that I think about it is, the patients and family members will be going through this anyway. We're trying to help improve their quality of life as they're going through it. And what you might find interesting is that these patients are so grateful. And their loved ones, they're so grateful. Even if they're nearing the end of life, just to have someone who's helping them see that, for instance, the pain could be better, or that they have more resources for the loved ones to be able to take care of them. And so, I think that helps sustain us, realizing that we are really having a positive benefit on the patients and also their family members. Dr Jones: Well, I think that's a great point to end on. And these are patients who need help. Even if we don't have a curative therapy, they do need support. And that's an important service and a function and an important facet of our profession. So, Dr Robinson, I want to thank you for joining us, and I want to thank you for such a great discussion of neuropalliative care. I learned a lot from our conversation today. I've learned a lot reading the articles and the experts that you put together. This is an important topic. I'm really grateful to you to having assembled this team of expert authors and put together an issue that I think will be really important for not only our junior readers, but also our more experienced subscribers as well. Dr Robinson: Thank you, Dr Jones, for the opportunity. Dr Jones: Again, we've been speaking with Dr Maisha Robinson, Guest Editor of Continuum's most recent issue and first issue fully dedicated to neuropalliative care. 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 the link in the episode notes to learn more and subscribe. Thank you for listening to Continuum Audio.

Dystrophinopathies are heritable muscle disorders caused by pathogenic variants in the DMD gene, leading to progressive muscle breakdown, proximal weakness, cardiomyopathy, and respiratory failure. Diagnosis and management are evolving areas of neuromuscular neurology. In this episode, Kait Nevel, MD, speaks with Divya Jayaraman, MD, PhD, an author of the article "Dystrophinopathies" in the Continuum® October 2025 Muscle and Neuromuscular Junction Disorders issue. Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana. Dr. Jayaraman is an assistant professor of neurology and pediatrics in the division of child neurology at the Columbia University Irving Medical Center in New York, New York. Additional Resources Read the article: Dystrophinopathies Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @IUneurodocmom Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Nevel: Hello, this is Dr Kate Nevel. Today I'm interviewing Dr Divya Jayaraman about her article on dystrophinopathies, which she wrote with Dr Partha Ghosh. This article appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Divya, welcome to the podcast, and please introduce yourself to the audience. Dr Jayaraman: Thank you so much, Dr Nevel. My name is Divya, and I am an assistant professor of Neurology and Pediatrics at Columbia University Irving Medical Center, and also an attending physician in the Pediatric Neuromuscular program there. In that capacity, I see patients with pediatric neuromuscular disorders and also some general pediatric neurology patients and also do research, primarily clinical research and clinical trials on pediatric neuromuscular disorders. Dr Nevel: Wonderful. Thank you for sharing that background with us. To set us on the same page for our discussion, before we get into some more details of the article, perhaps, could you start with some definitions? What comprises the dystrophinopathies? What are some of the core features? Dr Jayaraman: So, the dystrophinopathies, I like that term because it is a smaller subset from the muscular dystrophies. The dystrophinopathies are a spectrum of clinical phenotypes that are all associated with mutations in the DMD gene on chromosome X. So, that includes DMD---or, Duchenne muscular dystrophy---, Becker muscular dystrophy, intermediate muscular dystrophy (which falls in between the two), dilated cardiomyopathy, asymptomatic hyperCKemia, and manifesting female carriers. In terms of the core features of these conditions, so, there's some variability, weakness being prominent in Duchenne and also Becker. The asymptomatic hyperCKemia, on the other hand, may have minimal symptoms and might be found incidentally by just having a high CK on their labs. They all will have some degree of elevated CK. The dilated cardiomyopathy patients, and also the Becker patients to a lesser degree, will have cardiac involvement out of proportion to skeletal muscle involvement, and then the manifesting carriers likewise can have elevated CK and prominent cardiac involvement as well as some milder weakness. Dr Nevel: Now that we have some definitions, for the practicing neurologists out there, what do you think is the most important takeaway from your article about the dystrophinopathies? Dr Jayaraman: I like this question because it suggests that there's something that, really, any neurologist could do to help us pick up these patients sooner. And the big takeaway I want everyone to get from this is to check the CK, or creatine kinase, level. It's a simple, cheap, easy test that anyone can order, and it really helps us a lot in terms of setting the patient on the diagnostic odyssey. And in terms of whom you should be thinking about checking a CK in, obviously patients who present with some of the classic clinical features of Duchenne muscular dystrophy. This would include young boys who have toe walking, as they're presenting, sign; or motor delayed, delayed walking. They may have calf hypertrophy, which is what we say nowadays. You might have seen calf pseudohypertrophy in your neurology textbooks, but we just say calf hypertrophy now. Or patients can often have a Gowers sign or Gowers maneuver, which is named after a person called Gowers who described this phenomenon where the child will basically turn over and use their hands on the floor to stand up, usually with a wide-based gait, and then they'll sort of march their hands up their legs. That's the sort of classic Gowers maneuver. There are modified versions of that as well. So, if anyone presents with this classic presentation, for sure the best first step is to check a CK. But I would also think about checking a CK for some atypical cases. For example, any boy with any kind of motor or speech delay for whom you might not necessarily be thinking about a muscle disorder, it's always good practice to check a CK. Even a boy with autism for whom you may not get a good clinical exam. This patient might present to a general pediatric neurology clinic. I always check a CK in those patients, and you'll pick up a lot of cases that way. For the adult folks in particular, the adult neurologist, a female patient could show up in your clinic with asymptomatic hyperCKemia. And I think it's an important differential to think about for them because this could have implications not just for their own cardiac risks, but also for their family planning. Dr Nevel: So, tell us a little bit more about the timing of diagnosis. Biggest takeaway: check a CK if this is anywhere on your radar, even if somewhat of an atypical case. Why is it so important to get kiddos started on that diagnostic odyssey, as you called it, early? Dr Jayaraman: This is especially important for kids because if they especially get a Duchenne muscular dystrophy diagnosis, you might be making them eligible for treatments that we've had for some time, and also treatments that were not available earlier that hinge on making that diagnosis. So, for example, people may be skeptical about steroids, but there's population data to suggest that initiation and implementation of steroids could delay the onset of loss of ambulation as much as three years. So, you don't want to deprive patients of the chance to get that. And then all the newer emerging therapies---which we'll be talking about later, I'm sure---require a Duchenne muscular dystrophy diagnosis. So, that's why it's so important to check a CK, have this on your radar, and then get them to a good specialist. Dr Nevel: I know that you alluded already, or shared a few of the kind of exam paroles or findings among patients with dystrophinopathy. But could you share with us a little bit more how you approach these patients in the clinic who are presenting with muscle weakness, perhaps? And how do you approach this or think about this in terms of ways to potentially differentiate between a dystrophinopathy versus another cause of motor weakness or delay? Dr Jayaraman: It's helpful to think through the neuraxis and what kinds of disorders can present along that neuraxis. A major differential that I'm always thinking about when I'm seeing a child with proximal weakness is spinal muscular atrophy, which is a genetic anterior horn cell disorder that can also present in this age group. And some of the key differences there would be things like reflexes. So, you should have dropped reflexes in spinal muscular atrophy. In DMD, surprisingly, they might have preserved Achilles reflexes even if their patellar reflexes are lost. It may only be much later that they go on to lose their Achilles reflex. So, if you can get an Achilles reflex, that's quite reassuring, and if you cannot, then you need to be thinking about spinal muscular atrophy. They can both have low muscle tone and can present quite similarly, including with proximal weakness, and can even have neck flexion weakness. So, this is an important distinction to make. The reason for that is, obviously there are treatments for both conditions, but for spinal muscular atrophy, timing is very, very important. Time is motor neurons, so the sooner you make that diagnosis the better. Other considerations would be the congenital muscular dystrophies. So, for those that they tend to present a lot younger, like in infancy or very early on, and they can have much, much higher CKS in that age range than a comparable Duchenne or Becker muscular dystrophy patient. They can also have other involvement of the central nervous system that you wouldn't see in the dystrophinopathies, for example. My mnemonic for the congenital muscular dystrophies is muscle-eye-brain disease, which is one of the subtypes. So, you think about muscle involvement, eye involvement, and brain involvement. So, they need an ophthalmology valve. They can have brain malformations, which you typically don't see in the dystrophinopathies. I think those are some of the major considerations that I have. Obviously, it's always good to think about the rest of the neuraxis as well. Like, could this be a central nervous system process? Do they have upper motor neuron signs? But that's just using all of your exam tools as a neurologist. Dr Nevel: Yeah, absolutely. So, let's say you have a patient in clinic and you suspect they may have a dystrophinopathy. What is your next diagnostic step after your exam? Maybe you have an elevated CK and you've met with the patient. What comes next? Dr Jayaraman: Great question. So, after the CK, my next step is to go to genetics. And this is a bit of a change in practice over time. In the past we would go from the CK to the muscle biopsy before genetic testing was standard. And I think now, especially in kids, we want to try and spare them invasive procedures where possible. So, genetic testing would be the next step. There are a few no-charge, sponsored testing programs for the dystrophinopathies and also for some of the differential diagnosis that I mentioned. And I think we'll be including links to websites for all of these in the final version of the published article. So, those are a good starting point for a genetic workup. It's really important to know that, you know, deletions and duplications are a very common type of mutation in the DMD gene. And so, if you just do a very broad testing, like whole exome, you might miss some of those duplications and deletions. And it's important to include both checking for duplications and deletions, and also making sure that the DMD gene is sequenced. So always look at whatever genetic test you're ordering and making sure that it's actually going to do what you want it to do. After genetics, I think that the sort of natural question is, what if things are not clear after the genetics for some reason? We still use biopsy in this day and age, but we save it for those cases where it's not entirely clear or maybe the phenotype is a little bit discordant from the genotype. So, for mutations that disrupt the reading frame, those tend to cause Duchenne muscular dystrophy, whereas mutations that preserve the reading frame tend to cause Becker muscular dystrophy. There are some important exceptions to this, which is where muscle biopsy can be especially helpful in sorting it out. So, for example, there are some early mutations early in the DMD gene where, basically, they find an alternate start codon or an initiation codon to continue with transcription and translation. So, you end up forming a largely functional, somewhat truncated protein that gives you more of a milder Becker phenotype. On the other hand, you can have some non-frameshift or inframe mutations that preserve the reading frame, but because they disrupt a very key domain in the protein that's really crucial for its function, you can actually end up with a much more severe Duchennelike phenotype. So, for these sorts of cases, you might know a priori you're dealing with them, but might just be a child who is who you think has DMD has a mutation that's showed up on testing. There isn't enough in the literature to point you one way or another, but they look maybe a little milder than you would expect. That would be a good kid to do a biopsy in because there are treatment decisions that hinge on this. There are treatments that are only for Duchenne that someone with a milder phenotype would not be eligible for. Dr Nevel: So, that kind of stepwise approach, but maybe not all kids need a muscle biopsy is what I'm hearing from you. If it's a mutation that's been well-described in the literature to be fitting with Duchenne, for example. Dr Jayaraman: Absolutely. Dr Nevel: So, after you confirm the diagnosis through genetic testing---and let's say, you know, whether or not you do a muscle biopsy or not, after you know the diagnosis is a dystrophinopathy---how do you counsel the families and your patients? What are the most important points to relay to families, especially in that initial phase where the diagnosis is being made? Dr Jayaraman: This is a lot of what we do in pediatric neurology in general, right? So, I actually picked up this approach from the pediatric hematology oncology specialists at Boston Children's. They had this concept of a day-zero conversation, which is the day that you disclose the life-changing diagnosis or potentially, at some point, terminal diagnosis to a family. And some of the key components of that are a not beating around the bush, telling them what the diagnosis is, and then letting them have whatever emotional response they're going to have in the moment. And you may not get much further than that, but honestly, you want them to take away, this is what my child has. I did not do anything to cause this, nor could I have done anything to prevent this. Because often for these genetic conditions, there's a lot of guilt, a lot of parental guilt. So, you want to try and assuage that as much as possible. And then to know that they're not going to be alone on this journey; that, you know, they don't have to have it all figured out right then, but we can always come back and answer any questions they have. There's going to be a whole team of specialists. We're going to help the family and the kid manage this condition. Those are sort of my big takeaways that I want them to get. Dr Nevel: Right. And that segues into my next question, which is, who is part of that team? I know that these teams that help take care of people with dystrophinopathies and other muscle disorders can be very large teams that span multiple specialists. Can you talk a little bit more about that for this group of patients? Dr Jayaraman: Of course. So, the neuromuscular neurologist, really, our role is in coordinating the diagnosis, the initiation of any disease-specific treatments, and coordinating care with a whole group of specialists. So, we're sort of at the center of that, but everyone else is equally important. So, the other specialists include physical therapists; occupational therapists; rehab doctors or physiatrists; orthotists who help with all of the many braces and other devices that they might need, wheelchairs; pulmonology, of course, for managing the respiratory manifestations of this. It becomes increasingly important over time, and they are involved early on to help monitor for impending respiratory problems. Cardiac manifestations, this is huge and something that you should be thinking about even for your female carriers, the mother of the patient you're seeing in the clinic, or your patient who comes to adult clinic with asymptomatic hyperCKemia. if you end up making a diagnosis of DMD carrier for those patients, or if you make a Becker diagnosis, the cardiac surveillance is even more important because the cardiac involvement can be out of proportion to the skeletal muscle weakness. And of course, extremely important for the Duchenne patients as well. Endocrinologists are hugely important because in the course of treating patients with steroids, we end up giving them a lot of iatrogenic endocrinologic complications. Like they might have delayed puberty, they might have loss of growth, of height; and of course metabolic syndrome. So, endocrinology is hugely important. They're also important in managing things like fracture prevention, osteoporosis, prescribing bisphosphonates if necessary. Nutrition and GI are also important, not just later on when they might need assistance to take in nutrition, whether that's through tube feeds, but also earlier on when we're trying to manage the weight. Orthopedics, of course, for the various orthopedic complications that patients develop. And then finally, a word must be said for social work and behavioral and mental health specialists, because a lot of this patient population has a lot of mental health challenges as well. Dr Nevel: After you give the diagnosis, you've counseled the patient and families and you've had those kind of initial phase discussions, the day-zero discussion, when you start getting into discussions or thoughts about management, disease-specific medication. But what are the main categories of the treatment options, and maybe how do you kind of approach deciding between treatment options for your patients? Dr Jayaraman: So, there are two broad categories that I like to think about. So, one is the oral corticosteroids and oral histone deacetylase, or HDAC inhibitors, which share the common characteristic that they are non-mutation specific. And within corticosteroids, patients now have a choice between just Prednisone or Prednisolone, or Deflazacort or Vermilion. The oral HDAC inhibitors are newly FDA-approved as a nonsteroidal therapy in addition to corticosteroids in DMD patients above six years of age. I would say we're in the early phase of adoption of this in clinical practice. And then the other big category of treatment options would be the genetic therapies as a broad bucket, and this would include gene therapy or gene replacement therapy, of which the most famous is the microdystrophin gene therapy that was FDA-approved first on an accelerated approval basis for ages four to eight, and then a full approval in that age group as well as an accelerated approval for all comers, essentially, with DMD. This is obviously controversial. Different centers approach this a bit differently. I think our practice at our site has been to focus on the ambulatory population, just thinking about risk versus benefit, because the risks are not insignificant. So really this is something that should be done by experienced sites that have the bandwidth and the wherewithal to counsel patients through all of this and to manage complications as they arise with regular monitoring. And then another class that falls within this broader category would be the Exon-skipping therapies. So as the name suggests, they are oligonucleotides that cause an Exon to be skipped. The idea is, if there is a mutation in a particular Exon that causes a frame shift, and there's an adjacent Exon that you can force skipping of, then the resulting protein, when you splice the two ends together, will actually allow restoration of the reading frame. I think the picture I want to paint is that there's a wide range of options that we present to families, not all of which everyone will be eligible for. And they all have different risk profiles. And I really think the choice of a particular therapy has to be a risk-benefit decision and a shared decision-making process between the physician and the family. Dr Nevel: What is going on in research in this area? And what do you think will be the next big breakthrough? I know before we started the recording you had mentioned that there's a lot of things going on that are exciting. And so, I'm looking forward to hearing more. Dr Jayaraman: Of course. So, I'll be as quick as I can with this. But I mentioned that next-generation Exon skipping therapies, I think the hope is that they will be better at delivering the Exon skipping to the target tissue and cells and that they might be more efficacious. I'm also excited about next-generation gene therapies that might target muscle more specifically and hopefully reduce the off-target effects, or combination use of gene therapies with other immunosuppressive regimens to improve the safety profile and maybe someday allow redosing, which we cannot do currently. Or potentially targeting the satellite cells, which are the muscle stem cells, again, to improve the long term durability of these genetic therapies. Dr Nevel: That's great, thank you for sharing. Thank you so much for talking to me today about your article. I really enjoyed learning more about the dystrophinopathies. Today I've been interviewing Dr Divya Jayaraman about her article on the dystrophinopathies, which she wrote with Dr Partha Ghosh. This article appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Please be sure to check out the Continuum Audio episodes from this and other issues. Also, please read the Continuum articles for more details than what we were able to get to today during our discussion. Thank you, as always, so much to the listeners for joining us today, and thank you, Divya, for sharing all of your knowledge with us today. Dr Jayaraman: Thank you so much for having me on the podcast. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Myotonic dystrophies (DM), in addition to muscle weakness and myotonia, are associated with broad and variable multiorgan involvement. Neurologists need to recognize DM to ensure prompt diagnosis, effective symptom management, and prevention of life-threatening events. In this episode, Casey Albin, MD, speaks with Paloma Gonzalez Perez, MD, PhD, author of the article "Myotonic Dystrophy" in the Continuum® October 2025 Muscle and Neuromuscular Junction Disorders issue. Dr. Albin is a Continuum® Audio interviewer, associate editor of media engagement, and an assistant professor of neurology and neurosurgery at Emory University School of Medicine in Atlanta, Georgia. Dr. Gonzalez Perez is an assistant professor at Harvard Medical School in Boston, Massachusetts. Additional Resources Read the article: Myotonic Dystrophy 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: @caseyalbin Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Albin: Hello everyone, this is Dr Casey Albin. Today I'm interviewing Dr Paloma Gonzalez-Perez about her article on myotonic dystrophy, which appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Welcome to the podcast, Dr Gonzalez-Perez. I'd love for you to introduce yourself to our listeners. Dr Gonzalez-Perez: Thank you very much for the invitation. My name is Paloma Gonzalez-Perez. I'm a neuromuscular neurologist at Massachusetts General Hospital in Boston since 2018. And I'm originally from Spain. I did residency there and also here in Iowa City. And then I did the neuromuscular fellowship here at Mass General Brigham, and then I stayed here as a faculty. So, my focus is myopathies, and more specifically muscular dystrophies, and more particularly myotonic dystrophy, which is what we are going to talk today. Dr Albin: Wonderful. And this is a really fantastic tour de force article about myotonic dystrophy. And in reading your article, it really did stand out to me that these myotonic dystrophies are probably under-recognized. And so, I was hoping that, just to start, you could tell us a little bit about, what is a myotonic dystrophy, and how should we sort of situate that within the larger context of all muscular dystrophies? Dr Gonzalez-Perez: Yes, so muscular dystrophies, we have many of them, right? And mostly affecting the skeletal muscle. And basically, the definition of muscular dystrophy is a genetic or inherited muscle disease that causes a progressive muscle weakness. And also, in the muscle biopsies of patients with muscular dystrophies, we see some fractures that are characteristic of this category of muscle diseases, such as, for example, the nuclei of the muscle fibers are in the center---that's what we call internal nuclei---or maybe fat infiltration or increased connective tissue or a variability in the size of the muscle fibers. So, now in the last few years, the genetic testing is more accessible to us. So, we don't need muscle biopsies all the time to diagnose patients with muscular dystrophy. So many times, we go directly to genetic testing. And this is basically the category of muscular dystrophies. Myotonic dystrophy is very fascinating muscular dystrophy in the sense that many times not only affect the skeletal muscle, but other organs can be affected. And it is true that other muscular dystrophies can affect other organs such as, for example, the brain and the heart, which is something that we always have in mind as a clinician to make sure this muscular dystrophy affect the heart or affect the brain, because it is important for patient care. But myotonic dystrophy actually can affect any organ in the body. I think it is one of these muscular dystrophies in which there is a multisystem involvement of the body. So, the immune, immunological system can be affected and the endocrine system can be affected, the GI system can be affected. In addition to, obviously, to the brain, to the heart, to the skeletal muscle. And sometimes that is why it is under-recognized because of course, if there is a very severe phenotype, maybe the patient comes very easily to a neurologist who is very familiar with myotonic dystrophy. But if the phenotype is a little bit milder, and maybe it doesn't affect much the skeletal muscle. So, these patients probably are in the care of other specialists, such as, for example cardiology or GI doctors, and obviously these specialists are not really aware of this muscular dystrophy. So, I think it is a complex disease because it is very variable in phenotype, can affect many organs and can be also mild. Dr Albin: That is fantastic. That is just a wonderful overview of, really, muscular dystrophy. One of the things I was really curious about: the name includes myotonia. Is myotonia, like, always present, or is that a little bit misleading? Dr Gonzalez-Perez: Yeah. I would say that it is a little bit misleading---maybe not too much in myotonic dystrophy type one, because it is true that in adults with myotonic dystrophy type one, many times they have the myotonia, but not many times they complain about the myotonia. This is the thing. So, it is a diagnostic clue that we have at bedside when we ask the patient, for example, to squeeze the hands and then release and we see the myotonia there. And then, obviously, this can actually give you the diagnosis at bedside, but the patients usually don't come to the clinic complaining of this myotonia, which is delaying the relaxation of the muscles. Sometimes they don't- they are not bothered by that. They don't need treatment for that. But it is a very important clue at bedside. I have to say, adults, myotonic dystrophy type one, because the congenital myotonic dystrophy type one you don't see myotonia, clinical myotonia. These babies, right, are born with severe muscle weakness and we don't see myotonia. And then myotonic dystrophy type two, many patients don't have clinical myotonia. And then, you know, the absence of myotonia, the absence of this delay in the muscle relaxation doesn't rule out a myotonic dystrophy, and especially doesn't rule out a myotonic dystrophy type two. Dr Albin: Fantastic. So probably is going to be a feature of the adult-onset type one. May or may not be present in type two. And then the congenital forum where children are presenting as infants, they're not going to tell you that, oh, I have delayed relaxation. That's not going to be part of that. Dr Gonzalez-Perez: Exactly. Dr Albin: This is one of those things that I think, unless you're in neuromuscular clinic, you might not think to ask people about. Maybe the patient isn't actually saying, oh, I have this delayed reaction. How do you get them to give you that history? Like, what are the questions that you ask? Dr Gonzalez-Perez: Sometimes I will say, do your hands get locked? You know, this could be the first question that they noticed something there, and then they can give you maybe the clue. But actually, it's the exam more than the question. I will say it's more do the exam and, you know, intentionally test for myotonia. And you test for spontaneous myotonia and percussion myotonia. So spontaneous myotonia, we tell the patient to squeeze the hands very strongly and then open the hands quickly. And then if they cannot open the hands quickly, this is a delay in muscle relaxation. We call it grip myotonia, spontaneous grip myotonia. Or sometimes close your eyes very, very, very strongly and then open the eyes quickly. And if they have this delay in the eye opening, we call it eyelid myotonia. This eye is spontaneous myotonia, you don't touch the patient and you don't use your hammer yet. And then if we don't find anything, we go to the hammer. We use our reflex hammer, and then we try to test for percussion myotonia. And sometimes we with the reflect hammer, we tap the thinner eminence of the hand, and we can see that you tap, there is a contraction, and then the thumb goes up and then takes a while to go down again. It is a delay in the relaxation of the thinner eminence muscles. Or sometimes in the posterior aspect of the forearm, if we tap the extensor digitorum communis muscle. Again, so, there is a contraction of that muscle, the fingers go up and then take a while to go down. It is also a perfusion myotonia of the extensor digitorum communis muscle. Sometimes people do it even in the tongue. I don't do that because could be very painful. But you can, you know, use a tongue depressor and put it in the tongue, and you tap the tongue depressor and sometimes there is contraction of the tongue, which can be very painful. I don't do it. So- but this is the perfusion myotonia, that can give you also a clue. Dr Albin: That's fantastic. I think this is one of the most memorable things that I saw in pediatric neurology. I remember very distinctly a kid coming in, and then us also examining the mother and having that delayed relaxation. And just one of those really great neurologic exams, those little findings to tuck away to really make a diagnosis, recognizing that not all patients with muscular dystrophy or myotonic dystrophy will have that finding. But so beautiful. And I think that's a really great explanation. And I will also direct our listeners, if you are a Continuum subscriber, she has some really wonderful videos in her article from the EMG sounds of this, which is another layer of being able to appreciate the physical exam finding. One of the things that I was really struck by, and that you've already mentioned, is that there is this really incredible spectrum of disease. That some of the myotonic dystrophy patients may barely have any skeletal involvement, and the ones with congenital myotonic dystrophy may have significant mortality even within the first year of life. Given how many subtypes of this disease there are in that varied presentation, let's just walk through sort of starting with congenital myotonic dystrophy. What are some of the clues to that diagnosis? Dr Gonzalez-Perez: Yes. So, you know, these babies with congenital myotonic dystrophy, actually when they are born, the phenotype is what we call a floppy baby. Floppy baby syndrome right? So, they are very weak. There is generalized weakness, including the swallowing muscles and the respiratory muscles. So sometimes, you know, these patients, these babies have to be intubated---to have a feeling tube, right---to survive. So, that's why the mortality can be so high during the first year of life, because obviously swallowing and breathing is affected because the muscle, those muscles, are also affected. So, one of the clues, actually- you know, sometimes these patients may have, like, a tented mouth, which could be a sign of congenital myotonic dystrophy. The differential diagnosis for a floppy baby syndrome is very broad and can be caused by central nervous system problems or peripheral nervous system problems. So, it's very broad, but maybe the tented mouth can be a clue to suspect the congenital myotonic dystrophy type one. And I will say that also, examine the mom. Because sometimes the mom is not diagnosed with myotonic dystrophy, and as simple as going into the mom who is an adult and can have already the myotonia that we talked about before and maybe, you know, try to do, like, a grip myotonia, eyelid myotonia, or use your reflex hammer and tap a few muscles, and then can give you the diagnosis of potential congenital myotonic dystrophy in the baby. And I have to say that there is no newborn screening for myotonic dystrophy type one yet. Maybe in the future it's going to be, but not at this time. So, I'm pretty sure that pediatricians probably rule out other things before unless there is distinctive mouth or unless the mom is affected. Dr Albin: Great pearls about how to take it to the bedside and try to look for that hereditary nature of this. Let's move up a little bit in sort of the childhood and adolescent onset. What are some of the clues that you're seeing for those children who come to presentation a bit later in life, but still probably more likely to be seen in pediatric clinic? Dr Gonzalez-Perez: Yes. So, the childhood and adolescent onset in myotonic dystrophy type one, it is interesting because the skeletal muscle may not be the organ that is more affected or the organ that impacts the life of the patient and the family of the patient. So, it's- the phenotype is predominantly focused on behavioral and intellectual disabilities. They may develop at some point myotonia, and they may develop also muscle weakness. But for the most part they are ambulatory. They eat by themselves, they breathe okay, and there is not too much problem with the skeletal muscle, but mostly with behavioral problems such as, for example, ADHD or intellectual disability. So, they may need some help in school and things like that. So, it is more, I will say, a central nervous system phenotype at this age. Dr Albin: Yeah, I love that that this is- to me, this was part of the complexity of this was that, while we call it myotonic dystrophy, the muscle part of this disease really may not be the main issue for the patients and their families. And that we're actually looking for something that involves the central nervous system, endocrine system, GI system. And knowing that maybe the muscle is not the main problem here, why is it so important that these patients actually get the correct diagnosis? Dr Gonzalez-Perez: Exactly. So, it is very important. And I always think about the heart. You know, the heart can be affected in the sense like the rhythm of the heart can be abnormal. And sometimes, you know, the patient doesn't have symptoms. But it's important to detect this because, you know, an abnormal rhythm in the heart can cause sudden death. So that's why it's so important. The diagnosis of this muscular dystrophy at this time, and of course in the future when we have a treatment, right, will be very important also to have the diagnosis, the earlier is the better, because probably the treatment is going to be more effective in the earlier stages than in the later stages. But I will say that right now making sure that the heart is in a good shape and the patient has a cardiologist on board if they have myotonic dystrophy. And also, you know, there are consensus-based care recommendations for myotonic dystrophy type one for the pediatric population and the adult population, and also for myotonic dystrophy type two for the adult population, that are published. And I also included in the chapter because they are very important to look for things that maybe the patient it doesn't complain about, but it's important to look for them in the case that we can prevent some future complications. Dr Albin: Absolutely. I really love that. This is a systemic disease that has multiple manifestations, and while the skeletal muscle involvement may or may not be causing problems, we really do have to get the right diagnosis, particularly as it impacts the heart and preventing fatal cardiac arrhythmias. Up to this point, we've mostly been talking about type one myotonic dystrophy. What sets type two apart? Dr Gonzalez-Perez: Yes. So, type two is, I think, even more under-recognized, probably because the phenotype is even more variable than type one and can be much milder in some sense. We are not aware of, you know, like, there are some pediatric cases that have been reported, but for the most part it's an adult muscular dystrophy, type two. So, we diagnose these muscular dystrophies usually in the forties, fifties. The thing is, like, sometimes patients actually may only have muscle pain. And not even muscle weakness. And so… and actually some of these patients may receive a diagnosis of fibromyalgia, for example, just because of the muscle pain. And it is more difficult to obtain myotonia on exam, actually. I think there is a delay in diagnosis in this population, and also the multisystem involvement, which is present but maybe even more variable than that in type one. And we have less patients, so we understand less the phenotype of these patients. But for the most part it is, I think, more under-recognized in the type one. Dr Albin: Fascinating. So again, could have pretty mild skeletal involvement and may just have cramps and muscle pain. So, you have to be really sort of mindful of keeping this on the differential for people with multiple areas of pain in the muscles. When is this suspected? Are you usually sending genetic tests to confirm? How do we get to the diagnosis? Dr Gonzalez-Perez: In the history, in the past medical history, you have probably- sometimes you have the clue. For example, a patient with muscle pain, imagine like for example a forty-eight-year-old male with muscle pain comes to the clinic, and then he tells you that he had cataract surgery at the age of twenty. And then you see a CK that is a little bit more elevated than usual. And then at that time I will go for genetic testing right away, for my myotonic dystrophy type two. Because of the muscle pain is so characteristic of myotonic dystrophy type two, and the multiorgan involvement sometimes includes a very early cataracts, the same as in type one. But the muscle pain is much more typical for type two than for type one. So, that's why I will go, in this specific scenario to type two. If I still think that my alternative dystrophic type two is a possibility, although I'm not totally convinced if it is or not, I usually go for EMG. I mean, if you don't see myotonia at the side, maybe with the EMG and the needle in the muscle, you can see this electrical myotonia that I have some videos in the chapter to see if there is this motorcycle sound of the electrical discharges from the muscle that are consistent with- they can be seen in myotonic dystrophy type two. They are not as specific, but can be seen in myotonic dystrophy type two. So if I have a patient with muscle pain and then I see this electrical myotonia on EMG, so then I will go then next to a genetic testing for myotonic dystrophy type two. Sometimes if there are some family history, it gives you also clues about the possibility of myotonic dystrophy in general, but also myotonic dystrophy type two. Myotonic dystrophy type two, usually the muscle weakness, when it is present, it's more proximal. While in myotonic dystrophy type one it's more distal. So, this also, you know, helps you to differentiate. But specifically in this myotonic dystrophy area, I think the past medical history helps you a lot and the family history helps you too. If you see an autosomal dominant inheritance of muscle or other organ problems, you suspect this type of muscular dystrophy. And I have low threshold to test for this if it is possible because, as we mentioned before, knowing what the patient has helps a lot in their care. Dr Albin: Absolutely. I love that. Spoken like a true neurologist, using the history, the physical, thinking about the family history, using EMG as an extension of our physical to really find and clinch that diagnosis, and then using genetic tests as a confirmation to get to the right answer. I love the mention of early-onset cataract. Are there any other things that pop into your mind or when you're reading the chart and you look at the medical history that, like cataracts, stand out to you as, this really clues me into myotonic dystrophy? Dr Gonzalez-Perez: Yes. So, for example, a pacemaker at early age---in their thirties, in their forties---; a family history of sudden death---for example, having a surgery for whatever reason, having a surgery like for example, surgery for appendicitis and have complications from general anesthesia, like a delay in the awakening from the general anesthesia because patients with melatonin dystrophy are very sensitive to anesthetics and also any sedative medication. So, that gives me a clue that, you know, patients with melatonin dystrophy can have this type of history. I think that those will be the main ones. Sleep apnea is very common, but we know it's also common in the general population. So, maybe sometimes, actually, we may think too much and it is, you know, normal for the general population, more frequent in the general population. But, yeah. And daytime sleepiness that can be caused by the sleep apnea. But sometimes these patients have profound daytime sleepiness. Like, they really complain about that. You know, I need to nap very often during the day because of this. Those features, I think, increase my suspicion for myotonic dystrophy. Dr Albin: Fantastic. So, in the brief time that we have left, I'd love for you to tell us a little bit about what's on the horizon for treatment for these patients. Dr Gonzalez-Perez: Yes, we have exciting preclinical and clinical trials in myotonic dystrophy type one; not yet in myotonic dystrophy type two. And these trials try to target the genetic defect at the level of the DNA or at the level of RNA. So, we have small molecules in clinical trials. We have also some antisense oligonucleotides in clinical trials. We have some small interfering RNAs in clinical trials. And then the CRISPR, which is another new technology, that is trying, you know, to repair this long function that causes myotonic dystrophy type one. And the important thing is, like, once we know what works for myotonic dystrophy type one, we may have good clues also for myotonic dystrophy type two because they share the common pathogenic mechanism. Dr Albin: Fantastic. So, it sounds like there's some genetic therapy in the pipeline. There is some small molecule treatments that are going to be available. So, really an exciting time. There's going to be a lot of changes coming forward to these patients. Again, today I've been interviewing Dr Paloma Gonzalez-Perez about her article on myotonic dystrophy, which appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Be sure to check out Continuum Audio episodes from this and other issues, and thank you so much to our listeners for joining again today. Dr Gonzalez-Perez: Thank you very much for the invitation. My pleasure. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Genetic variants that underlie skeletal muscle channelopathies and rhabdomyolysis can also cause persistent and progressive muscle weakness. The availability and expanded use of genetic testing allows for the identification of new genes causing periodic paralysis and rhabdomyolysis. In this episode, Teshamae Monteith, MD, FAAN speaks with Hani Kushlaf, MD, MS, FAAN, author of the article "Muscle Channelopathies and Rhabdomyolysis" in the Continuum® October 2025 Muscle and Neuromuscular Junction Disorders 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. Kushlaf is a professor of neurology and pathology as well as the director of the Neuromuscular Division, director of Neuromuscular Research, and director of the Neuromuscular Medicine Fellowship in the Department of Neurology and Rehabilitation Medicine and the Department of Pathology and Laboratory Medicine at the University of Cincinnati College of Medicine in Cincinnati, Ohio. Additional Resources Read the article: Muscle Channelopathies and Rhabdomyolysis 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: @HaniKushlaf Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Monteith: This is Dr Teshamae Monteith. Today I'm interviewing Dr Hani Kushlaf about his article on muscle channelopathies and rhabdomyolysis, which appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Hi, Hani. How are you? Dr Kushlaf: Good. How are you doing? Thank you for having me. Dr Monteith: Well, thank you for coming on our podcast. So why don't you introduce yourself? Dr Kushlaf: So, I'm Hani Kushlaf. I'm a professor of Neurology and Pathology in the Department of Neurology and Rehabilitation Medicine at the University of Cincinnati in Cincinnati, Ohio. Dr Monteith: And what got you interested in muscle disorders? Dr Kushlaf: So, this is a long story. At first in residency, I was interested in epilepsy, but the moment I started doing a rotation in neuromuscular, I became enamored with neuromuscular disorders. I remember seeing the first patient in the rotation who had myofibrillar myopathy, and I found out that there is very little known about muscle disease at the time. So, I became very interested and I immediately changed direction as I started doing nerve conduction studies and EMGs and having that procedure base, I just decided that I want to pursue neuromuscular disorders. Dr Monteith: Well, that doesn't sound like a long story. It sounds like love at first sight. Dr Kushlaf: Yes, I think part of it is not very far from neuromuscular disorders and that it does have some electrophysiology involved. But muscle disease and nerve disorders, they need that detailed neurologic examination, which I love in terms of doing the localization exercise. Dr Monteith: Great. So why don't we talk about the objectives of your article? Dr Kushlaf: This article was written to review muscle channelopathies that include myotonic disorders and periodic paralysis, and also rhabdomyolysis, with emphasis on genetic causes of rhabdomyolysis more than acquired causes. Dr Monteith: So, why was this update so important? Dr Kushlaf: I think this area of muscle disorders hasn't seen a lot of progress in recent years, but there are interesting findings that we're learning that spark, hopefully, more research into the area, because we do have significant gaps that are related to understanding pathophysiology of some of these disorders. For example, in patients with periodic paralysis, it's clearly known now that these patients over time develop muscle weakness, and the muscle weakness is unrelated to how many episodes of weakness they have---basically, the episodic paralysis part of the disease. So, this is an important finding that I think we need to look more into it and understand that these disorders actually progress, even though that they may not have episodes of paralysis. In addition, there are genetic therapies that have been introduced into most of neuromuscular medicine at this time, including muscle disorders, while this specific part of muscle diseases has not had that luxury yet. And I'm hoping over time that there will be an introduction of gene therapies for these diseases. Dr Monteith: Great. So, it sounds like there's some clinical advances, then, as well as genetic advances. Now, you also spoke about rhabdomyolysis and that there's newer ways of thinking about that from perhaps when I was in residency. So why don't you update me on these newer approaches? Dr Kushlaf: The rhabdomyolysis… first, the definition of it is changing. We used to use a cut off, a CK of about a thousand, to call it rhabdomyolysis. And very recently it's clear that that level of CK is not sufficient to call it rhabdomyolysis. So, now the level went up in terms of exertion of rhabdomyolysis, up to ten thousand, has to be more than ten thousand. And in patients who haven't had exercise, the level is up to five thousand. So, it's no longer actually one thousand. And that refinement in the definition is important because there are some patients who exercise all the time and they may exercise at an athletic level and they have very high CK's. And those patients should not be labeled as having rhabdomyolysis. Basically, they are doing strenuous physiologic exercise. In addition, not only the definition of rhabdomyolysis is changing, it is our approach to which disorders to consider first and how we should work up patients with rhabdomyolysis. So, acquired rhabdomyolysis remains the most important etiology to be ruled out first. So, I always tell my fellows and residents that, think about acquired rhabdomyolysis first before you think about the genetic disorder. After you rule out the fact that it is not a toxic or metabolic or medication-induced rhabdomyolysis, then think about a genetic etiology. But when you get that consultation from the hospital that the patient has rhabdomyolysis and we want you to figure it out, always look at the medication list and make sure that there isn't anything on it that causes, actually, a rhabdomyolysis. And in many instances, you find out that it's actually a toxic or metabolic etiology for the rhabdomyolysis. And as part of this article, there's also an acronym that's now being used to identify those patients who would benefit from genetic testing. The acronym is called RHABDO. It's as is the word, RHABDO. R refers to Recurrent exertion of rhabdomyolysis. So, it's not just one episode. And the H refers to HyperCKemia, and the hyperCKemia should persist more than eight weeks after the episodes of rhabdomyolysis. And if it is exertional, then the person has not done an unaccustomed exercise. So, they have changed the way that they do exercise and now they are exercising for two hours instead of one hour or they have introduced a new way of exercise into their exercise regimen. Then that should not be considered. It's not considered necessary to test these patients for a genetic cause. Also, the muscle enzyme typically, in genetic causes of rhabdomyolysis, goes more than fifty times above the upper limit of normal, which is more than a thousand. So that has to be taken into account. And then for the D it's Drugs and medications. This has to be ruled out before you say yes, we need to find the genetic cause of rhabdomyolysis. And then the O, it's basically family history. If you find that there is other family members who are affected or they have a high CK, then of course that would point you toward doing genetic testing. Dr Monteith: Great. So, it sounds like there's some advances there in how we approach these patients. In what way is this practice changing? You mentioned, you know, really important to rule out these potentially reversible causes first. Dr Kushlaf: Yeah. So, once you identify the theology, it becomes easier to manage the patient. So, if it is a statin-induced rhabdomyolysis, you know that you want to stop the statin and you are not going to have this problem again. So, that's quite important. The statins, of course, will have to not be reintroduced in the future for that specific patient who developed statin-induced rhabdomyolysis. But for the genetic causes of rhabdomyolysis, if you go down the path of genetic rhabdomyolysis, of course we have no cures for these disorders. We may have treatments. One of the conditions that I have alluded to as one of the case presentations in the article is a patient who has riboflavin responsive multiple acid CoA dehydrogenase deficiency, and I wanted to highlight this disorder because it's a disorder not to be missed. It does have a treatment, which is riboflavin, and that comes from the name riboflavin-responsive. So that's why I put there in the article as part of the manuscript. However, some of these disorders, once you find the genetic etiology, there may be a way of preventing it in the future generation. Family planning, reproductive medicine technologies, can help in this instance and prevent this disease from occurring in the future generations. Dr Monteith: So, why don't we move on to episodic skeletal disorders? What is your general approach for these types of diseases? Dr Kushlaf: Muscle channelopathies, skeletal muscle channelopathies, are ultra-rare disorders. And part of the issue is not giving them a high index of suspicion in the diagnostic process. So, these patients typically come to us in clinics with very vague symptoms, and they may have lived with these symptoms for a very long time. So, they may have muscle pain, they may have fatigue, they may have muscle stiffness. Even though in most instances they do not tell you that they have muscle stiffness, they will tell you that when I wake up in the morning, I feel like I walk like a robot. My legs feel rigid, something like that. The word stiffness is not usually in the vocabulary of patients. When they come to see you and you examine them and you find out that the muscle strength is normal, you may not think much about the myotonic disorder. And that's where the issue is. You always have to keep these disorders in your differential diagnosis. So, you elicit for myotonia and for paramyotonia on examination, look at the muscle size, see if there is any muscle hypertrophy that happens in fluoride channelopathies, and that will typically guide you toward the diagnosis. And also ask about whether their symptoms get worse in a cold environment. So, sometimes they tell you they don't like winter because during winter everything is not doing well. They may report that they even feel like they cannot move their face because of facial stiffness in wintertime, especially in states where it snows outside and patients will be walking outside. So, these are things, typically, that give you clues about the diagnosis. But in patients who are affected minimally with the disease, sometimes you do not catch them, really, till they come to the EMG lab because of another reason. If they develop a neck pain and someone thinks that they may have a cervical radiculopathy and they want to do an EMG on them, or if they develop carpal tunnel symptoms, they send them to the EMG lab for carpal tunnel. And the moment we see them in the EMG lab, we start doing the needle examination and we find out that there is myotonic discharges in every muscle that we stick with the needle. And we're like, well, this person must have a myotonic disorder. And you ask them more about their symptoms. They may have symptoms, but they will tell you that they have ignored them for too long because it's something that they live with throughout their lives since childhood. They thought this is what is normal for them and this is what normal people might have. They may have aches and pains here and there and that is normal. So, these are clues, typically, for the diagnosis. Once you find the myotonia, your next bet to identify the exact genetic abnormalities to do genetic testing. And nowadays I think the field has benefited from the availability of free genetic testing so we can find out which channel is affected and then move on toward freezing that disorder. Dr Monteith: So, you spoke about nondystrophic myotonia. What are some bedside tips to try and really get at the diagnosis? Dr Kushlaf: So as I said, first is, look at the muscle build of the patient. So, these disorders, chloride channelopathies---so, the autosomal dominant and autosomal recessive chloride channelopathies---can cause muscle hypertrophy. So, these patients can have an athletic appearance even though when you ask them, do you exercise? I don't exercise at all. Do you lift weights? I don't lift weights at all. And they look like bodybuilders, so that's something to think about. Also eliciting the myotonia and typically we elicit the myotonia by using, of course, the reflex hammer. You can either tap on the phenol eminence and notice the myotonia in the thumb as it moves inward and stays in that position for some time. Depending on the severity of the myotonia, you can tap on the extensor digitorum in the forearm and notice the middle finger as it gets up and gets stuck for some time before it goes down. You can also ask patients to squeeze your fingers and then release quickly. Squeeze forcefully, of course, and find out how long does it take them to release their fingers, and that way you can identify the myotonia. Also, you may need to repeat the elicitation of myotonia several times because it can be not myotonia but paramyotonia, which is the opposite of myotonia. It's basically worsening of the myotonia as you keep doing the eliciting activity. So, the more they squeeze your fingers, the more difficult it is for them to improve. While the warm up phenomenon, which is the opposite of paradoxical myotonia, is, for them, as they repeat squeezing, they are able to do it better and better. They would be able to release more quickly with each attempt. In some patients, you can also ask them to close their eyes if they have facial myotonia, to close their eyes forcefully and see how quickly does it take for them to open their eyes. You may see that they do not open their eyes quickly. Or if you repeat in patients with paramyotonia, if you ask them to close and open, close and open, close and open, there will come a point where they really cannot open their eyes anymore, and that tells you there is paramyotonia. Of course, if you find paramyotonia, then you know that this is a sodium channel abnormality, that the genetic testing would just confirm that. Dr Monteith: And what about for periodic paralysis? Is there anything new in the field? Dr Kushlaf: Periodic paralysis… if I can say one thing about periodic paralysis, it's to talk about Andersen Tawil syndrome. It's an ultra-rare disorder also, but the episodes of paralysis that happens in patients with Andersen Tawil syndrome, they occur either with hypokalemia, so it can be hypokalemic---like, exactly hypokalemic periodic paralysis---or with hyperkalemia. So, it's hyperkalemic periodic paralysis. It doesn't really matter whether it's hyperkalemic or hypokalemic. These patients they typically have dysmorphic features. And the most common dysmorphic feature, and I chose a picture for the article, is a patient who has a small mandible. That is the most common dysmorphic feature. There are other dysmorphic features which include short stature, hypertelorism---which is the distance between eyes, the eyes become widened. Also, scoliosis and low-set ears. So, the ears are lower than the level of the eyes. So, these are dysmorphic features one can look for, but they do not exist in every patient with Andersen Tawil syndrome. The problem with Andersen Tawil syndrome is that these patients, as opposed to hyperkalemic and hypokalemic periodic paralysis, they have cardiac involvement. And the cardiac involvement can be deadly. So, it's very important that these patients are identified quickly. And anyone who has episodic weakness should have an EKG and should have halter monitoring to recognize if there are any arrhythmias or EKG abnormalities. So, one can identify anything that needs to be corrected from the cardiac standpoint. I think that is the most important point about periodic paralysis. Overall, these disorders… I mean, they are disabling and they can have huge effect on patient's life in terms of productivity and employment. And the diagnosis can be very difficult, especially that we do not know all the genes that are associated with periodic paralysis. Right now, the genetic testing that's available to us includes five genes that are associated with periodic paralysis. But I think we need to know more. There's a proportion of patients who do not have an identifiable abnormality at this time. So, I think as time goes on, we'll recognize more causes for periodic paralysis. Dr Monteith: I'm just reading your really great article, and it sounds like there's a lot of variability in presentation from I'm not feeling that well or I'm not feeling my best for mild disease, and then very severe disease where the whole body can be weak without alteration in consciousness. Dr Kushlaf: That's correct. So, my patients tell me that you never know when you're going to develop episodes of weakness. And sometimes they can recognize the precipitant, sometimes they cannot. Stress, sometimes, is a precipitant. At times, they really cannot tell what happened. And the weakness can be affecting one limb or more than one limb. It can be isolated to an arm or isolated to one leg. And that is the issue with the diagnosis, is that for those who do not suspect periodic paralysis, they are labeled as a functional neurologic disorder and they do not get the care that they need. I'm hoping that this article will shed a light on how to think about these disorders and how to diagnose them because treating them can have a significant impact on patient's life. Dr Monteith: How useful are these laboratory tests? Dr Kushlaf: So, in any patients where I suspect periodic paralysis, I would always do thyroid function testing to rule out hyperthyroidism because it can cause episodes of paralysis similar to hyperkalemic and hypokalemic paralysis. And I also do EKG and halter monitoring to make sure that I'm not missing the cardiac manifestations of Andersen Tawil syndrome. On top of that, then I would do genetic testing. And the genetic testing, as I said, at this time includes five genes. So, we will recognize any genetic abnormality that comes on that genetic testing. And if it is negative and I still have a high suspicion for the disease, I will do a long exercise test. The long exercise testing is, we record from a muscle in the hand---it's called the productive digit minimi---and stimulate the unknown nerve. We record, typically, baseline responses and then exercise the muscle for five minutes and keep recording after five minutes of exercise for up to forty minutes after. We're looking for a change in the amplitude of the motor response that typically happens over time. Dr Monteith: Great. Well, thank you so much for being on our podcast. Dr Kushlaf: I appreciate it. Thank you very much. Dr Monteith: Again, today I've been interviewing Dr Hani Kushlaf, whose article on episodic skeletal muscle disorders, muscle channelopathies, and rhabdomyolysis appears in the most recent issue of Continuum on muscle disease. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining today. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Inflammatory myopathies are a large group of disorders associated with an inflammatory response targeting skeletal muscle. Treatment hinges on the use of evolving immunotherapies and diagnostic tools to quickly identify inflammatory myopathy, initiate appropriate therapy, and exclude underlying malignancy or infection of other organs. In this episode, Katie Grouse, MD, FAAN speaks with Anthony A. Amato, MD, an author of the article "Idiopathic Inflammatory Myopathies" in the Continuum® October 2025 Muscle and Neuromuscular Junction Disorders 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. Amato is the Brigham and Women's Hospital Distinguished Chair in Neurology and the director of neuromuscular research at Mass General Brigham, and is a professor of neurology at Harvard Medical School in Boston, Massachusetts. Additional Resources Read the article: Idiopathic Inflammatory Myopathies 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. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Grouse: This is Dr Katie Grouse. Today I'm interviewing Dr Anthony Amato about his article on idiopathic inflammatory myopathies, which he wrote with Dr Kian Salajegheh. This article appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Welcome to the podcast, and please introduce yourself to our audience. Dr Amato: Thank you. And I am Tony Amato. I'm in Boston at Mass General Brigham. Dr Grouse: It is a distinct pleasure to have you here with us today, and I'm really excited to talk with you about your article. I thought it was a fantastic overview of the subject. And I'd like to start by asking what you hope will be the key takeaway for those who are reading this article. Dr Amato: I think it's kind of basic: how to make a diagnosis, describe about the inflammatory myopathy as approach to, again, diagnosis, and then a little bit on pathogenesis, which… and kind of leading to the treatments, and hopefully we'll have more treatments based on the distinct pathogenesis in the future. Dr Grouse: Can you give a brief overview of the categories of inflammatory myopathies you reviewed in your article? Dr Amato: So, I mean, the major inflammatory myopathies, radiopathic inflammatory myopathies, are dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy, inclusion body myositis, and polymyositis. Now, that's been a big change, as you know. I mean it used to be, you know, we all started off it was dermato or poly. But I've kind of made a name for myself- a bad name for myself in the early 2000s saying, I'm not sure there's much of a thing called polymyositis. I think it's a hodgepodge and it's not distinct. And that's come to be, now most of those cases are- now we find out having antisynthetase syndrome or necrotizing myositis or IBM. Dr Grouse: Could you walk us through your diagnostic approach with a patient in your clinic presenting with symptoms that are suspicious for inflammatory myopathy? Dr Amato: So, you want to really make sure that they have inflammatory myopathy as opposed to some other kind of myopathy, a muscular dystrophy, for example. Taking family history first is going to be important, clueing in are they really weak or what they're complaining of is fatigue or muscle pain? Are they feel weak but what they really are complaining of is stiffness and rigidity from parkinsonism, or they have a sensory ataxia so they can't modulate? I want to know about other organ system involvement. Do they have a rash? Do they have joint swelling and pain that you might see with arthritis? Do they have shortness of breath that you might see with interstitial lung disease or ventilatory muscle weakness? Or do they have a cardiomyopathy? What kind of weakness do they have? Is it proximal weakness in the arms or legs? Getting out of a chair, climbing stairs. Do they have problems lifting their arms over their head---so, proximal weakness---or do they have more problems with grip, finger flexion, holding a pen, tripping? Do they have swallowing problems? Do they have ocular problems? So that's the big history on the exam. Again, I'm looking for pattern of involvement. So, on my exam, is there atrophy or weakness in muscles---you know, fasciculations---which would take it out of the motor? Is it mainly proximal? Is it distal? Again, is there ocular bulbar involvement? Is it symmetric, particularly in, like, the IBM? Most of the other inflammatory myopathies are going to be mainly and proximal and mainly symmetric. IBM is different, and that the- at least in the hands it's more distal, and it's finger flexors. So, you're looking at flexing the tips of the fingers, you're looking at the forearms, best looked at in a semipronated position to see if it's atrophied. And that leads you to an IBM if you see that. So that's the main things on exam. Dr Grouse: That's a really helpful overview. I was wondering, in earlier training days, the convention was you- once you've suspected myopathy, you get your CK, you get your EMG, then that may give you the information you need for your diagnosis. It seems that things have been turned a little on their head. We're often skipping those things to go straight to the antibody testing. When should we be going for the myositis-specific antibodies before considering other things like EMG or muscle biopsy? Dr Amato: I would always get a CK first. You know, in somebody who's weak. You know, the EMG, I don't need an EMG if the CK is two or three thousand. I mean, EMG is- localize it to, is it muscle, nerve, neuromuscular junction. If it's very elevated CK, it really doesn't help me there.  Sometimes if I have myotonic discharges or something that might make me think of a myotonic dystrophy or something else like that. But you can see that with the inflammatory myopathy. So, if I'm pretty sure of a myositis, I don't always do an EMG, or- unless I really need it to help guide what muscle biopsies I do. if I'm suspicious then on my exam and I see the CK---or they come to me already with the CK, which often happens, and it's very elevated---that's when I'll do the myositis-specific antibody panels if I'm really thinking that. And the important thing to know from that is, you have antibodies for dermatomyositis and antisynthetase that are on the panel that are available, and even signal recognition particle, which is a necrotizing myositis. But what's not on the panel is HMGCR antibodies, which is important because that's 70% of the necrotizing myocidites are HMGCR, and then the IBM antibody and T5-C1A is not on that. So, you need to order those separately. If somebody doesn't know, they order a myositis-specific antibody and think that it's all-inclusive, but it doesn't have IBM or the HMGCR antibody. And the other test that I sometimes will do is a skeletal-muscle MRI to help in the evaluation. Sometimes, not all the time, but I'm not sure it's a dystrophy, is it a myositis when I see a lot of STIR signal, which is edema. And you can still see STIR signal in a dystrophy and toxic. But sometimes I'll do it depending on whether I need a biopsy or not. Dr Grouse: What is the benefit of an open biopsy versus a needle biopsy, and when should we be considering using one over the other? Dr Amato: So, it really is not our decision. It's the pass lab. So, it's the technicians and the pathologists who read the biopsies need to be able to process a needle biopsy, which might be much smaller. Needle biopsies show to be fairly accurate in a lot of the hereditary disorders where you might just look for central nuclear core, and they might be- so, mainly in kids, but in the inflammatory myopathies, it's really patchy. So, if I'm thinking of an inflammatory, I like an open biopsy. I think it's hit and miss. And so, I like open biopsies for the adults that I'm thinking of inflammatory. Dr Grouse: Do you have any other tips or tricks in the diagnosis of inflammatory myopathies that you could share with our listeners? Dr Amato: I would say first, in terms of what muscle to biopsy, you're not doing them yourself, but you're referring to a surgeon. You have to tell them what to do with the biopsy. And you want to pick a muscle that's about an MRC grade 4 because if it's a normal muscle, the muscle strength, the biopsy, is likely to be normal. If it's less than a 4, you might just have end-stage muscle. And saying you can't tell end-stage muscle from a bad myositis, from a dystrophy, from a severe end-stage neurogenic. If I don't have a muscle that I would typically biopsy that's an MRC grade 4---for example, somebody with an early weakness and they're only weak, say, in their in their hip girdle. So hip flexors, abductors, extensors, and we're usually not biopsying the iliopsoas or the gluteal muscles. Then what do you pick? That's when I like to do an EMG on one side of the body and look at proximal and distal muscles and select one that's irritable, you know, some fibs and positive sharp waves that I might biopsy. And then maybe consider doing a skeletal muscle MRI to go from muscle that's abnormal, that has a lot of edema in it, to increase the yield. Dr Grouse: That's really helpful. And then, I think, jumping from that, what are pitfalls that you've seen neurologists fall into in this diagnosis or other challenging aspects of the diagnosis that you could review with us? Dr Amato: Some of the things that we see are hard to pick up. It might be hard to pick up a rim vacuole. They're very rare, too. And so, you might miss it, particularly if you don't see a lot. Sometimes, like looking at the dermato and that's the, on the exam question, perifascicular atrophy, but that's a late stage, usually. And so, if you're really attuned and you're a good clinician, you make that diagnosis really quick. You do a biopsy, you might not see that paraphysical atrophy. So, they don't know that in a necrotizing myopathy, the pathologists often think of what they see in a toxic myopathy or a metabolic where there's a lot of necrotic fibers. But in most of the autoimmune necrotizing, it's not. It's actually what you see is more regenerating fibers, a few necrotic fibers. It's because it's usually been smoldering along for a while, and so you have many more regenerating fibers than ones that are actively, and that can fool a lot of people. So, that's a pitfall from that end of things. Some of these myositis specific antibodies aren't specific and at a low titer, particularly if you have more than one antibody being positive, that would be a red flag that it could be false. That's another pitfall. I think a lot of people don't, when they're examining people, really look at the finger flexors and stuff. And again, if I have somebody over the age of fifty, the most common muscle disease is IBM. Number two is IBM, number three is IBM. If you don't- and you have to think about that, and you need to examine the distal finger flexors because it doesn't get better with immunotherapy. You don't want to put people at the risk of immunotherapy when they're not going to get better. I talked a lot about the biopsies, and biopsy, biopsy, biopsy. But you know, sometimes you can make the diagnosis without a biopsy. So, if somebody's like a classic dermato rash and they have a dermato antibody, do they need a biopsy? No. If they have, you know, CKs of ten thousand proximal weakness, they're on a statin and they have HMGCR antibody, do they need us have a biopsy to confirm? Probably not. Dr Grouse: Those are some really great pearls that you've shared with us, and I think will be very helpful to many of our listeners. Now, you mentioned earlier about the diminishing category of polymyositis as other types of myosidites have been discovered and better described. Do you think that is the most controversial aspect of this field currently, or are there other controversial areas or areas of ongoing debate that exist? Dr Amato: It was very controversial twenty years ago, or maybe ten years ago. So, the rheumatology guidelines, they're the ones that are often saying, oh yeah, we were right. Polymyositis, it's just hodgepodge, and it's ever-shrinking. So that's not so controversial anymore. I mean, the controversies that we have, what's the pathogenesis of dermato? It's still a little debated, some- the old theory was that it was a complement-mediated microangiopathy and the damage was caused by ischemia. That's probably not the case. It looks more and more like it's a type 1 interferonopathy, and that's toxic to the vessels in the muscle. There's still a little bit of a debate about that or, you know, you have complement might be on it, but how much that might be damaging, or it's just a secondary phenomenon. I think in the antisynthetase things, I think there's some interesting things also with that these antibodies. We used to think of that they're just diagnostic biomarkers. But there's some recent studies suggesting that these antibodies which are directed against intracellular targets, which is interesting and applies to other autoimmune diseases and that are in the brain too. And we would think that, oh, if it's a intracellular target, it it's secondary. But there's suggestion now that- again, it did demonstrate that the antibodies actually get into muscle fibers. And they bind to these targets. So maybe they're just not epiphenomenon, but they might be binding to a target and causing pathology. And that's what there's some preliminary studies that are impressed, I will say, that have antibodies, anti-HMGCR, that actually go into the cell and they inhibit the enzyme. And that might be causing the pathology. And so that's interesting. And then IBM is a big field. Is this a primary autoimmune disease that has these other kinds of degenerative features like REM vacuoles, or is it a primary degenerative that has secondary inflammation, or is it a combination of both? So, that's probably the biggest controversy these days. It is probably with IBM. What the heck is causing it? Dr Grouse: Sounds like a lot that we still have to understand about these diseases. This does lead me to wonder, though, have some of these new discoveries and ideas led to or will lead to any new breakthroughs, either in diagnostics or in therapeutics? Dr Amato: So, certainly in therapeutics. So, the discovery of dermato being an interferonopathy, probably a beta-interferonopathy, has led to development of monoclonal antibodies that target interferon, and there's trials underway. And in phase 2 studies, I can tell you from talking to colleagues that participate just melted away the rash of dermato. So, I think that's going to be a very, very good drug in the future for dermato. There's others, like JAK. JAK inhibitors work on that interferon pathway too. So, I think we'll be going towards, like, less broad-spectrum steroids, IVIG, to going, let's go to the target. Certainly, in dermato, I mean, IBM, we don't know. There is an inflammatory cell that we see in IBM that has a receptor, KCRRN receptor, and there's a monoclonal antibody that targets that in IBM, and that's a phase 3 trial right now. Hopefully that study should be ending in December, and so early next year we'll have results about that. The fact that these antibodies might be pathogenic of themselves is other ways to get rid of the antibodies. So, getting rid of plasma cells and B cells, and FCRN receptors which have been approved or antagonists that are approved for myasthenia. Now CIDP might work in some of the inflammatory myopathies where we think the antibodies might be pathogenic. So, FCRN receptor antagonist and they're in trial now as well. And there's CAR-T therapies to knock out the antibody-producing lymphocytes and plasma cell. So, I think we're going to move into the field of individualized therapies as we find the distinct pathogenesis of these disorders. Dr Grouse: That's really exciting to hear and I can't wait to see what's coming down the pipeline as more of these discoveries are made and the clinical trials advance. It has been such a pleasure. I've learned so much. So much is packed into the article. So again, I can't stress enough, please take the time to check out this article. I think you'll learn a lot, and it'll really help you fine-tune your diagnostic pathway in relation to myopathies. Dr Amato: Oh, my pleasure. Thank you. Anybody has questions, please feel free to send me an email. Dr Grouse: We may just take you up on that. Again, today I've been interviewing Dr Anthony Amato about his article on idiopathic inflammatory myopathies, which he wrote with Dr Kian Salajegheh. This article appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining today. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Inclusion body myositis (IBM), the most common myopathy in adults, is a disease of aging characterized by slowly progressive weakness. Diagnosis of IBM requires the integration of historical, clinical, and laboratory data, while management consists of a multidisciplinary approach to address comorbidities and potential complications. In this episode, Aaron Berkowitz, MD, PhD, FAAN speaks with Elie Naddaf, MD, author of the article "Inclusion Body Myositis" in the Continuum® October 2025 Muscle and Neuromuscular Junction Disorders issue. Dr. Berkowitz is a Continuum® Audio interviewer and a professor of neurology at the University of California San Francisco in the Department of Neurology in San Francisco, California. Dr. Naddaf is an associate professor of neurology at the Mayo Clinic College of Medicine in Rochester, Minnesota. Additional Resources Read the article: Inclusion Body Myositis Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Guest: @ElieNaddaf3 Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Berkowitz: This is Dr Aaron Berkowitz, and today I'm interviewing Dr Elie Naddaf about his article on inclusion body myositis, which appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Welcome to the podcast, Dr Naddaf, and would you please introduce yourself to our audience? Dr Naddaf: Thank you for having me. I am Elie Naddaf, a neuromuscular neurologist at Mayo Clinic in Rochester, Minnesota, and one of my main focus research-wise is about inclusion body myositis. Dr Berkowitz: Fantastic. Well, this is a great article on inclusion body myositis, or IBM, as we may refer to it today. It has a lot of clinically practical tips for examining patients at the bedside and a lot of important updates for us on how to diagnose this condition. So, I encourage our listeners to check out the article, and I look forward to discussing some of the key aspects here and learning from your expertise. First, tell us about the classic presentation of IBM, when the disease is pretty easy to recognize at the bedside based on the history and exam. Dr Naddaf: Luckily, IBM is one of those diseases that has a very particular pattern of weakness that makes it easier to diagnose. However, in real life it can be very challenging for several reasons, which we will cover in this podcast and in the article. However, a typical presentation of IBM is that of an older patient, more likely to be a male---twice more likely to be a male---,presenting with slowly progressive weakness over a couple years or so. And the weakness predominantly affects the deep finger flexors in the hand. So, they most commonly present with hand grip weakness, or the quadriceps muscle presenting with some lower limb weakness. However, some patients can present with one or the other, not necessarily with both at the same time. It is usually a painless disease,, and because of the lingering course, patients tend to present within two to three years from their symptom onset. So, with that, on examination, if the patient is presenting with the hand weakness, they would demonstrate weakness in the deep finger flexors, which are the muscles that we use to flex the distal intralaryngeal joints. This weakness is often asymmetric and can be in only one hand; and also, even within the same hand, you can have a variable severity from one finger to the other. And that's one reason, although it sounds a classic phenotype, if you can imagine a patient just presenting with hand weakness, a lot of other things come to mind, whether it's a compressive neuropathy or whether it's a radiculopathy or motor neuron disease. Similarly, in the leg, the quadriceps is a big and strong muscle. So, it's often that patients' symptoms originally or in the beginning get dismissed because the physician did not demonstrate any weakness on manual motor testing. Because it's a strong muscle, it needs to lose a certain amount of strength to be able to demonstrate that weakness by just pushing against the patient trying to extend their knee from about a 90 degree or so. That's why another way in those cases would be to examine them more functionally whether they're kneeling or squatting. It is usually a pure motor disease, although patients can commonly have a peripheral neuropathy. But typically, on exam, you mainly see muscle weakness. Dr Berkowitz: Perfect. So, if we see a patient who's an older man with progressive painless weakness of the finger flexors, quadriceps, this is sort of the classic presentation where we would consider IBM. But you mentioned in your article that some patients can present somewhat atypically when we might not immediately think of this diagnosis. What are some of the atypical presentations we should be aware of that should lead us to think about IBM as a possible etiology for the patient's pattern of weakness? Dr Naddaf: So, IBM indeed can present in any muscle group. That's why about 14% of patients may have the weakness onset beyond the finger flexors or knee extensions. And there are very particular phenotypes that stand out. Especially the most common in that scenario would be patients presenting with pure difficulty swallowing, isolated dysphasia that can sometimes precede the limb weakness by several years, and that's especially common in females. Other phenotypes including just a proximal weakness, like a limb-girdle weakness; an axial weakness, for example, head drop or camptocormia or a foot drop. And because it's an asymmetric disease, you can see the challenge there---if someone just presenting with a foot drop on one side, that it could be challenging to just think of IBM. So, those are the main phenotype. One particular phenotype that is super interesting is, patients present with severe facial weakness as if they have severe bilateral Bell's palsy. And that's the, usually, the most common first misdiagnosis. And all these patients reported so far in the literature are only females. This has not been reported in any male patients. So yes, the finger flexor quadriceps weakness is the most common typical presentation. However, IBM can present, technically, in any other muscle in the body. Dr Berkowitz: Great. Well that's very helpful information that especially comes from experts like you who see a lot of these patients and are able to make these diagnoses of these rare phenotypes. Whereas many of us general neurologists, like myself, might think of IBM only with finger flexor weakness and quadriceps weakness, perhaps with some foot drop dysphagia associated. Sounds like this is a diagnosis to consider in atypical presentations or atypical presentations of myopathy that aren't fitting other phenotypes or aren't yielding diagnostic results for other phenotypes. And you have in your article a very helpful table that goes through some of the common sites of weakness in IBM and the differential diagnosis for myopathies and other conditions to consider in patients who have the classic and less typical presenting features. So, let's say that we see a patient with clinical features suggestive of IBM. How do we go about confirming the diagnosis? What are the main diagnostic tests we would use to try to make a firm diagnosis here? Dr Naddaf: So, the gold standard so far for diagnosis for inclusion body myositis, as it is an acquired disease, has been a muscle biopsy. So, muscle biopsy is the probably most important tool in the diagnostic approach to IBM. Even in patients with a classical phenotype, that all like in any other test, it depends on your pretest probability and how sure you are the patient has IBM. But even with the classic phenotype, it is characteristic of IBM, but not pathognomic of IBM. Because if we see a high number of patients with similar phenotypes, we will run into a lot of other disorder that present similarly. And some patients---especially for instance, with myotonic dystrophies, specially type two---may be very difficult to distinguish from IBM, especially those that present in adulthood that they don't have the classic picture of a myotonic dystrophy patient you would think of. And some of them may not even have percussion myotonia. Because of that, the biopsy is very important to confirm your diagnosis in that regard. And on the biopsy, you want to see evidence of inflammation, basically, and the mesial inflammation, without going into a lot of details, to set it apart from those genetic ones. But in IBM it's not a pure inflammatory disease. There are other features on the biopsy that are very particular to IBM, two main other things we need to find. One is that of the accumulation of autophagic vacuole and protein aggregates and that of mitochondrial dysfunction. So, the other test for patients, presenting with weakness---again that depends on your clinical suspicion---would be first to establish that the underlying process is a myopathy; and hence, the EMG. And also, that's particularly important in patient with symptoms in one limb to differentiate it from compressive neuropathies or from a motor neuron disorder or other. So, the EMG tells you it's a myopathy with fibrillation potential, helps you also choose a muscle for biopsy. So as far as blood tests, the main blood test is that of the cytosolic nucleosidase 1A, or people call them IBM antibody. That's present in about half of the patients with IBM, 50%. Specificity originally reported to be high in the 90s, but in real-life practice with commercial lab it's probably lower in the 70s. There is a growing interest in the use of muscle imaging as well and IBM is one of those diseases similar to the clinical phenotype that has some distinctive pattern on imaging on MRI. But again, like the clinical phenotype, it is helpful, it is characteristic. It's not diagnostic on its own. Other blood tests in IBM include creatine kinase level. As long as you're not seeing creatine kinase in the 10,000 or 20,000, that would be very unusual in IBM and other routine blood tests that are discussed in the article. Dr Berkowitz: Right. That's a very helpful overview of the testing we would consider when we're trying to make this diagnosis that can include, as you mentioned, EMG, muscle MRI, and this five-prime cytosolic nucleosidase 1A antibody. As you said, many of these have variable sensitivity and specificity. We can diagnose a myopathy generally, or muscle inflammation more specifically, using EMG and muscle MRI respectively. It's interesting to hear that that antibody, I know there was a lot of excitement about that originally. Sounds like less sensitive and less specific than one would have hoped. In your article, you discussed sort of how to use some of these tools to try to meet the diagnostic criteria that were updated in 2024 for diagnosing IBM. And correct me if I'm wrong, this is my first time reading about these. I want to make sure I understand that essentially, you always require a biopsy for definitive diagnosis of this disease. Is that right? Dr Naddaf: That's correct. That's because of the issues that you raised with the antibody and because, even with people with the classic phenotype, you still could have other diseases that can mimic IBM that are associated with different complications, comorbidity profiles. For instance, myotonic dystrophy requires very close monitoring of cardiac rhythm, which is usually not affected in IBM. Hence, there is still the need for a biopsy, as we don't have a better test so far. The antibody has its own challenging, but I still find it very helpful in certain situations, and that's also reflected in the new criteria. It's definitely not a standalone diagnostic test. I don't think you can just draw the antibody, if it's positive, tell the patient they have IBM. To me, it's helpful in two ways, at least in my practice. One way is, it makes me think of IBM in situations where I was not considering IBM. In the end IBM is the most common disease in adulthood, so it's not a bad habit to just check the antibodies in any unusual case. Or where inconclusive case, it's just me saying, huh, that could be IBM that I missed. Then I go and try to confirm it. The other scenario that it helps me, there are a lot of cases that remain inconclusive. For instance, you just saw inflammation on biopsy, you have some pattern on MRI. You just need another piece of information to further make the case for the diagnosis. And that's where I find the antibodies helpful. And that's reflected in the new criteria. Dr Berkowitz: I see. So, if you- Yeah, so just to pick up on the antibody here, since I'm sure people be interested in when or whether to send this. You sort of use this in atypical cases where you know it's a myopathy or not. You haven't yet made a diagnosis. And you think, well, if I send this and it's positive, that's not 100% specific, but going to tip me a little more towards thinking this could be an atypical IBM case. But if it's negative, it doesn't sort of tell you either way, since you said it's only about 50% sensitive, right? Am I understanding correctly how you use the antibody? Dr Naddaf: Yes, this is correct. So basically, you don't have to check it if you think it is IBM; that also depends on your style of practice. To me, I think at some stage, with all the progress we're seeing in research in systems biology, so far there's no indication that the antibody predicts severity, and I don't think it does. But there could be at some time down the road that there are different underlying pathways or disease mechanisms that are associated with people that have the antibodies. So, it's more like for the future, it's good to know if the patient is positive or not. Dr Berkowitz: Okay. So, if biopsy is really necessary to make this diagnosis, if you see a classic presentation with an older man, as we've said before, with slowly progressive painless finger flexor weakness and quadriceps weakness, do we even need EMG or muscle MRI or this antibody or do you just go straight to biopsy in those cases when the clinical phenotype looks relatively certain? Do you still think one or more of those tests are helpful in the classic presentation? Or are those EMG, muscle MRI, and the antibody ones used more when you think, this looks sort of like IBM but it's either it's maybe early and it's not sort of fully kind of developed into the classic phenotype or it's very asymmetric, which you can see in IBM, or whether it's sort of has more atypical features or only one of the classic features? How do you use EMG muscle MRI in the antibodies when you know you're going to need biopsy ultimately, if this is the diagnosis you have in mind? Dr Naddaf: That's a great question. And all of the above would be correct depending on the setting you practice in. If I were practicing in a community where I have the privilege to do things step by step, I might approach it a little bit differently. Being at the referral center with many patients coming with a one-stop shop and they need to do everything possible rather than returning, that's also another different practice scenario. But in general, you want the EMG if you're not sure it's a myopathy, especially that these patients are asymmetric and sometimes the findings are in a single limb. So, you would want the EMG when you're not sure it's a myopathy, or also you need a little bit more information on what muscle to biopsy, you could use the EMG. If those questions have already been answered, you don't have to do the EMG. Now regarding the biopsy, if it is the classic phenotype and you think it's going to be a bingo with the biopsy, you might not need to do any antibody or MRI or any further testing. Now with one caveat that the biopsy might not give you the full picture or all the features, then you could go back and do the rest. And that's actually all integrated in the new criteria. So, in the new 2024 revised European Neuromuscular Center diagnostic criteria for IBM, the main differences are the following: now you can use additional test measures to support the diagnosis in addition to the biopsy. So that will probably reduce the need to have a repeated muscle biopsy. Two, you could have an atypical form and still have the diagnosis. You don't have to wait until your finger flexor or knee extensors are involved. And that's very important also, because criteria generally are made for clinical trials where you want to know for sure who you are treating. But at the same time, you don't want to wait till advanced stages of the disease where treatments might not work. Diagnostic criteria are not made to be used in clinical practice, but at the same time they offer a good framework, a good suggestion for people to use in their clinical practice. And just always remember to tailor it to your particular patients that you're seeing. In those criteria, basically, we go by scenario depending on your level of suspicion. There is no possible probable. You either make the diagnosis or you don't make it. And as you said, if you have a classic phenotype patient with deep finger flexor weakness in the upper limb and knee extends her weakness in the lower limb, your pretest probability is very high, and the chances that you're wrong are low. They're not zero, they're low. That's why I was just showing in the mesial inflammation on the biopsy, which would rule out your genetic mimicor. You're pretty confident of the diagnosis. And the other scenarios, then let's say you have only one limb, then you need a little bit more support. And you have an atypical form where the differential is very wide. You want to provide more supportive criteria, and the supportive criteria could be other features in the biopsy, whether it's the CCO negative fibers or derma vacuoles, or you could use MRI and antibodies if they're available to you. In many countries, these are still not available, but if they're available, that's good. You could use them as supportive criteria. That was the logic behind those revised criteria that are discussed by scenario in detail in the article. Dr Berkowitz: Fantastic. That's very helpful. Yeah, as you mentioned this- the criteria reviewed in the article, you have a very helpful figure there with all the branch points of how to get to the diagnosis, but very helpful to hear how you think about combining these tests in practice in different scenarios to get to the final diagnosis. So, IBM is considered an inflammatory myopathy, right? Like dermatomyositis and antisynthetase syndrome and immune-mediated necrotizing myopathy. And yet it gets its own separate article each time we do a Continuum issue on muscle disorders, right? Because it's unique in that it doesn't respond to any immune- immunomodulatory or immunosuppressive therapy like these other inflammatory myopathies. So why do you think, or why is it thought by experts in the field like yourself, that this is an inflammatory myopathy but it, at least from a treatment perspective, appears to behave so differently from the other inflammatory myopathies and doesn't respond to immunomodulatory therapy---or at least we haven't found the right key in the right block of immunomodulatory therapy to treat this disease? Dr Naddaf: That's a great question, and it's an area that I'm particularly interested in from a research standpoint. So, all these entities were classified as idiopathic inflammatory myopathies because they had inflammation on muscle biopsy. And IBM does have inflammation on muscle biopsy. Even when we study gene expression, all the immunoglobulin, interferon-related genes, the data are very, very highly expressed in IBM. However, IBM histopathology is not just inflammation. There are other features of IBM that are shared with other diseases of aging, and IBM only affects the aging population. So, by definition it is a disease of aging, and it shares a lot of similarities with other diseases of aging such as Alzheimer's disease or Parkinson's disease or those others that occur with aging. And IBM, unlike any other idiopathic inflammatory myopathy, it is twice more common in males and does not have a juvenile form. Taking all of this together, we could argue that IBM is a disease of aging, and those diseases usually are very complex and have involvement of different pathways---including but not restricted to inflammatory pathways, disrupted protein homeostasis, mitochondrial abnormalities and so on and so forth. And that's why so far we have not had any luck with any immunosuppressive or immunomodulatory therapy in IBM. Now the type of inflammation in IBM is also different, that's mediated by highly differentiated cytotoxic CD8 cells that may not respond to the other treatment. But again, IBM is not just inflammation, and unfortunately in these complicated disorders, we're still at early stages of understanding them, let alone intervene on them. There have been a lot of progress in the last few years in the area of aging in general, and hopefully we would see some new developments in IBM and in other diseases that would help at least slow down the progression. Dr Berkowitz: Fantastic. Well, we've only gotten an opportunity to scratch the surface of your article today talking about the clinical presentation, diagnosis, and a little bit about some of the challenges in treatment. But there's a lot more for our listeners to refer to in your article related to some of the aspects of management, not yet a disease-modifying therapy, but other important aspects of management and many other clinical pearls in this article. So, I encourage our listeners to take a look at your article in this issue. Dr Naddaf: Thanks a lot. Dr Berkowitz: Again, today I've been interviewing Dr Elie Naddaf about his article on inclusion body myositis, which appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Be sure to check out Continuum Audio episodes from this and other issues, and thank you again 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 the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Limb-girdle muscular dystrophies (LGMDs) encompass a group of genetically heterogeneous skeletal muscle disorders. There has been an explosion of newly identified LGMD subtypes in the past decade, and results from preclinical studies and early-stage clinical trials of genetic therapies are promising for future disease-specific treatments. In this episode, Gordon Smith, MD, FAAN, speaks with Teerin Liewluck, MD, FAAN, FANA, author of the article "Limb-Girdle Muscular Dystrophies" in the Continuum® October 2025 Muscle and Neuromuscular Junction Disorders issue. Dr. Smith is a Continuum® Audio interviewer and a professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia. Dr. Liewluck is a professor of neurology at the Division of Neuromuscular Medicine and Muscle Pathology Laboratory at Mayo Clinic College of Medicine in Rochester, Minnesota. Additional Resources Read the article: Limb-Girdle Muscular Dystrophies 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: @TLiewluck Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Smith: This is Dr Gordon Smith with Continuum Audio. Today I'm interviewing Dr Teerin Liewluck, a good friend of mine at the Mayo Clinic, about his article on the limb girdle muscular dystrophies. This article appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders, a topic that is near and dear to my heart. Teerin, welcome to the podcast, and maybe you can introduce yourself to our listeners. Dr Liewluck: Thank you very much, Gordon, and I want to say hi to all the Continuum fans. So, I'm Dr Teerin Liewluck, I'm the professor of neurology at Mayo Clinic in Rochester, Minnesota. So, my practice focus on all aspects of muscle diseases, both acquired and genetic myopathies. Glad to be here. Dr Smith: I just had the great pleasure of seeing you at a seminar in Houston where you talked about this topic. And so, I'm really primed for this conversation, which I'm very excited about. I find this topic a little hard, and I'm hoping I can learn more from you. And I wonder if, as we get started, recognizing many of our listeners are not in practices focused purely on muscle disease, maybe you can provide some context about why this is important for folks doing general neurology or even general neuromuscular medicine? Why do they need to know about this? Dr Liewluck: Yes, certainly. So, I would say limb girdle muscular dystrophy probably the most complex category of subgroup of muscle diseases because, by itself, it includes thirty-four different subtypes, and the number's still expanding. So, each subtype is very rare. But if you group together, it really have significant number of patients, and these patients present with proximal weakness, very high CK, and these are common patients that can show up in the neurology clinic. So, I think it's very important even for general neurologists to pick up what subtle clues that may lead to the diagnosis because if we are able to provide correct diagnosis for the patients, that's very important for patient management. Dr Smith: So, I wonder if maybe we can talk a little bit about the phenotype, Terran. I mean, your article does a great job of going over the great diversity. And you know, I think many of us here, you know, limb girdle muscular dystrophy and we think of limb girdle weakness, but the phenotypic spectrum is bananas, right? Rhabdomyolysis, limb girdle distal myopathy. I mean, when should our listeners suspect LGMD? Dr Liewluck: Yes, I think by the definition to all the LGMD patients will have limb girdle of proximal weakness and very high CK. So, these are common phenotypes among thirty-four different subtypes. But if it did take into details, they have some subtle differences. In the article, what I try to simplify all these different subtypes that we can categorize at least half of them into three main group that each group the underlying defect sharing among those subtypes and also translate into similar muscles and extra muscular manifestations. You will learn that some of the limb girdle muscular dystrophy may present with rhabdomyolysis. And we typically think of this as metabolic myopathies. But if you have a rhabdomyolysis patient, the CK remain elevated even after the acute episode, that's the key that we need to think this could be LGMD. That's for an example. Dr Smith: So, I wonder if maybe we can start there. I was going to go in a different direction, but this is a good transition. It's easy to see the opportunity to get confused between LGMD or, in that case, a metabolic myopathy or other acquired myopathies. And I think particularly adult neurologists are more accustomed to seeing acquired muscle disease. Are there particular clues that, or pearls that adult neurologists seeing patients with muscle disease can use to recognize when they should be thinking about LGMD given the diverse phenotype? Dr Liewluck: Yes. What I always tell the patient is that there are more than a hundred different types of muscle diseases, but we can easily divide into groups: acquired and genetic or hereditary. So, the acquired disease is when you encounter the patients who present with acute or subacute cause of the weakness, relatively rapidly progressive. But on the opposite, if you encounter the patient who present with a much more slowly progressive cause of weakness over several months or years, you may need to think about genetic disease of the muscle with also including limb-girdle muscular dystrophy. The detailed exam to be able to distinguish between each type of muscular dystrophy. For example, if proximal weakness, certainly limb girdle muscular dystrophy. If a patient has facial weakness, scapular winking, so you would think about facial scapular hematoma dystrophy. So, the slowly progressive cause of weakness, proximal pattern of weakness, CK elevation, should be the point when you think about LGMD. Dr Smith: So, I have a question about diagnostic evaluation. I had a meeting with one of my colleagues, Qihua Fan, who's a great peripheral nerve expert, who also does neuromuscular pathology. And we were talking about how the pathology field has changed so much over the last ten years, and we're doing obviously fewer muscle biopsies. Our way of diagnosing them has changed a lot with the evolution of genetic testing. What's your diagnostic approach? Do you go right to genetic testing? Do you do targeted testing based on phenotype? What words of wisdom do you have there? Dr Liewluck: Yes, so, I mean, being a muscle pathologist myself, it is fair to say that the utility of muscle biopsies when you encounter a patient with suspects that limb girdle muscular dystrophy have reduced over the year. For example, we used to have like fifteen, seventeen hundred muscle biopsies a year; now we do only thirteen hundred biopsies a year. Yes, as you pointed out, the first step in my practice if I suspect LGMD is to go with genetic testing. And I would prefer the last gene panel that not only include the LGMD, but also include all other genetic muscle disease as well as the conjunctive myopic syndrome, because the phenotype can be somehow difficult to distinguish in certain patients. Dr Smith: So, do you ever get a muscle biopsy, Teerin? I mean you obviously do; only thirteen hundred. Holy cow, that's a lot. So, let me reframe my question. When do you get a muscle biopsy in these patients? Dr Liewluck: Muscle biopsy still is present in LGMD patients, it's just we don't use it at the first-tier diagnostic test anymore. So, we typically do it in selected cases after the genetic testing in those that came back inconclusive. As you know, you may run into the variant of unknown significance. You may use the muscle biopsy to see, is there any histopathology or abnormal protein Western blot that may further support the heterogenicity of the VUS. So, we still do it, but it typically comes after genetic testing and only in the selected cases that have inconclusive results or negative genetic testing. Dr Smith: I'd like to ask a question regarding serologic testing for autoantibodies. I refer to a really great case in your article. There are several of them, but this is a patient, a FKRP patient, who was originally thought to have dermatomyositis based on a low-titer ME2 antibody. You guys figured out the correct diagnosis. We send a lot of antibody panels out. Wonder if you have any wisdom, pearls, pitfalls, for how to interpret antibody tests in patients with chronic myopathies? We send a lot of them. And that's the sort of population where we need to be thinking about limb-girdle muscular dystrophies. It's a great case for those, which I hope is everyone who read your article in detail. What do you have to say about that? Dr Liewluck: Yes, so myositis antibodies, we already revolutionized a few of muscle diseases. I recall when I finished my fellowship thirteen years ago, so we don't really have much muscle myositis antibodies to check. But now the panel is expanded. But again, the antibodies alone cannot lead to diagnosis. You need to go back to your clinical. You need to make sure the clinical antibodies findings are matched. For example, if the key that- if the myocytes specific antibodies present only at the low positive title, it's more often to be false positive. So, you need to look carefully back in the patient, the group of phenotypes, and when in doubt we need to do muscle biopsies. Now on the opposite end, the other group of the antibody is the one for necrotizing autoimmune myopathy; or, the other name, immune-mediated necrotizing myopathy. This is the new group that we have learned only just recently that some patients may present as a typical presentation. I mean, when even thinking about the whole testing autoimmune myopathy, we think about those that present with some acute rapidly progressive weakness, maybe has history of sudden exposures. But we have some patients that present with very slowly progressive weakness like muscular dystrophies. So now in my practice, if I encounter a patient I suspect LGMD, in addition to doing genetic testing for LGMD, I also test for necrotizing doing with myopathy antibodies at the same time. And we typically get antibody back within what, a week or two, but projected testing would take a few months. Dr Smith: Yeah. And I guess maybe you could talk a little bit about pitfalls and interpretation of genetic tests, right? I think you have another case in your article, and I've certainly seen this, where a patient is misdiagnosed as having a genetic myopathy, LGMD, based on, let's say, just a misinterpretation of the genetic testing, right? So, I think we need to think of it on both sides. And I like the fact that the clinical aspects of diagnosis really are first and foremost most important. But maybe you can talk about wisdom in terms of interpretation of the genetic panel?  Dr Liewluck:Yes. So genetic testing, I think, is a complex issue, particularly for interpretation. And if you're not familiar with this, it's probably best to have your colleagues in genetics that help looking at this together. So, I think the common scenario we encounter is that in those dystrophies that are autosomal recessive, so we expect that the patient needs to have two abnormal copies of the genes to cause the disease. And if patients have only one abnormal copy, they are just a carrier. And commonly we see patients refer to us as much as dystrophy is by having only one abnormal copy. If they are a carrier, they should not have the weakness from that gene abnormality. So, this would be the principle that we really need to adhere. And if you run into those cases, then maybe you need to broaden your differential diagnosis. Dr Smith: I want to go back to the clinical phenomenology, and I've got a admission to make to you, Teerin. And I find it really hard to keep track of these disorders at, you know, thirty-four and climbing a lot of overlap, and it's hard to remember them. And I'm glad that I'm now going to have a Continuum article I can go to and look at the really great tables to sort things out. I'm curious whether you have all these top of mind? Do you have to look at the table too? And how should people who are seeing these patients organize their thoughts about it? I mean, is it important that you memorize all thirty-four plus disorders? How can you group them? What's your overall approach to that? Dr Liewluck: I need to admit that I've not memorize all twenty-four different subtypes, but I think what I triy to do even in my real-life practice is group it all together if you can. For example, I think that the biggest group of these LGMD is what we call alpha-dystroglycanopathies. So, this include already ten different subtypes of recessive LGMD. So alpha-dystroglycan is the core of the dystrophin-associated glycoprotein complex. And it's heavy glycosylated protein. So, the effect in ten different genes can affect the glycosylation or the process of adding sugar chain to this alpha-dystroglycan. And they have similar features in terms of the phenotype. They present with proximal weakness, calf pseudohypertrophy, very high CK, some may have recurrent rhabdomyolysis, and cardiac and rhythmic involvement are very common. This is one major group. Now the second group is the limb-girdle muscular dystrophy due to defective membrane repair, which includes two subtypes is the different and on dopamine five. The common feature in this group is that the weakness can be asymmetric and despite proximal weakness, they can have calf atrophy. On muscle biopsy sometimes you can see a myeloid on the muscle tissues. And the third group is the sarcoglycanopathy, which includes four different subtypes, and the presentation can look like we share. For the rest, sometimes go back to the table. Dr Smith: Thank you for that. And it prompts another question that I always wonder about. Do you have any theories about why such variability in the muscle groups that are involved? I mean, you just brought up dystroglycanopathy, for instance, as something that can cause a very distal predominant myopathy; others do not. Do we at this point now have an understanding given the better genetics that we have on this and work going on in therapeutic development, which I want to get to in a minute, that provides any insight why certain muscle groups are more affected? Dr Liewluck: Very good question, Gordon. And I would say the first question that led me interested in muscle disease---and this happened probably back in 2000 when I just finished medical school---is why, why, why? Why does muscle disease tend to affect proximal muscles? I thought by now, twenty-five years later, we'd have the answer. I don't. I think this, you don't know clearly why muscle diseases, some affect proximal, some affect distal. But the hypothesis is, and probably my personal hypothesis is, that maybe certain proteins may express more in certain muscles and that may affect different phenotypes. But, I mean, dysferlin has very good examples that can confuse us because some patients present with distal weakness, some patients present with proximal weakness, that's by the same gene defect. And in this patient, when we look at the MRI in detail, actually the patterns of fatty replacements in muscle are the same. Even patient who present clinically as a proximal or distal weakness, the imaging studies show the same finding. Bottom line, we don't know. Dr Smith: Yeah, who knew it could be so complex? Teerin, you brought up a really great point that I wanted to ask about, which is muscle MRI scan, right? We're now seeing studies that are doing very broad MR imaging. Do you use some muscle MRI very frequently in your clinical evaluation of these patients? And if so, how? Dr Liewluck: Maybe I don't use it as much as I could, but the most common scenario I use in this setting is when I have the genetic testing come back with the VUS. So, we look at each VUS, each gene in detail. And if anything is suspicious, what I do typically go back to the literature to see if that gene defect in particular has any common pattern of muscle involvement on the MRI. And if there is, I use MRI as one of the two to try to see if I can escalate the pathogenicity of that VUS. Dr Smith: And a VUS is a "Variant of Unknown Significance," for our listeners. I'm proud that I remember that as a geneticist. These are exciting times in neurology in general, but particularly in an inherited muscle disease. And we're seeing a lot of therapeutic development, a lot going on in Duchenne now. What's the latest in terms of disease-modifying therapeutics and gene therapies in LGMD? Dr Liewluck: Yes. So, there are several precritical and early-phase critical trials for gene therapy for the common lymphoma of muscular dystrophies. For example, the sarcoglycanopathies, and they also have some biochemical therapy that arepossible for the LGMD to FKRP. But there are many things that I expect probably will come into the picture broader or later phase of critical tryouts, and hopefully we have something to offer for the patients similar to patients with Duchenne muscular dystrophy. Dr Smith: What haven't we talked about, I mean, holy cow? There's so much in your article. What's one thing we haven't talked about that our listeners need to hear? Dr Liewluck: Good questions. So, I think we covered all, but often we get patients with proximal weakness and high CK, and they all got labeled as having limb-girdlemuscular dystrophy. What I want to stress is that proximal weakness and high CK is a common feature for muscle diseases, so they need to think broad, need to think about all possibilities. Particularly don't want to miss something treatable. Chronic, slowly progressive cause, as I mentioned earlier, we think more about muscle dystrophy, but at the cranial range, we know that rare patients with necrotic autonomyopathy and present with limb good of weakness at a slowly progressive cost. So, make sure you think about these two when suspecting that LGMD patient diabetic testing has come back inconclusive. Dr Smith: Well, that's very helpful. And fortunately, there's several other articles in this issue of Continuum that help people think through this issue more broadly. Teerin, you certainly don't disappoint. I enjoyed listening to you about a month ago, and I enjoyed reading your article a great deal and enjoy talking to you even more. Thank you very much. Dr Liewluck: Thank you very much, Gordon. Dr Smith: Again, today I've been interviewing Dr Teerin Liewluck about his article on limb-girdle muscular dystrophy, which appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Please be sure to check out Continuum Audio episodes for this and other issues. And thanks to our listeners for joining today. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy, affecting individuals across the lifespan with variable severity. Advances in genetic understanding and therapeutic development have led to an era of promising disease-modifying strategies. In this episode, Katie Grouse, MD FAAN, speaks with Renatta N. Knox, MD, PhD, author of the article "Facioscapulohumeral Muscular Dystrophy" in the Continuum® October 2025 Muscle and Neuromuscular Junction Disorders 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. Knox is an assistant professor of neurology in the Division of Pediatric Neurology and Neuromuscular Section at Washington University School of Medicine in St. Louis, Missouri. Additional Resources Read the article: Facioscapulohumeral Muscular Dystrophy 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. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Grouse: This is Dr Katie Grouse. Today I'm interviewing Dr Renatta Knox about her article on fascioscapulohumeral muscular dystrophy, which appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Welcome to the podcast, and please introduce yourself to our audience. Dr Knox: Hi Katie, thank you so much for the invitation for the audio interview. I'm looking forward to our conversation. As she mentioned, my name is Renata Knox. It's a pleasure to be here today. Dr Grouse: I'd like to start by asking, what is the key message that you hope your readers will take from your article? Dr Knox: I would say two things. The first is an appreciation and understanding of the unique genetic mechanism that leads to FSHD. And the second is the really exciting therapy landscape that we find ourselves in. So, we're hopeful that there will actually be disease-modifying therapies for FSHD soon. Dr Grouse: We're really looking forward to learning more about that. Now, before we get to that piece, could you just remind us of the clinical manifestations and features that are specific to FSHD? Dr Knox: So, one of the most unique things about FSHD that we see clinically is the pattern of weakness. So, one of the first features is that it's asymmetric. And then there are certain muscle groups that typically are affected, and that's partly where the name comes from. So, we see effects in the face, the limbs, the trunk; and so, those are some of the unique features that we see clinically. Dr Grouse: I'd love it if you could walk us through how you approach diagnosing a patient who presents with proximal weakness where FSHD is in your differential. Dr Knox: Yeah, it's a really great question. So, I would say it depends. So, I actually focus on FSHD in my clinical practice. So, many times patients are referred to me because there's a very high suspicion or there's a known family history of FSHD. So, that's one category of cases. I would say the other category of case is where it's, as you said, maybe more proximal weakness more broadly. Someone that's before me who has a known family history, they really have some of the characteristic physical features---which I'm pretty attuned to, as this is, you know, part of my subspecialty---I'll actually go directly to FSHD genetic testing. And that is one of the unique features of this disease, that the next-generation sequencing panels that are typically used for some of our other muscle diseases, FSHD is not captured on those. So, we actually have to send targeted testing for FSHD to diagnose it. So, that is one category where, again, I have a very high suspicion either based on their clinical presentation and/or a known family history, then I will actually go directly to FSHD-targeted genetic testing. In the second case, where it is one of the conditions that I'm considering among others, I will do more broad testing. So, I will get a CK level to see if there's evidence of muscle breakdown. I'll likely also do one of the next-generation sequencing panels that we have access to, which will allow us to identify, potentially, one to two hundred potential muscle diseases. And then again, if FSHD is higher on my differential in that second group of patients, then I will also send targeted FSHD-specific testing. Dr Grouse: That's really helpful. And I'm wondering if you have any thoughts about common pitfalls that you've seen when providers are trying to work this up? Dr Knox: I don't know if I would say pitfalls. I think I would acknowledge that it's challenging. My subspecialty training in neuromuscular medicine and also gene therapy. And so FSHD is pretty high on my radar. But I would say in neurology in general---and then, you know, the general medical population---,it really isn't something that many people are seeing. So, I would say what patients will communicate to us sometimes is some frustration that maybe it took time to make the diagnosis, but I just have a deep understanding that it's not something that is on many people's radars. And I think, again, it's tricky because it's not picked up on these next-generation sequencing panels, which many of us can send pretty easily. It will be missed. And I will say the biggest pitfall is, again, if you're not thinking about it and you don't send that testing, you actually- it's very difficult to diagnose it. Dr Grouse: Thank you so much for highlighting that. I think there are many people who are not aware that those different panels really aren't picking that up and that they have to test specifically. So, I think that's a great thing for all of us to keep in mind. Are there any tips or tricks to the diagnosis, other than the genetic issues that you mentioned, that sometimes can really bring this diagnosis to the forefront? Dr Knox: I think things that really tip me off to having a higher suspicion for FSHD is facial weakness that we can detect on our exam. Scapular winging---again, there's a small subset of disorders which can impact that. Someone who's presenting with foot drop, you know, with facial weakness, I think definitely about FSHD more. Also, clinically, kind of the presentation or things that they're beginning to have difficulty with is a tip-off. So, if someone is an athlete, like, they're a volleyball player or basketball player and they say, oh, I'm having difficulties, you know, with movements that require them to elevate their arm, which can be a sign of the shoulder weakness that we classically see. Or someone who says, oh, I'm having a harder time shampooing my hair or combing my hair. So those can be tip-offs again, which are basically referencing the type of weakness that they have. Another feature of FSHD which isn't necessarily as broadly appreciated is that pain and fatigue are very common. So, if someone is coming in and saying, actually, I also have a significant amount of fatigue as well or a lot of pain, that's something that can tip me off to it. Hearing loss is something that we can also see in up to 20% of patients with FSHD. So, if they are having those symptoms or saying they're ringing in their ears, these are some things that will make me begin to think about it more. Dr Grouse: Oh, really helpful. I also found it really fascinating reading some of the very FSHD-specific clinical signs, some interesting- some diagrams and pictures as well, that are very specific to the pattern of weakness that develops in FSHD. So, I encourage our listeners to check that out. But are there any highlights from those little clinical pearls that you'd like to point out? Dr Knox: I think the poly-hill sign---so, these are these literal hills that we can see in the shoulders of patients with FSHD---is pretty classic. Popeye arms, which is this older term that we still use that has to do with which muscle groups are preserved versus those that have atrophy. So that's a common feature. And then I would say, really, the asymmetry is something that is a unique feature in FSHD. And again, we did our best to provide good representative images. So again, as you mentioned, Katie, I would really encourage people to look at those images and then think about cases that they may have seen and how similar they are so they can begin to recognize those signs as well. Dr Grouse: Now going back to the genetic topic, the complex genetic underpinnings of FSHD are really well-explained in your article; and again, worth taking a look at to remind ourselves of everything that's of that pathology. Now, I was wondering though, if you could give us a brief overview of how we should approach genetic testing in a suspected case of FSHD? You mentioned some specific panels, but it does sound like there's some more complexity to it as well. Dr Knox: Yes, and I'll just kind of briefly explain that complexity. Part of the thing that we're detecting in the genetic testing is the repeat number. And so, we're actually looking for a contraction in a repeat number. So, not an expansion, which were typical for some of the diseases that we think about, the trinucleotide repeat disorders. And this is why it's not captured in the next-generation sequencing panels, because they do not currently have the ability to do that. And so, again, what the type of testing that I do really depends on my suspicion. So again, if my suspicion is very high for FSHD---they have a family history, they have the classic features---then I will actually go directly to an FSHD-specific testing, which is available from various sources. If, again, it's among different things that I'm thinking about, I will get a CK lab. I typically will also send a next-generation sequencing panel specific for muscle diseases, perhaps muscular dystrophy; again, depending on what I'm thinking about. And then I will also send in a specific FSHD genetic test as well. People are beginning to use whole-genome sequencing, which is capturing some of our true nucleotide repeat disorders and becoming more comprehensive. So, my hope is that as that becomes more standard of care---like, whole-exome sequencing can be gotten pretty routinely now---that it may be easier for us to make some of these diagnoses. Dr Grouse: Well, that's really helpful, and thanks for that overview. Now another thing that you mentioned that I thought was really interesting in your article was that patients with, you know, history of FSHD, perhaps in the family, who are pregnant and want to screen for this disease would not be able to use sort of the more common screening tests like cell-free DNA testing and may have to go to other means to do that. What is generally their route to this type of testing? Dr Knox: Yeah, great question, and really important question for family planning purposes, and it definitely comes up in clinical practice. And so again, because of the unique genetics of FSHD, you actually have to do invasive genetic testing currently to be able to test it. And so that's, you know, amnio or chorio, and then send it to a lab that can perform, again, FSHD-specific testing on the samples that are presented. And there are obviously labs that are capable of doing that and centers that are capable of doing that, but it is not picked up on the cell-free DNA panels that are being very routinely used. You or your provider has to be thinking about it to send that specific testing, similar to our patients that come into clinic and have not yet been diagnosed. Dr Grouse: Once you have the diagnosis, what are our options for therapy? I think it sounds like at this current time, it looks to be mostly supportive. What are some of the supportive care options we should keep in mind? Dr Knox: Yes, so that is definitely accurate. Care today is supportive, but again, we're very excited about the clinical trial and therapy landscape for FSHD. So, I work very closely with my physical therapy colleagues that are in clinic with me. So, we work very closely with physical and occupational therapists to help with supportive measures, adaptive measures, doing assessments, helping our patients to be able to move and exercise safely and effectively. As I mentioned, pain is very common in FSHD and so we can treat that with medications. The most common medication that we use to treat for pain in FSHD are NSAIDs. And then other than that it's really, you know, supportive measures. Do they need to see other subspecialists? There are some surgical options. Those are used very rarely to help with some of the scapular weakness, but typically it's physical therapy, occupational therapy, supportive devices. We treat the pain as we're able to, and then we work with other subspecialists to screen, monitor and support our patients to the best of our ability. Dr Grouse: Well, without further ado, I'd love to hear more about what's coming down the pipeline in clinical trials. What can we look forward to seeing, hopefully, in future years to treat these patients? Dr Knox: Yes. And so, this is actually what got me interested in the neuromuscle space in general is that, because we now for many years have known the genetic cause of many of these disorders as well as some of the underlying mechanisms, we can actually use advances in therapeutics to do what we call targeted therapies. So, rather than treating symptoms or indirect methods or doing kind of broad drug screens---which, again, still do take place and still do have their place---we actually can target mechanisms directly. And so, we know that the underlying biology of FSHD is due to this protein called DUX4 being expressed when it should not be. So, it's what we call a toxic gain of function. And so, the targeted way to address this is to suppress DUX4 expression. And so, kind of broadly speaking, what we're really excited about are a couple of products that are currently in clinical trials right now that actually caused DUX4 suppression to be suppressed. And again, these are targeted pathways. And so, again, the hope is that by doing that, we can hopefully slow the progression of the disease, potentially stop progression of the disease, and potentially reverse. Again, we don't know if that might be possible, but that is one of the hopes. Dr Grouse: Well, that's really exciting, and I know we're all looking forward to more coming down the pipeline soon, and hopefully more things that can really offer some exciting treatments for our patients with this condition. Now, a little more deep-dive into our patients who are diagnosed. You've reviewed some of the treatments currently available and hopefully may someday soon be available. Are there other things that we should be keeping in mind in this population? For instance, screenings that we should be doing for other extramuscular manifestations that we need to be thinking about? Dr Knox: I will answer that question two ways. I think something that's very important to acknowledge is the impact that these diagnoses and these conditions have on our patient practically, psychologically. One of the other unique features of FSHD is, it's autosomal-dominant. So, if it is in a family, you can have many family members who are affected, but the variability is very high. And so, you can have in the same family someone who is wheelchair-dependent, and someone else in the family with the same underlying genetics who has no signs or symptoms or is very mildly affected. And that is something that is definitely challenging for our families and patients to navigate if they're very different than their family members with the same condition. And just navigating the world with a condition that, you know, can be physically debilitating and cause changes to what they're able to do or not able to do, progression is something that's very difficult to handle. So, I think that's one set of things. And we try our best, you know, with my team and my other colleagues in the space, to support our families and patients in the best way that we can. Secondly, there is very important screening that needs to be done for this condition. So, one of the things- and the current guidelines which are actually being updated, the last update was in 2015 is all patients that undergo pulmonary function testing or PFTs. And so that's something we do at baseline and we do at least annually in my practice. Young kids who are presenting very early or patients with certain genetics that we know are more predisposed to extra muscular manifestations, we recommend screening for hearing, which is one of the manifestations, and ophthalmologic exam to look for retinovascular changes, which is one of the manifestations as well. Those are the more common ones that are typically done. There's also some evidence in pediatric patients with very severe manifestations that there may be some cognitive impacts, learning impacts. And so, that is something we're also thinking about screening and supporting our patients in that way. And again, we typically work with these patients in a multidisciplinary team depending on what manifestations and the degrees to which they're impacted by the disorder. Dr Grouse: Thank you so much for that answer. I think a lot of us forget sometimes when we get really focused on what can we do now, that we forget to kind of stop and reflect on sort of the more holistic approach. How is this affecting the patient? How is this affecting the patient's family dynamic, and what other ways are they going through life with this condition that we need to be thinking about? So, I appreciate you bringing that up. I wanted to ask, sort of based on what you're talking about and what you mentioned already, you happened to mention that what initially drew you that to this work was your interest in some of the really exciting breakthroughs in the field. Well, was there anything else that drew you to, specifically, congenital neuromuscular diseases, and FSHD in particular? Dr Knox: I'm a physician scientist by training, and so I would describe myself also as a molecular biologist. So, I love getting into the nitty gritties of disease mechanisms, what genes are doing in bodies, how they function. And so, as I mentioned earlier, in the neuromuscle space, we've known for many years the genetic cause of many of these disorders and have done great, you know, mechanistic work to kind of define why we see the disease. And then now we're at this intersection of that knowledge marrying with these really novel therapeutic approaches, gene therapy approaches, being able to intersect and then in very creative ways actually target diseases very directly. And so, I would say it really is the combination of those two things. FSHD has a really fascinating unique biology, which again, we encourage everyone to read about more in the article. That really drew me to it. I'm very interested in gene regulation, transcription. This is one of the underlying mechanisms that is gone awry in the disorder, and then that being married to advances in therapeutics. So, you could wed those two pieces of information and actually meaningfully impact patient 's lives. And again, that's the real privilege and honor to witness is how these therapies can transform lives. And I saw it happened with this one case for this one disorder when I was a resident where there was no treatment. Young children, unfortunately, would not survive the disease. And then I saw the therapy come be in development and literally change the trajectory. And this is what we're very hopeful for in the FSHD space, that wedding, this wonderful basic science research, translational research, companies working together to develop these therapies that can transform lives. It is just so beautiful to witness and see, and it's something that I get to do. You know, it's a part of my job, so it's a real privilege. Dr Grouse: Well, I have to say, it's really inspiring hearing you talk about it. And I imagine that many neurologists-in-training who are listening to this may be inspired as well and may be convinced to go into this field for that very reason. So, thank you so much for sharing all of this information with us today. I learned a lot, and I think all of our listeners have too. Dr Knox: Thank you. It's really been a pleasure. Dr Grouse: Again, today I've been interviewing Dr Renatta Knox about her article on fascioscapulohumeral muscular dystrophy, which appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

While genetic testing has replaced muscle biopsy in the diagnosis of many genetic myopathies, clinical assessment and the integration of clinical and laboratory findings remain key elements for the diagnosis and treatment of muscle diseases. In this episode, Casey Albin, MD, speaks with Margherita Milone, MD, PhD, FAAN, FANA, author of the article "A Pattern Recognition Approach to Myopathy" in the Continuum® October 2025 Muscle and Neuromuscular Junction Disorders issue. Dr. Albin is a Continuum® Audio interviewer, associate editor of media engagement, and an assistant professor of neurology and neurosurgery at Emory University School of Medicine in Atlanta, Georgia. Dr. Milone is a professor of neurology and the director of the Muscle Pathology Laboratory at Mayo Clinic College of Medicine and Science in Rochester, Minnesota. Additional Resources Read the article: A Pattern Recognition Approach to Myopathy 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: @caseyalbin Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Albin: Hello, this is Dr Casey Albin. Today I'm interviewing Dr Margherita Milone on her article on a pattern recognition approach to myopathy, which appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Welcome to the podcast, Dr Milone. Thank you so much for joining us. I'll start off by having you introduce yourself to our listeners. Dr Milone: Hello Casey, thank you so much for this interview and for bringing the attention to the article on muscle diseases. So, I'm Margherita Milone. I'm one of the neuromuscular neurologists at Mayo Clinic in Rochester. I have been interested in muscle disorders since I was a neurology resident many years ago. Muscle diseases are the focus of my clinical practice and research interest. Dr Albin: Wonderful. Thank you so much. When I think about myopathies, I generally tend to think of three large buckets: the genetic myopathy, the inflammatory myopathies, and then the necrotizing myopathies. Is that a reasonable approach to conceptualizing these myopathies? Dr Milone: Yeah, the ideology of the myopathies can be quite broad. And yes, we have a large group of genetic muscle diseases, which are the most common. And then we have immune-mediated muscle diseases, which include inflammatory myopathies as well as some form of necrotizing myopathies. Then we have some metabolic myopathies, which could be acquired or could be genetic. And then there are muscle diseases that are due to toxins as well as to infection. Dr Albin: Wow. So, lots of different etiologies. And that really struck me about your article, is that these can present in really heterogeneous ways, and some of them don't really read the rule book. So, we have to have a really high level of suspicion, for someone who's coming in with weakness, to remember to think about a myopathy. One of the things that I like to do is try to take us through a little bit of a case to sort of walk us through how you would approach if someone comes in. So, let's say you get, you know, a forty-year-old woman, and she's presenting with several months of progressive weakness. And she says that even recently she's noted just a little bit of difficulty swallowing. It feels to her like things are getting stuck. What are some of the things when you are approaching the history that would help you tease this to a myopathy instead of so many other things that can cause a patient to be weak? Dr Milone: Yes. So, as you mentioned, people who have a muscle disease have the muscle weakness often, but the muscle weakness is not just specific for a muscle disease. Because you can have a mass weakness in somebody who has a neurogenic paralysis. The problem with diagnosis of muscle diseases is that patients with these disorders have a limited number of symptom and sign that does not match the large heterogeneity of the etiology. So, in someone who has weakness, that weakness could represent a muscle disease, could represent an anterior horn cell disease, could represent a defect of neuromuscular junction. The clinical history of weakness is not sufficient by itself to make you think about a muscle disease. You have to keep that in the differential diagnosis. But your examination will help in corroborating your suspicion of a muscle disease. Let's say if you have a patient, the patient that you described, with six months' history of progressive weakness, dysphagia, and that patient has normal reflexes, and the patient has no clinical evidence for muscle fatigability and no sensory loss, then the probability that that patient has a myopathy increases. Dr Albin: Ah, that's really helpful. I'm hearing a lot of it is actually the lack of other findings. In some ways it's asking, you know, have you experienced numbness and tingling? And if not, that's sort of eliminating that this might not be a neuropathy problem. And then again, that fatigability- obviously fatigability is not specific to a neuromuscular junction, but knowing that is a hallmark of myasthenia, the most common of neuromuscular disorders. Getting that off the table helps you say, okay, well, it's not a neuromuscular junction problem, perhaps. Now we have to think more about, is this a muscle problem itself? Are there any patterns that the patients describe? I have difficulty getting up from a chair, or I have difficulty brushing my hair. When I think of myopathies, I historically have thought of, sort of, more proximal weakness. Is that always true, or not so much? Dr Milone: Yeah. So, there are muscle diseases that involve predominantly proximal weakness. For example, the patient you mentioned earlier could have, for example, an autoimmune muscle disease, a necrotizing autoimmune myopathy; could have, perhaps, dermatomyositis if there are skin changes. But a patient with muscle disease can also present with a different pattern of weakness. So, myopathies can lead to this weakness, and foot drop myopathies can cause- can manifest with the weakness of the calf muscles. So, you may have a patient presenting to the clinic who has no the inability to stand on tiptoes, or you may have a patient who has just facial weakness, who has noted the difficulty sealing their lips on the glasses when they drink and experiencing some drooling in that setting, plus some hand weakness. So, the muscle involved in muscle diseases can vary depending on the underlying cause of the muscle disease. Dr Albin: That's really helpful. So, it really is really keeping an open mind and looking for some supporting features, whether it's bulbar involvement, extraocular eye muscle involvement; looking, you know, is it proximal, is it distal? And then remembering that any of those patterns can also be a muscle problem, even if sometimes we think of distal being more neuropathy and proximal myopathy. Really, there's a host of ranges for this. I really took that away from your article. This is, unfortunately, not just a neat way to box these. We really have to have that broad differential. Let me ask another question about your history. How often do you find that patients complain of, sort of, muscular cramping or muscle pain? And does that help you in terms of deciding what type of myopathy they may have? Dr Milone: Many patients with muscle disease have muscle pain. The muscle pain could signal a presence of inflammation in skeletal muscle, could be the result of overuse from a muscle that is not functioning normally. People who have myotonia experience muscle stiffness and muscle pain. Patients who have a metabolic myopathy usually have exercise-induced muscle pain. But, as we know, muscle pain is also very nonspecific, so we have to try to find out from the patient in what setting the pain specifically occurs. Dr Albin: That's really helpful. So, it's asking a little bit more details about the type of cramping that they have, the type of pain they may be experiencing, to help you refine that differential. Similarly, one of the things that I historically have always associated with myopathies is an elevation in the CK, or the creatinine kinase. How sensitive and specific is that, and how do you as the expert sort of take into account, you know, what their CK may be? Dr Milone: So, this is a very good point. And the elevation of creatine kinase can provide a clue that the patient has a muscle disease, but it is nonspecific for muscle disease because we know that elevation of creatine kinase can occur in the setting of a neurogenic process. For example, we can see elevation of the creatine kinase in patients who have ALS or in patients who have spinal muscular atrophy. And in these patients---for example, those with spinal muscular atrophy---the CK elevation can be also of significantly elevated up to a couple of thousand. Conversely, we can have muscle diseases where the CK elevation does not occur. Examples of these are some genetic muscle disease, but also some acquired muscle diseases. If we think of, for example, cases where inflammation in the muscle occurs in between muscle fibers, more in the interstitium of the muscle, that disease may not lead to significant elevation of the CK. Dr Albin: That's super helpful. So, I'm hearing you say CK may be helpful, but it's neither completely sensitive nor completely specific when we're thinking about myopathic disorders. Dr Milone: You are correct. Dr Albin: Great. So, coming back to our patients, you know, she says that she has this dysphasia. How do bulbar involvement or extraocular eye movement involvement, how do those help narrow your differential? And what sort of disorders are you thinking of for patients who may have that bulbar or extraocular muscle involvement? Dr Milone: Regarding dysphagia, that can occur in the setting of acquired myopathies relatively frequent; for example, in inclusion body myositis or in other forms of inflammatory myopathy. Your patient, I believe, was in their forties, so it's a little bit too young for inclusion body myositis. Involvement of the extraocular muscles is usually much more common in genetic muscle diseases and much less frequent in hereditary muscle disease. So, if there is involvement of the extraocular muscles, and if there is a dysphagia, and if there is a proximal weakness, you may think about oculopharyngeal muscular dystrophy, for example. But obviously, in a patient who has only six months of history, we have to pay attention of the degree of weakness the patient has developed since the symptom onset. Because if the degree of weakness is mild, yes, it could still be a genetic or could be an acquired disease. But if we have a patient who, in six months, from being normal became unable to climb stairs, then we worry much more about an acquired muscle disease. Dr Albin: That's really helpful. So, the time force of this is really important. And when you're trying to think about, do I put this in sort of a hereditary form of muscle disease, thinking more of an indolent core, something that's going to be slowly progressive versus one of those inflammatory or necrotizing pathologies, that's going to be a much more quick onset, rapidly progressive, Do I have that right? Dr Milone: In general, the statement is correct. They tend, acquired muscle disease, to have a faster course compared to a muscular dystrophy. But there are exceptions. There have been patients with immune mediated necrotizing myopathy who have been misdiagnosed as having limb-girdle muscular dystrophy just because the disease has been very slowly progressive, and vice versa. There may be some genetic muscle diseases that can present in a relatively fast way. And one of these is a lipid storage myopathy, where some patients may develop subacutely weakness, dysphagia, and even respiratory difficulties. Dr Albin: Again, I'm hearing you say that we really have to have an open mind that myopathies can present in a whole bunch of different ways with a bunch of different phenotypes. And so, keeping that in mind, once you suspect someone has a myopathy, looking at the testing from the EMG perspective and then maybe laboratory testing, how do you use that information to guide your work up? Dr Milone: The EMG has a crucial role in the diagnosis of muscle diseases. Because, as we said earlier, weakness could be the result of muscle disease or other form of neuromuscular disease. If the EMG study will show evidence of muscle disease supporting your diagnostic hypothesis, now you have to decide, is this an acquired muscle disease or is this a genetic muscle disease? If you think that, based on clinical history of, perhaps, subacute pores, it is more likely that the patient has an acquired muscle disease, then I would request a muscle biopsy. The muscle biopsy will look for structural abnormalities that could help in narrowing down the type of muscle disease that the patient has. Dr Albin: That's really helpful. When we're sending people to get muscle biopsies, are there any tips that you would give the listeners in terms of what site to biopsy or what site, maybe, not to biopsy? Dr Milone: This is a very important point. A muscle biopsy has the highest diagnostic yield if it's done in a muscle that is weak. And because muscle diseases can result in proximal or distal weakness, if your patient has distal weakness, you should really biopsy a distal muscle. However, we do not wish to biopsy a muscle that is too weak, because otherwise the biopsy sample will result just in fibrous and fatty connected tissue. So, we want to biopsy a muscle that has mild to moderate weakness. Dr Albin: Great. So, a little Goldilocks phenomenon: has to be some weak, but not too weak. You got to get just the right feature there. I love that. That's a really good pearl for our listeners to take. What about on the flip side? Let's say you don't think it's an acquired a muscular disease. How are you handling testing in that situation? Dr Milone: If you think the patient has a genetic muscle disease, you pay a lot of attention to the distribution of the weakness. Ask yourself, what is the best pattern that represent the patient's weakness? So, if I have a patient who has facial weakness, dysphagia, muscle cramping, and then on examination represent myotonia, then at that point we can go straight to a genetic test for myotonic dystrophy type one. Dr Albin: That's super helpful. Dr Milone: So, you request directly that generic test and wait for the result. If positive, you will have proof that your diagnostic hypothesis was correct. Dr Albin: You're using the genetic testing to confirm your hypothesis, not just sending a whole panel of them. You're really informing that testing based on the patient's pattern of weakness and the exam findings, and sometimes even the EMG findings as well. Is that correct? Dr Milone: You are correct, and ideally, yes. And this is true for certain muscle diseases. In addition to myotonic dystrophy type one, for example, if you have a patient who has fascial scapulohumeral muscular weakness, you can directly request a test for FSHD. So, the characterization of the clinical phenotype is crucial before selecting the genetic test for diagnosis. Dr Albin: Wonderful. Dr Milone: However, this is not always possible, because you may have a patient who has just a limb-girdle weakness, and the limb-girdle weakness can be limb-girdle muscular dystrophy. But we know that there are many, many types of limb-girdle muscular dystrophies. Therefore, the phenotype is not sufficient to request specific genetic tests for one specific form of a limb-girdle muscular dystrophy. And in those cases, more complex next-generation sequencing panels have a higher chance of providing the answer. Dr Albin: Got it, that makes sense. So, sometimes we're using a specific genetic test; sometimes, it is unfortunate that we just cannot narrow down to one disease that we might be looking for, and we may need a panel in that situation. Dr Milone: You are correct. Dr Albin: Fantastic. Well, as we wrap up, is there anything on the horizon for muscular disorders that you're really excited about? Dr Milone: Yes, there are a lot of exciting studies ongoing for gene therapy, gene editing. So, these studies are very promising for the treatment of genetic muscle disease, and I'm sure there will be therapists that will improve the patient's quality of life and the disease outcome. Dr Albin: It's really exciting. Well, thank you again. Today I've been interviewing Dr Margarita Malone on her article on a pattern recognition approach to myopathy, which appears in the October 2025 Continuum issue on muscle and neuromuscular junction disorders. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining us today. And thank you, Dr Milone. Dr Milone: Thank you, Casey. Very nice chatting with you about this. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Functional movement disorders are a common clinical concern for neurologists. The principle of "rule-in" diagnosis, which involves demonstrating the difference between voluntary and automatic movement, can be carried through to explanation, triage, and evidence-based multidisciplinary rehabilitation therapy. In this episode, Gordon Smith, MD, FAAN speaks Jon Stone, PhD, MB, ChB, FRCP, an author of the article "Multidisciplinary Treatment for Functional Movement Disorder" in the Continuum® August 2025 Movement Disorders issue. Dr. Smith is a Continuum® Audio interviewer and a professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia. Dr. Stone is a consultant neurologist and honorary professor of neurology at the Centre for Clinical Brain Sciences at the University of Edinburgh in Edinburgh, United Kingdom. Additional Resources Read the article: Multidisciplinary Treatment for Functional Movement Disorder Subscribe to Continuum®: shop.lww.com/Continuum 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: @jonstoneneuro Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. This exclusive Continuum Audio interview is available only to you, our subscribers. We hope you enjoy it. Thank you for listening. Dr Smith: Hello, this is Dr Gordon Smith. Today I've got the great pleasure of interviewing Dr Johnstone about his article on the multidisciplinary treatment for functional neurologic disorder, which he wrote with Dr Alan Carson. This article will appear in the August 2025 Continuum issue on movement disorders. I will say, Jon, that as a Continuum Audio interviewer, I usually take the interviews that come my way, and I'm happy about it. I learn something every time. They're all a lot of fun. But there have been two instances where I go out and actively seek to interview someone, and you are one of them. So, I'm super excited that they allowed me to talk with you today. For those of our listeners who understand or are familiar with FND, Dr Stone is a true luminary and a leader in this, both in clinical care and research. He's also a true humanist. And I have a bit of a bias here, but he was the first awardee of the Ted Burns Humanism in Neurology award, which is a real honor and reflective of your great work. So welcome to the podcast, Jon. Maybe you can introduce yourself to our audience. Dr Stone: Well, thank you so much, Gordon. It was such a pleasure to get that award, the Ted Burns Award, because Ted was such a great character. I think the spirit of his podcasts is seen in the spirit of these podcasts as well. So, I'm a neurologist in Edinburgh in Scotland. I'm from England originally. I'm very much a general neurologist still. I still work full-time. I do general neurology, acute neurology, and I do two FND clinics a week. I have a research group with Alan Carson, who you mentioned; a very clinical research group, and we've been doing that for about 25 years. Dr Smith: I really want to hear more about your clinical approach and how you run the clinic, but I wonder if it would be helpful for you to maybe provide a definition. What's the definition of a functional movement disorder? I mean, I think all of us see these patients, but it's actually nice to have a definition. Dr Stone: You know, that's one of the hardest things to do in any paper on FND. And I'm involved with the FND society, and we're trying to get together a definition. It's very hard to get an overarching definition. But from a movement disorder point of view, I think you're looking at a disorder where there is an impairment of voluntary movement, where you can demonstrate that there is an automatic movement, which is normal in the same movement. I mean, that's a very clumsy way of saying it. Ultimately, it's a disorder that's defined by the clinical features it has; a bit like saying, what is migraine? You know? Or, what is MS? You know, it's very hard to actually say that in a sentence. I think these are disorders of brain function at a very broad level, and particularly with FND disorders, of a sort of higher control of voluntary movement, I would say. Dr Smith: There's so many pearls in this article and others that you've written. One that I really like is that this isn't a diagnosis of exclusion, that this is an affirmative diagnosis that have clear diagnostic signs. And I wonder if you can talk a little bit about the diagnostic process, arriving at an FND diagnosis for a patient. Dr Stone: I think this is probably the most important sort of "switch-around" in the last fifteen, twenty years since I've been involved. It's not new information. You know, all of these diagnostic signs were well known in the 19th century; and in fact, many of them were described then as well. But they were kind of lost knowledge, so that by the time we got to the late nineties, this area---which was called conversion disorder then---it was written down. This is a diagnosis of exclusion that you make when you've ruled everything out. But in fact, we have lots of rule in signs, which I hope most listeners are familiar with. So, if you've got someone with a functional tremor, you would do a tremor entrainment test where you do rhythmic movements of your thumb and forefinger, ask the patient to copy them. It's very important that they copy you rather than make their own movements. And see if their tremor stops briefly, or perhaps entrains to the same rhythm that you're making, or perhaps they just can't make the movement. That might be one example. There's many examples for limb weakness and dystonia. There's a whole lot of stuff to learn there, basically, clinical skills. Dr Smith: You make a really interesting point early on in your article about the importance of the neurological assessment as part of the treatment of the patient. I wonder if you could talk to our listeners about that. Dr Stone: So, I think, you know, there's a perception that- certainly, there was a perception that that the neurologist is there to make a diagnosis. When I was training, the neurologist was there to tell the patient that they didn't have the kind of neurological problem and to go somewhere else. But in fact, that treatment process, when it goes well, I think begins from the moment you greet the patient in the waiting room, shake their hand, look at them. Things like asking the patient about all their symptoms, being the first doctor who's ever been interested in their, you know, horrendous exhaustion or their dizziness. You know, questions that many patients are aware that doctors often aren't very interested in. These are therapeutic opportunities, you know, as well as just taking the history that enable the patient to feel relaxed. They start thinking, oh, this person's actually interested in me. They're more likely to listen to what you've got to say if they get that feeling off you. So, I'd spend a lot of time going through physical symptoms. I go through time asking the patient what they do, and the patients will often tell you what they don't do. They say, I used to do this, I used to go running. Okay, you need to know that, but what do they actually do? Because that's such valuable information for their treatment plan. You know, they list a whole lot of TV shows that they really enjoy, they're probably not depressed. So that's kind of useful information. I also spend a lot of time talking to them about what they think is wrong. Be careful, that they can annoy patients, you know. Well, I've come to you because you're going to tell me what's wrong. But what sort of ideas had you had about what was wrong? I need to know so that I can deal with those ideas that you've had. Is there a particular reason that you're in my clinic today? Were you sent here? Was it your idea? Are there particular treatments that you think would really help you? These all set the scene for what's going to come later in terms of your explanation. And, more importantly, your triaging of the patient. Is this somebody where it's the right time to be embarking on treatment, which is a question we don't always ask yourself, I think. Dr Smith: That's a really great point and kind of segues to my next question, which is- you talked a little bit about this, right? Generally speaking, we have come up with this is a likely diagnosis earlier, midway through the encounter. And you talked a little bit about how to frame the encounter, knowing what's coming up. And then what's coming up is sharing with the patient our opinion. In your article, you point out this should be no different than telling someone they have Parkinson's disease, for instance. What pearls do you have and what pitfalls do you have in how to give the diagnosis? And, you know, a lot of us really weren't trained to do this. What's the right way, and what are the most common land mines that folks step on when they're trying to share this information with patients? Dr Stone: I've been thinking about this for a long time, and I've come to the conclusion that all we need to do with this disorder is stop being weird. What goes wrong? The main pitfall is that people think, oh God, this is FND, this is something a bit weird. It's in a different box to all of the other things and I have to do something weird. And people end up blurting out things like, well, your scan was normal or, you haven't got epilepsy or, you haven't got Parkinson's disease. That's not what you normally do. It's weird. What you normally do is you take a deep breath and you say, I'm sorry to tell you've got Parkinson's disease or, you have this type of dystonia. That's what you normally say. If you follow the normal- what goes wrong is that people don't follow the normal rules. The patient picks up on this. What's going on here? This doctor's telling me what I don't have and then they're starting to talk about some reason why I've got this, like stress, even though I don't- haven't been told what it is yet. You do the normal rules, give it a name, a name that you're comfortable with, preferably as specific as possible: functional tremor, functional dystonia. And then do what you normally do, which is explain to the patient why you think it's this. So, if someone's got Parkinson's, you say, I think you've got Parkinson's because I noticed that you're walking very slowly and you've got a tremor. And these are typical features of Parkinson. And so, you're talking about the features. This is where I think it's the most useful thing that you can do. And the thing that I do when it goes really well and it's gone badly somewhere else, the thing I probably do best, what was most useful, is showing the patient their signs. I don't know if you do that, Gordon, but it's maybe not something that we're used to doing. Dr Smith: Wait, maybe you can talk more about that, and maybe, perhaps, give an example? Talk about how that impacts treatment. I was really impressed about the approach to physical therapy, and treatment of patients really leverages the physical examination findings that we're all well-trained to look for. So maybe explore that a little bit. Dr Stone: Yeah, I think absolutely it does. And I think we've been evolving these thoughts over the last ten or fifteen years. But I started, you know, maybe about twenty years ago, started to show people their tremor entrainment tests. Or their Hoover sign, for example; if you don't know Hoover sign, weakness of hip extension, that comes back to normal when the person's flexing their normal leg, their normal hip. These are sort of diagnostic tricks that we had. Ahen I started writing articles about FND, various senior neurologists said to me, are you sure you should write this stuff down? Patients will find out. I wrote an article with Marc Edwards called "Trick or Treat in Neurology" about fifteen years ago to say that actually, although they're they might seem like tricks, there really are treats for patients because you're bringing the diagnosis into the clinic room. It's not about the normal scan. You can have FND and MS. It's not about the normal scan. It's about what you're seeing in front of you. If you show that patient, yes, you can't move your leg. The more you try, the worse it gets. I can see that. But look, lift up your other leg. Let me show you. Can you see now how strong your leg is? It's such a powerful way of communicating to the patient what's wrong with them diagnostically, giving them that confidence. What it's also doing is showing them the potential for improvement. It's giving them some hope, which they badly need. And, as we'll perhaps talk about, the physio treatment uses that as well because we have to use a different kind of physio for many forms of functional movement disorder, which relies on just glimpsing these little moments of normal function and promoting them, promoting the automatic movement, squashing down that abnormal pattern of voluntary movement that people have got with FND. Dr Smith: So, maybe we can talk about that now. You know, I've got a bunch of other questions to ask you about mechanism and stuff, but let's talk about the approach to physical therapy because it's such a good lead-in and I always worry that our physical therapists aren't knowledgeable about this. So, maybe some examples, you have some really great ones in the article. And then words of wisdom for us as we're engaging physical therapists who may not be familiar with FND, how to kind of build that competency and relationship with the therapist with whom you work. Dr Stone: Some of the stuff is the same. Some of the rehabilitation ideas are similar, thinking about boom and bust activity, which is very common in these patients, or grading activity. That's similar, but some of them are really different. So, if you have a patient with a stroke, the physiotherapist might be very used to getting that person to think and look at their leg to try and help them move, which is part of their rehabilitation. In FND, that makes things worse. That's what's happening in Hoover sign and tremor entrainment sign. Attention towards the limb is making it worse. But if the patient's on board with the diagnosis and understands it, they'll also see what you need to do, then, in the physio is actively use distraction in a very transparent way and say to the patient, look, I think if I get you to do that movement, and I'll film you, I think your movement's going to look better. Wouldn't that be great if we could demonstrate that? And the patient says, yeah, that would be great. We're kind of actively using distraction. We're doing things that would seem a bit strange for someone with other forms of movement disorder. So, the patients, for example, with functional gait disorders who you discover can jog quite well on a treadmill. In fact, that's another diagnostic test. Or they can walk backwards, or they can dance or pretend that they're ice skating, and they have much more fluid movements because their ice skating program in their brain is not corrupted, but their normal walking program is. So, can you then turn ice skating or jogging into normal walking? It's not that complicated, I think. The basic ideas are pretty simple, but it does require some creativity from whoever's doing the therapy because you have to use what the patient's into. So, if the patient used to be a dancer- we had a patient who was a, she was really into ballet dancing. Her ballet was great, but her walking was terrible. So, they used ballet to help her walk again. And that's incredibly satisfying for the therapist as well. So, if you have a therapist who's not sure, there are consensus recommendations. There are videos. One really good success often makes a therapist want to do that again and think, oh, that's interesting. I really helped that patient get better. Dr Smith: For a long time, this has been framed as a mental health issue, conversion disorder, and maybe we can talk a little bit about early life of trauma as a risk factor. But, you know, listening to you talk, it sounds like a brain network problem. Even the word "functional", to me, it seems a little judgmental. I don't know if this is the best term, but is this really a network problem? Dr Stone: The word "functional", for most neurologists, sounds judgmental because of what you associate it with. If you think about what the word actually is, it's- it does what it says on the tin. There's a disordered brain function. I mean, it's not a great word. It's the least worst term, in my view. And yes, of course it's a brain network problem, because what other organ is it going to be? You know, that's gone wrong? When software brains go wrong, they go wrong in networks. But I think we have to be careful not to swing that pendulum too far to the other side because the problem here, when we say asking the question, is this a mental health problem or a neurological one, we're just asking the wrong question. We're asking a question that makes no sense. However you try and answer that, you're going to get a stupid answer because the question doesn't make sense. We shouldn't have those categories. It's one organ. And what's so fascinating about FND---and I hope what can incite your sort of curiosity about it---is this disorder which defies this categorization. You see some patients with it, they say, oh, they've got a brain network disorder. Then you meet another patient who was sexually abused for five years by their uncle when they were nine, between nine and fourteen; they developed an incredibly strong dissociative threat response into that experience. They have crippling anxiety, PTSD, interpersonal problems, and their FND is sort of somehow a part of that; part of that experience that they've had. So, to ignore that or to deny or dismiss psychological, psychiatric aspects, is just as bad and just as much a mistake as to dismiss the kind of neurological aspects as well. Dr Smith: I wonder if this would be a good time to go back and talk a little bit about a concept that I found really interesting, and that is FND as a prodromal syndrome before a different neurological problem. So, for instance, FND prodromal to Parkinson's disease. Can you talk to us a little bit about that? I mean, obviously I was familiar with the fact that patients who have nonepileptic seizurelike events often have epileptic seizures, but the idea of FND ahead of Parkinson's was new to me. Dr Stone: So, this is definitely a thing that happens. It's interesting because previously, perhaps, if you saw someone who was referred with a functional tremor---this has happened to me and my colleagues. They send me some with a functional tremor. By the time I see them, it's obvious they've got Parkinson's because it's been a little gap. But it turns out that the diagnosis of functional tremor was wrong. It was just that they've developed that in the prodrome of Parkinson's disease. And if you think about it, it's what you'd expect, really, especially with Parkinson's disease. We know people develop anxiety in the prodrome of Parkinson's for ten, fifteen years before it's part of the prodrome. Anxiety is a very strong risk factor for FND, and they're already developing abnormalities in their brain predisposing them to tremor. So, you put those two things together, why wouldn't people get FND? It is interesting to think about how that's the opposite of seizures, because most people with comorbidity of functional seizures and epilepsy, 99% of the time the epilepsy came first. They had the experience of an epileptic seizure, which is frightening, which evokes strong threat response and has somehow then led to a recapitulation of that experience in a functional seizure. So yeah, it's really interesting how these disorders overlap. We're seeing something similar in early MS where, I think, there's a slight excess of functional symptoms; but as the disease progresses, they often become less, actually. Dr Smith: What is the prognosis with the types of physical therapy? And we haven't really talked about psychological therapy, but what's the success rate? And then what's the relapse rate or risk? Dr Stone: Well, it does depend who they're seeing, because I think---as you said---you're finding difficult to get people in your institution who you feel are comfortable with this. Well, that's a real problem. You know, you want your therapists to know about this condition, so that matters. But I think with a team with a multidisciplinary approach, which might include psychological therapy, physio, OT, I think the message is you can get really good outcomes. You don't want to oversell this to patients, because these treatments are not that good yet. You can get spectacular outcomes. And of course, people always show the videos of those. But in published studies, what you're seeing is that most studies of- case series of rehabilitation, people generally improve. And I think it's reasonable to say to a patient, that we have these treatments, there's a good chance it's going to help you. I can't guarantee it's going to help you. It's going to take a lot of work and this is something we have to do together. So, this is not something you're going to do to the patient, they're going to do it with you. Which is why it's so important to find out, hey, do they agree with you with the diagnosis? And check they do. And is it the right time? It's like when someone needs to lose weight or change any sort of behavior that they've just become ingrained. It's not easy to do. So, I don't know if that helps answer the question. Dr Smith: No, that's great. And you actually got right where I was wanting to go next, which is the idea of timing and acceptance. You brought this up earlier on, right? So, sometimes patients are excited and accepting of having an affirmative diagnosis, but sometimes there's some resistance. How do you manage the situation where you're making this diagnosis, but a patient's resistant to it? Maybe they're fixating on a different disease they think they have, or for whatever reason. How do you handle that in terms of initiating therapy of the overall diagnostic process? Dr Stone: We should, you know, respect people's rights to have whatever views they want about what's wrong with them. And I don't see my job as- I'm not there to change everyone's mind, but I think my job is to present the information to them in a kind of neutral way and say, look, here it is. This is what I think. My experience is, if you do that, most people are willing to listen. There are a few who are not, but most people are. And most of the time when it goes wrong, I have to say it's us and not the patients. But I think you do need to find out if they can have some hope. You can't do rehabilitation without hope, really. That's what you're looking for. I sometimes say to patients, where are you at with this? You know, I know this is a really hard thing to get your head around, you've never heard of it before. It's your own brain going wrong. I know that's weird. How much do you agree with it on a scale of naught to ten? Are you ten like completely agreeing, zero definitely don't? I might say, are you about a three? You know, just to make it easy for them to say, no, I really don't agree with you. Patients are often reluctant to tell you exactly what they're thinking. So, make it easy for them to disagree and then see where they're at. If they're about seven, say, that's good. But you know, it'd be great if you were nine or ten because this is going to be hard. It's painful and difficult, and you need to know that you're not damaging your body. Those sort of conversations are helpful. And even more importantly, is it the right time? Because again, if you explore that with people, if a single mother with four kids and, you know, huge debts and- you know, it's going to be very difficult for them to engage with rehab. So, you have to be realistic about whether it's the right time, too; but keep that hope going regardless. Dr Smith: So, Jon, there's so many things I want to talk to you about, but maybe rather than let me drive it, let me ask you, what's the most important thing that our listeners need to know that I haven't asked you about? Dr Stone: Oh God. I think when people come and visit me, they sometimes, let's go and see this guy who does a lot of FND, and surely, it'll be so easy for him, you know? And I think some of the feedback I've had from visitors is, it's been helpful to watch, to see that it's difficult for me too. You know, this is quite hard work. Patients have lots of things to talk about. Often you don't have enough time to do it in. It's a complicated scenario that you're unravelling. So, it's okay if you find it difficult work. Personally, I think it's very rewarding work, and it's worth doing. It's worth spending the time. I think you only need to have a few patients where they've improved. And sometimes that encounter with the neurologist made a huge difference. Think about whether that is worth it. You know, if you do that with five patients and one or two of them have that amazing, really good response, well, that's probably worth it. It's worth getting out of bed in the morning. I think reflecting on, is this something you want to do and put time and effort into, is worthwhile because I recognize it is challenging at times, and that's okay. Dr Smith: That's a great number needed to treat, five or six. Dr Stone: Exactly. I think it's probably less than that, but… Dr Smith: You're being conservative. Dr Stone: I think deliberately pessimistic; but I think it's more like two or three, yeah. Dr Smith: Let me ask one other question. There's so much more for our listeners in the article. This should be required reading, in my opinion. I think that of most Continuum, but this, I really truly mean it. But I think you've probably inspired a lot of listeners, right? What's the next step? We have a general or comprehensive neurologist working in a community practice who's inspired and wants to engage in the proactive care of the FND patients they see. What's the next step or advice you have for them as they embark on this? It strikes me, like- and I think you said this in the article, it's hard work and it's hard to do by yourself. So, what's the advice for someone to kind of get started? Dr Stone: Yeah, find some friends pretty quick. Though, yeah, your own enthusiasm can take you a long way, you know, especially with we've got much better resources than we have. But it can only take you so far. It's really particularly important, I think, to find somebody, a psychiatrist or psychologist, you can share patients with and have help with. In Edinburgh, that's been very important. I've done all this work with the neuropsychiatrist, Alan Carson. It might be difficult to do that, but just find someone, send them an easy patient, talk to them, teach them some of this stuff about how to manage FND. It turns out it's not that different to what they're already doing. You know, the management of functional seizures, for example, is- or episodic functional movement disorders is very close to managing panic disorder in terms of the principles. If you know a bit about that, you can encourage people around you. And then therapists just love seeing these patients. So, yeah, you can build up slowly, but don't- try not to do it all on your own, I would say. There's a risk of burnout there. Dr Smith: Well, Dr Stone, thank you. You don't disappoint. This has really been a fantastic conversation. I really very much appreciate it. Dr Stone: That's great, Gordon. Thanks so much for your time, yeah. Dr Smith: Well, listeners, again, today I've had the great pleasure of interviewing Dr Jon Stone about his article on the multidisciplinary treatment for functional neurologic disorder, which he wrote with Dr Alan Carson. This article appears in the August 2025 Continuum issue on movement disorders. Please be sure to check out Continuum Audio episodes from this and other issues. And listeners, thank you once again for joining us today. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. We hope you've enjoyed this subscriber-exclusive interview. Thank you for listening.